key: cord-0043969-aa4iqtuf authors: DUNGWORTH, D.L. title: The Respiratory System date: 2012-12-02 journal: Pathology of Domestic Animals DOI: 10.1016/b978-0-12-391606-8.50014-4 sha: 281cf43a9e8d1c6f4daf7ec53c56f3cbec610251 doc_id: 43969 cord_uid: aa4iqtuf nan The responses of the respiratory tract to injury, and the resulting patterns of disease, are determined largely by the structural and functional complexity of the system. Most of the diseases of the respiratory system are caused by damaging agents arriving by either the airborne (aerogenous) or blood-borne (hematogenous) routes, each with its own special pathogenetic considerations. The respiratory system is constantly under assault from potentially injurious agents, which include airborne micro organisms, oropharyngeal flora, toxic particulates and gases in ambient air, and a wide array of infectious agents and extrinsic or intrinsic toxins delivered via the pulmo nary circulation. Pulmonary defense mechanisms are re markably effective under most circumstances in pre venting disease agents from entering or remaining in the lung and in neutralizing these agents if they penetrate initial barriers. A brief overview of general structural and functional features of the respiratory system is presented to provide a framework for understanding its responses to injury. The nasal airways, in contrast to most respiratory con ducting passages, are noncollapsible structures, which are encased in bone and contain osseous and cartilaginous turbinates (conchae) and are divided by a cartilaginous nasal septum. The mucosa of the nasal cavity has at least four distinct epithelial types: stratified squamous, transi tional, ciliated respiratory, and olfactory epithelium. The submucosa has a richly supplied vascular plexus and abun dant submucosal glands. The nasal airways contribute -50% of total respiratory resistance, and hyperemia of nasal plexuses plays an important regulatory role in modu lating nasal airway caliber and resistance to airflow. Most of the epithelial lining of nasal mucosa is com posed of ciliated respiratory epithelium which is pseudostratified and shares many similarities in structure and response to injury with tracheal and bronchial epithelium. Ciliated respiratory epithelium of the nasal mucosa in cludes ciliated, mucous, nonciliated columnar, cuboidal, and basal cells. Olfactory epithelium forms a large percent age of total nasal epithelium in some species and is com posed of olfactory sensory cells, sustentacular cells, and basal cells. Olfactory epithelium is rich in cytochrome P-450-dependent monooxygenase enzyme activity and is susceptible to many of the respiratory toxins that are also metabolized in the lung, and which can damage bronchio lar epithelium and components of alveolar septa. The nasopharynx is lined by ciliated pseudostratified epithelium with zones of stratified squamous epithelium. Abundant lymphoid nodules are present throughout the submucosa. The auditory (Eustachian) tubes extend from the nasopharynx to the middle ears and have ventral di verticula in horses forming the guttural pouches, which are subject to ascending bacterial and fungal infections. The larynx is supported by cartilages which resist defor mation and obstruction of the lumen, and the mucosa is lined by stratified squamous epithelium as well as ciliated respiratory epithelium. Trachea and bronchi in most domestic animals are lined by pseudostratified epithelium composed of ciliated, mu cous, and nonciliated cells. Major varieties of nonciliated cells are serous, basal, and neuroendocrine. Also within the epithelium are resident inflammatory cells such as lymphocytes and globule leukocytes, and intraepithelial nerve fibers. Tracheal and bronchial epithelium consists of a stable cell population with continual low-level turn over and differentiation of new epithelial cells. Following injury to tracheobronchial epithelium, a stereotypic pat-539 tern of repair usually follows. Ciliated cells are terminally differentiated and have little or no regenerative capacity. Sloughing of these cells with replacement of the epithelial lining with nonciliated cell types is a frequent early event following mucosal injury. Mucous cells and nonciliated cells are the primary cells that effect epithelial repair, with a lesser contribution by basal cells. Basal cells may play a more important role in attachment of columnar cells to the basement membrane than they do in epithelial regener ation. Mucous cells and nonciliated cells have the capacity to regenerate themselves as well as to undergo differentia tion into ciliated cells and other epithelial types of the trachea and bronchi. Normal mucociliary clearance of particulates that inter act with the mucosa requires coordinated ciliary function and a normal lining of the gel-sol liquid layer of mucus, which is derived from surface mucous cells and submuco sal glands. Submucosal glands include both mucous cells and serous secretory cells. In addition to its barrier func tion, mucous secretory capacity, and mucociliary trans port function, tracheobronchial epithelium synthesizes and secretes neutral endopeptidase. This is an important enzymatic regulator of airway neuropeptides such as sub stance P and neurokinin A, which in turn can stimulate increased vascular permeability and airway smooth mus cle contraction. Nonciliated epithelial cells (Clara cells), which are components of tracheobronchial epithelium of some animal species, have high cytochrome P-450 monooxygenase activity and can activate many xenobiotic compounds to toxins that can cause pulmonary injury. Furthermore, tracheobronchial epithelial cells actively metabolize arachidonic acid to eicosanoids such as prosta glandin E 2 and 12-HETE (hydroxyeicosatetraenoic acid), which may regulate local smooth-muscle tone and vascu lar flow. Bronchial epithelial cells also can up-regulate expression of intercellular adhesion molecule-1 (ICAM-1) following injury and interaction with cytokines; ICAM-1 promotes adhesion and migration of circulating neutro phils and monocytes into airways during an inflammatory reaction. Trachea, bronchi, and bronchioles contain lymphoid tissue (bronchus-associated lymphoid tissue or BALT) in the lamina propria and submucosa, analogous to gutassociated lymphoid tissue (GALT) in function. In addi tion, there can be a more diffuse distribution of lympho cytes and plasma cells. Other cells such as macrophages, dendritic cells, neutrophils, and mast cells at low density within the lamina propria participate in normal baseline immune and inflammatory processes. Both B cells and T cells have been demonstrated in BALT, with B cells the predominant component. B cells have been demonstrated to be positive for immunoglobulin A (IgA), IgG, IgM, and IgE antibodies. Immunoglobulin A cells are distributed throughout the lamina propria and in association with BALT; BALT and GALT IgA cells are the principal source of IgA in serum. Viral-specific and bacterialspecific secretory IgA antibody on the respiratory mucosa is recognized as one of the most important components of host immunity to respiratory pathogens. In respiratory secretions, IgA can prevent binding of bacteria and ad sorption of virus to respiratory epithelial cells, and block infection. High viral-specific IgA in upper respiratory tract secretions is recognized as being associated with the most effective form of immunity to respiratory viral reinfection. Concentrations of IgA are highest in the airways, but IgG and IgM predominate in the alveoli. An important feature of the distribution of lymphocytes in the respiratory tract is the existence of localized traffic. Antigen-reactive cells are generated mainly in local lymph nodes (e.g., mediasti nal and bronchial), and activated lymphocytes (memory cells) migrate preferentially back to BALT and other pul monary sites. Trachea and bronchi contain hyaline cartilage rings, and intrapulmonary bronchi are surrounded by abundant peribronchial connective tissue which compartmentalizes the largest conducting airways from the surrounding alve olar tissue. Airway patency in trachea and bronchi is main tained by the minimally deformable cartilage rings. The abundant peribronchial connective tissue insulates bron chi from lung-volume-induced changes in airway diameter and acts under most circumstances to prevent suppurative inflammatory processes from spreading from the bronchial wall directly into surrounding alveolar tissue. Although bronchi have large individual cross-sectional areas, it is estimated that -80% of resistance to airflow in pulmonary conducting airways is present in the first 4-7 divisions of the bronchial tree. Airflow is rapid in these airways, and even minimal bronchoconstriction or airwall edema and inflammatory cell infiltration can result in profound in creases in overall respiratory resistance and auscultable airway sounds. Bronchioles, in contrast to bronchi, have no cartilage in their walls to prevent airway collapse. Instead, airway patency is dependent on the close attachment of interalveolar septa to a thin connective tissue layer in the bronchio lar wall. As the lung increases in volume during inspira tion, the radially arranged interalveolar septa pull on the bronchiolar wall in a radial tethering fashion to result in maximal luminal diameter during maximal lung volume. During expiration, the radial tethering forces of the interal veolar septa decrease, and the bronchiolar lumen de creases in diameter. Small bronchioles may collapse nor mally toward the end of the expiratory cycle, and airflow out of the pulmonary acini supplied by the bronchioles ceases unless there is sufficient collateral ventilation. Be cause of their smaller diameter, collapsibility, and thinwalled structure, bronchioles are much more susceptible to pathologic processes occurring in the surrounding alve olar parenchyma than are bronchi. Their small luminal size makes them much more likely to become obstructed by inflammatory exudate during an acute inflammatory reaction. Inflammatory processes centered on bronchioles are highly likely to extend into adjacent alveoli. Although the resistance to airflow in individual bronchioles is high, the total cross-sectional area of all generations of bronchi oles is much greater than that of bronchi. Therefore, pathologic processes affecting small numbers of bronchi oles might not result in clinical signs of airway obstruction. A large percentage of bronchioles must be affected before clinical evidence of disease is detected (e.g., hypoxemia due to ventilation/perfusion abnormalities or dyspnea due to small airway obstruction). Bronchioles in proximal generations are often lined by epithelium which is indistinguishable from that in distal bronchi. More distally, small-caliber bronchioles are lined by a simple columnar to cuboidal epithelial lining almost entirely composed of ciliated cells and nonciliated bron chiolar (Clara) cells. The nonciliated cells function as stem cells for repair in the bronchiole and have the capacity to divide and differentiate into ciliated cells or other noncili ated cells. The nonciliated cells lining bronchioles in some animal species have abundant agranular endoplasmic re ticulum in their apical cytoplasmic projections and are the pulmonary cells with the greatest concentration of cytochrome P-450-monooxygenase enzyme systems. The latter places them among the most exquisitely sensitive pulmonary cells to toxic injury by xenobiotic compounds. Alveolar parenchyma is divided into structural and func tional units called acini. An acinus is the gas-exchange unit of the lung supplied by a single terminal bronchiole. An acinus includes all of the branches of respiratory bron chioles, alveolar ducts, alveolar sacs, alveoli, and associ ated blood vessels supplied by branching of one terminal bronchiole. Many acini (equivalent to primary lobules) are grouped together and surrounded by connective tissue septa in some species such as cattle, sheep, and horses to form grossly visible lobules. An earlier convention of dividing alveolar parenchyma into primary and secondary lobules has been dropped because of the confusion it caused. Patterns of respiratory disease often follow these grossly and histologically detectable structural units, and the lesion distributions are frequently referred to as being panacinar, centriacinar, or lobular. The most important cells of the alveolar parenchyma are type I and type II alveolar epithelial cells (pneumonocytes or pneumocytes), alveolar capillary endothelial cells, fibroblasts and other interstitial cells, and alveolar macrophages. Type II alveolar epithelial cells (granular pneumocytes) are cuboidal cells, lining interalveolar septa, and contain characteristic osmiophilic lamellar inclusions in their cyto plasm. The primary recognized functions of type II cells are to synthesize pulmonary surfactant and to serve as progenitor cells for replacement and turnover of alveolar epithelium. Pulmonary surfactant is a complex mixture of phospholipids and small amounts of protein synthesized by type II epithelial cells. Its main function is to decrease surface tension in the alveolar space during expiration. Type II alveolar cells divide during alveolar development and postnatal lung growth and serve as stem cells following normal turnover and loss of alveolar epithelial cells. Type II cells can proliferate rapidly to repopulate denuded base ment membrane following injury to type I alveolar epithe lial cells. Following division and migration to cover the bare basement membrane, type II cells can differentiate into type I alveolar epithelial cells. Type II cells synthesize a variety of matrix components including fibronectin, type IV collagen, and proteoglycans. Type II cells also metabo lize arachidonic acid to form eicosanoids, such as prosta glandin E 2 , which may modulate function of other alveolar cells, and there is evidence that they can express major histocompatibility complex (MHC) class II molecules and function as antigen-presenting cells. Type I alveolar epithelial cells are squamous cells which line -93% of the alveolar surface. They have limited ca pacity to adapt to injury, in part because of their large membrane surface area and minimal enzymatic defense mechanisms. Injury to type I cells is usually quickly fol lowed by sloughing of these cells from the alveolar base ment membrane. Alveolar capillary endothelial cells are part of the largest capillary bed of any tissue in the body. They func tion as the initial permeability barrier between the capil lary lumen and pulmonary interstitium and have important transport functions for solutes, water, and gases. They have numerous metabolic functions including the uptake or clearance of serotonin, norepinephrine, prostaglandins E and F, bradykinin, hormones, and drugs. Endothelial cells have angiotensin-converting enzyme activity, which converts angiotensin I to angiotensin II. Cytochrome P-450 monooxygenase activity has been identified with immunocytochemical techniques in alveolar endothelium, and this may in part explain the sensitivity of endothelial cells in some species to toxic damage by xenobiotic com pounds. Endothelial cell exposure to mediators such as leukotriene B 4 and cytokines such as tumor necrosis factor and interleukins 1-8 can up-regulate expression of endo thelial cell adhesion molecules to facilitate attachment and migration of neutrophils and other leukocytes into intersti tium and alveoli. Alveolar fibroblasts include a morphologically heterog enous group of connective tissue cells (e.g., interstitial cells) that may have varying protein synthetic activity, contractile function, and cell and matrix interactions. They are responsible for synthesis of interstitial matrix and collagen types I, III, IV, V, and VI, as well as elastin. Collagen types I and III predominate. Pulmonary fibro blasts also synthesize laminin, fibronectin, glycosaminoglycans, and proteoglycans which, together with the other synthesized components, contribute to the mechanical properties of lung. Macrophage populations in the lung include alveolar macrophages, interstitial macrophages, pulmonary intra vascular macrophages, and dendritic cells. Alveolar macrophages form the first line of pulmonary defense against infectious agents and particles that are able to penetrate defense mechanisms of the upper respira tory tract and intrapulmonary airways. In normal lung, alveolar macrophages are derived from blood monocytes that migrate into the lung after undergoing a maturation step in the interstitial space. During inflammatory states, alveolar macrophages are derived directly from infiltrating blood monocytes. Macrophages can also be derived from division of local macrophages, although this probably con tributes little to the expansion of pulmonary macrophage populations that occur in most inflammatory lung diseases. Alveolar macrophages have a wide array of functions in addition to their capacity to phagocytose and kill infec tious agents and to degrade other phagocytosed particles. They function as regulatory cells controlling inflamma tory, immune, and repair processes through release of a wide array of cytokines and other regulatory molecules. Inflammatory and immune functions are promoted by macrophage synthesis and release of cytokines such as interleukin-1, tumor necrosis factor, alpha and gamma interferon, and histamine release factor, as well as by release of inflammatory mediators that include leukotriene B 4 and C 4 , platelet-activating factor, and thromboxane A 2 . Repair processes are generally promoted or otherwise regulated by release of cytokines that include transforming growth factor-beta and -alpha, fibroblast growth factor, insulinlike growth factor, and platelet-derived growth fac tor (PDGF). Alveolar macrophages play a role in induction of cellular and humoral immune responses through antigen presentation and other accessory cell functions, but the dendritic cells in the lung may be much more effective at accessory cell function than macrophages. Dendritic cells are bone marrow-derived motile leuko cytes with enhanced antigen-presenting capacity in the interstitium of alveolar parenchyma and the lamina propria of airways. These cells have numerous, long, irregular dendritic processes, an extremely irregular and folded nu cleus, and an absence of phagolysosomes. They constitutively express high levels of MHC class I and II molecules and common leukocyte antigen but are incapable of phagocytosing particles efficiently. The cells lack many of the cytoplasmic surface markers of mononuclear phagocytes. Pulmonary intravascular macrophages (PIMs) are unique mononuclear phagocytes found in the lung. They are large, mature macrophages, present in the pulmonary alveolar capillaries, which form membrane adhesive com plexes with the underlying endothelium. Species in which PIMs have been found include cattle, sheep, pigs, goat, cats, and humans. These cells are highly phagocytic and play a role in the clearance of circulating bacteria and particulates in the pulmonary circulation. They also re lease an array of inflammatory mediators following inter action with particulates, including leukotriene B 4 , and hence can help recruit neutrophils and other inflammatory cells into the lung during an acute inflammatory reaction. Pulmonary defenses serve principally to protect the delicate alveolar parenchyma of the lung from damage. This is accomplished by removing harmful agents as much as possible in the nasal passages and conducting airways. Alveolar mechanisms form a second level of defense. The upper respiratory tract functions to warm and humidify inspired air, and to remove larger particles and water-soluble gases by means of the mucous lining. Warming and humidifying occur principally during passage of air through the nose, and are facilitated by the extensive surface area and the rich, readily engorged vascular plexus in the submucosa, particularly of the turbinates and nasal septum. Many particles in inspired air are first deposited on the mucous lining of nasal passages and conducting airways and are then cleared by movement of the mucocili ary blanket. The larger the particles, the more efficient is their removal in the upper airways. Deposition on surfaces is mainly by inertial impaction, gravitational sedimenta tion, diffusion, or a combination of these. Inertial im paction is chiefly in the nasal passages and pharynx and at points of branching of airways where the airstream changes its direction and where turbulence occurs. The efficiency of nasopharyngeal trapping depends on the ana tomical complexity of the nasal passages, especially with regard to the turbinates, and on the pattern of respiration. The gravitational settlement of particles is directly propor tional to their size and density, and is favored in the rela tively still air of deeper parts of the respiratory system. Diffusion of particles is due to molecular collision and affects only the very smallest of them-particles of less than -0.3 ^im in size. Since displacement velocity by diffusion is low, deposition by this method is effective only in the alveoli where movement of gases is also by diffusion rather than linear flow. Deposition of particles greater than -10 fxm aerody namic diameter is virtually complete above the larynx. In addition, a large percentage of inhaled particulates smaller than 10 fim also interact initially with the mucosa of the nasal cavity and nasopharynx. As a result, many viral and bacterial diseases have initial stages of replication or multiplication in the epithelium and lymphoid tissue of the upper respiratory system before they either spread systemically or are nebulized during inspiration to be re distributed into the lower respiratory tract. With decreas ing particle size less than 10 jam, an increasing proportion of inhaled particles pass into the deep lung, many being subsequently exhaled. The critical feature, from the point of view of pulmonary homeostasis, is that droplet nuclei and other irritant or infectious particles -1 -2 fim in diame ter mostly deposit at the bronchiolar-alveolar junction. This is because the total cross-sectional area of airspaces increases suddenly, linear velocity of the airstream falls to zero, and there is time for the particles to deposit by gravitational settling. As will be discussed later, this is one of the reasons for the vulnerability of the bronchiolaralveolar junction to damage by inhaled irritants. Statements on relationship between particle size and deposition are relative rather than absolute. Sizes quoted for mathematical modeling of particle deposition are in terms of equivalent cross-sectional diameters of unit den sity spheres (aerodynamic diameter). The most obvious exception to the generalization that particles greater than 10 fjum in diameter do not penetrate beyond the larynx is that fine fibers as long as 100 fim or longer, notably of asbestos, do reach alveolar parenchyma. Additionally, there might be opportunity for redistribution of particles deposited in the proximal respiratory tract by reflux of excess secretions or aspiration of fluid. Once particles are deposited on the mucus of airways, clearance by normally functioning mucociliary transport is highly efficient. Most particles are removed from central airways within a few hours and even from distal airways within 24 hr. The mucociliary blanket consists of cilia bathed in a watery sol on top of which lies mucus with physical properties of a viscoelastic gel. Whether the mu cus usually forms a patchy or continuous surface layer is still debated, but it appears to be mostly continuous in trachea and large bronchi of healthy individuals and per haps patchy in smaller airways. In any event, the cilia beat mostly in the watery hypophase except during the active forward stroke when their tips contact the overlying mu cus. The net effect of a ciliary frequency of -1000 beats per minute is to propel the mucus toward the pharynx at a linear velocity in the order of 5-15 mm/min. The greater density of ciliated cells in proximal airways, the more rapid ciliary beat, and possibly absorption of a portion of the aqueous periciliary fluid are believed to prevent swamping of these airways, especially the trachea, by fluid collected from the large number of distal airways. Most of the mucous secretions of the respiratory tract, and the particulate matter they carry, reach the pharynx and are swallowed. The concentration of material into the nasopharynx coincides with well-developed diffuse and focal lymphoid tissue of the tonsillar region and dorsal nasopharynx. This enhances the efficiency of develop ment of immune responses, but also makes the region vulnerable to primary infections by organisms such as Brucella spp. and Mycobacterium a. paratuberculosis. Swal lowing of material originating in the lungs also serves as a mode of spread of diseases such as tuberculosis and as part of the migratory pathway of helminth eggs and larvae. The specific roles and controlling influences of mucous cells, serous cells, and other secretory cells in surface epithelium and submucosal glands, and the differences among species, are still poorly understood. In addition to the physical aspects of the sol and gel phases of the secretion, however, a variety of other components with defensive capabilities are recognized. As mentioned pre viously, the major immunoglobulin is locally synthesized IgA, although IgE, IgG, and other classes are present. Important nonspecific humoral components of the secre tions are interferon, which helps limit viral infection in nonimmune hosts, and lysozyme (muramidase) and lactoferrin, which have selective antibacterial activity. Tra cheal antibacterial peptides are secreted by bovine tra cheal cells, but their relative importance in defense needs to be established. The normal bacterial flora of the nose and nasopharynx are important in that by specific adher ence of their specialized surface structures (adhesins) to receptors on cilia and surfaces of epithelial cells, they prevent adherence and colonization by more virulent flora. The physical and humoral defenses of the mucociliary blanket, which are constantly in operation, are boosted by cellular and humoral mechanisms recruited from blood at the onset of inflammation, and by sneezing, coughing, and bronchoconstriction provoked by irritation of airway receptors. Normal mucociliary function depends on struc turally and functionally intact ciliated epithelium as well as normal viscous properties and quantity of secretions. Interference with one or more of these predisposes to infection, as will be considered under pathogenesis of bronchopneumonia. Alveolar defense against small-sized particles depends heavily on phagocytosis by alveolar macrophages. Phago cytosis of readily ingested particles, for instance, opso nized bacteria, is largely complete by 4 hr after alveolar deposition. Actual physical removal of particulates from alveoli is inefficient, in contrast to their removal when deposited on the mucociliary blanket. Fifty percent clear ance of particles deposited in alveoli takes from several days to months or longer, depending on their physical nature and irritant capability. Most particles are therefore phagocytosed by macrophages and either inactivated or sequestered. The alveolar macrophages move toward the bronchioles and hence eventually onto the mucociliary blanket. Reasons for their centripetal movement are not known, but the surface-lining liquid in alveoli is also be lieved to move centripetally, possibly because of its con tinual secretion and a "milking" action of respiratory movements. Alternative fates of particles in alveoli are clearance in the lining liquid without phagocytosis, or penetration into the pulmonary interstitium. The latter becomes of increasing importance as the particulate load increases. It appears that most particles reach the intersti tium by endocytosis across the alveolar type I epithelial cells. Once in the interstitial space, particles move with the flow of lymph and are phagocytosed by interstitial macrophages. Particle-laden macrophages associated with lymphatics occur in peribronchiolar and perivascular clus ters, and some eventually find their way to the local lymph nodes. Overloading the alveolar macrophage system fa vors accumulation of particles in the interstitium, as oc curs in the pneumoconioses. Sterility of alveoli is thus maintained largely by the ability of macrophages to kill ingested bacteria and to secrete cytokines and other regulatory molecules, as re ferred to earlier. These activities are enhanced by immu noglobulin, particularly through the opsonizing effect of IgG, which is the predominant immunoglobulin in the alve olar lining liquid. Surfactant also has important opsonizing functions. Lysozyme, lactoferrin, and complement are also pres ent in alveolar lining liquid. Humoral components capable of inhibiting inflammatory mediators or destructive en zymes are of great importance, particularly the glutathione peroxidase system and catalase, which help protect against injury by reactive oxygen radicals, and a,-antitryp sin (a,-antiprotease), which is important in protection against the development of alveolar emphysema and acute lung injury. Just as factors interfering with mucociliary defense During the embryonic stage of lung growth (30-50 days of gestation in a bovine fetus), the branches of the lung bud continue to grow and divide to form the segmental bronchi, which are surrounded by mesenchyme. Ciliated cells are developed in the airways at this period. During the pseudoglandular stage of lung growth (50-120 days of gestation in the bovine fetus), the remainder of the primary conducting airways develop by asymmetric dichotomous branching. Ciliated cells as well as mucous cells become differentiated within the airway epithelium, and bronchial glands and cartilage develop. At the end of the pseudoglandular pe riod, all branches of conducting airways have developed and are embedded in mesenchymal stroma. Distal airway branches are lined by cuboidal to columnar epithelial cells, which contain abundant cytoplasmic glycogen. During the canalicular stage of growth (120-180 days of gestation), the vascular system becomes extensively developed, and capillaries become closely approximated with airway epi thelium. The distal airways continue to give rise to more distal spaces, which will become respiratory exchange surfaces such as alveolar ducts and alveoli. The frame work of the pulmonary acinus begins to form along with increased vascular density, and there is a proportionate reduction in the relative amount of mesenchyme to air spaces. Type I and type II alveolar epithelial cells begin to differentiate in the newly formed terminal air spaces. During the saccular stage of lung growth (180-240 days of gestation in the bovine fetus), lung volume and gasexchange surface increase markedly, and there is further reduction in mesenchyme between air spaces. Small crests with two capillary layers protrude into the immature sac cules to result in further subdivision of the air spaces. During the alveolar stage of lung growth (240-260 days), true alveoli form by further ingrowth of septa from the intersaccular crests. The ingrowth of the septa is associ ated with the simplification of the capillary structure so that there is a single capillary layer per interalveolar septum. Further subdivision of alveolar septa results in contin ued increases in alveoli and alveolar surface area during the period of rapid postnatal growth. Airways increase in diameter and length through coordinated growth as overall lung volume and weight increase. The rate and coordination of intrauterine lung growth are influenced by a number of complex factors. Compres sion of the thoracic cavity during development, such as occurs secondarily to chest wall abnormalities or dia phragmatic hernia, results in pulmonary hypoplasia with abnormally low numbers of alveoli. Decreased respiratory efforts of the fetus, and conditions associated with loss of volume of amniotic fluid (oligohydramnios), also result in pulmonary hypoplasia. Endogenous pulmonary growth factors such as gastrin-related peptide and transforming growth factor-beta, as well as hormonal factors such as thyroxine and glucocorticoids, regulate intrauterine lung development. Most of the congenital pulmonary anoma lies described subsequently under this heading presum ably are associated with localized or generalized distur bances of one or more of these regulating factors. Respiratory diseases can be caused by a large variety of infectious or noninfectious agents. The site of damage in the respiratory tract is determined by the interplay of portal of entry of the agent, the nature and concentration of the agent, and the relative susceptibility of the tissues exposed to the agent. The portal of entry is the major determinant. Aerogenous insult, as would be expected, usually leads to damage centered on airways. Nasal passages and upper airways are mostly affected by irritants contained in large particles, by highly soluble gases, or by infectious agents whose cell receptors are most numerous or more readily accessible in upper respiratory epithelium. Distal airways are more affected by fine particles, weakly soluble gases, and by infectious agents with affinity for bronchiolar or alveolar epithelium. The greater vulnerability of the bronchiolar-alveolar junction to damage is also an extremely important determinant at this level (see Bronchopneumo nia, Section VI,F,1 of this chapter). In instances in which viruses have tropism for both terminal bronchiolar epithelium and type II alveolar epi thelial cells, viral replication occurring in these cells re sults in an inflammatory reaction centered on terminal airways as well as on surrounding interalveolar septa (i.e., proximal acinar areas) to result in a mixed pattern of damage (bronchointerstitial pneumonia.) The pattern of damage induced by viruses as well as other infectious agents can be greatly altered by variations in the efficiency of the systemic and pulmonary immune systems. For in stance, when an immunosuppressive virus such as canine distemper virus infects dogs, it can induce a much more diffuse interstitial pneumonia with bronchiolitis than is typical for other less immunosuppressive paramyxoviridae, such as parainfluenza virus. Hematogenous insult to the lungs is manifest, depending on the cause, as diffuse, patchy, or widely disseminated multifocal lesions without orientation on airways. An im portant exception to the generalization that blood-borne agents affect alveolar septa and pulmonary interstitium more than airways occurs when an ingested toxin specifi cally damages bronchiolar epithelium. An example of this is the necrosis of nonciliated bronchiolar epithelial (Clara) cells of the horse caused experimentally by 3-methylindole toxicosis. Localization of damage to nonciliated bronchio lar cells in the horse can be explained by cellular binding and then selective metabolism of 3-methylindole to toxic intermediates by the cytochrome P-450-monooxygenase system present in nonciliated cells of this species. Other, less common types of injuries to the respiratory tract are traumatic, as by penetration of a foreign body, or by extension of lesions along fascial planes and lymphatics from adjacent tissues or cavities. Differences in patterns of lesions among species of ani mals are well recognized, and some can be explained by species differences in anatomy or tissue distributions of metabolizing enzymes. One example is the complete lobu lar septation and absence of collateral ventilation (low interdependence) in the bovine lung, which predisposes it to poor resolution of bronchopneumonia and to the devel opment of acute interstitial emphysema under conditions of greatly forced expiratory efforts with concurrent bronchoconstriction and increased airway resistance. Speciesassociated differences in distribution of metabolizing enzymes among pulmonary cells are presumably the ex planation for differing patterns of damage of experimental 3-methylindole toxicosis in horses and cattle. In horses it induces necrosis of only bronchiolar epithelial cells, whereas in cattle it causes widespread damage to alveolar type I epithelium and alveolar capillary endothelium, as well as to bronchiolar epithelium. Congenital anomalies of the nasal region are rare but occur in all species. They are usually part of more exten sive craniofacial defects in which they accompany various combinations of malformations of mouth and eyes. Ani mals with absent, underdeveloped, or severely distorted nasal regions are usually stillborn or die immediately after birth, often because of an imperforate buccopharyngeal membrane (choanal atresia). The milder defect of cleft palate is compatible with life, but affected animals gener ally die because of aspiration pneumonia. A variety of localized, developmentally related defects that affect the nasal region can take time to become appar ent. Defects of tooth-germ origin are especially likely to be of this type. Maxillary cysts in foals or young adult horses can distort the profile of the maxillary bone suffi ciently to cause obstruction of the ipsilateral nasal pas sage, destruction of the nasal turbinates, and deviation of the nasal septum. Deposits of amyloid sometimes occur in the nasal sub mucosa of horses. The deposition is not part of a general ized amyloidosis, although there might be concurrent cuta neous amyloidosis, particularly of head, neck, and cranial thorax. The nasal vestibule and anterior portions of the septum and turbinates are mostly involved, but the depos its may extend to the larynx. The amyloid may be in nodules of various sizes or as a diffuse deposition. Re sulting stenosis can be severe enough to cause signs of nasal obstruction. The amyloid deposits have a smooth surface and the usual waxy sheen of amyloid on the cut surface. The amyloid is deposited in the walls of submuco sal vessels and the basement membrane of mucosal glands as well as in the connective tissues. Macrophages and lymphocytes are usually intermingled with the interstitial amyloid deposits, and giant cells are found adjacent to nodular deposits. There may be severe ulceration of the mucosa, especially overlying large nodular masses. Nasal amyloidosis in horses appears to be analogous to AL amyloidosis in humans, in which the major amyloid protein is composed of light chains of immunoglobulin or of light chain fragments. Primary (AL) amyloidosis is idiopathic or associated with myelomatosis in humans. One case of nasal and cutaneous amyloidosis in a horse was associated with a malignant lymphoid tumor. The arteries, veins, and capillaries of the nasal mucosa are capable of remarkable adaptive changes in the content of blood. Vascular engorgement occurs by relaxation of the arteries and contraction of the thick tunica media of the veins. This lability of the vessels is responsible for the frequency of hyperemia and edema. Active hyperemia is part of the acute stage of inflammation. Passive congestion is the result of local or general circulatory failure. Of more concern is nasal hemorrhage or epistaxis. The term epistaxis is used in a general sense to refer to hemor rhage from the nose, but this does not necessarily mean that the source of bleeding is within the nasal passages or sinuses. The hemorrhage might be from the nasopharynx or from deep within the respiratory tract. This distinction is particularly important in horses in which, in epistaxis associated with heavy exercise, the blood originates from the lung. The condition is more appropriately termed exer cise-induced pulmonary hemorrhage and will be described under that heading. Bloodstained foam is frequently pres ent in and issuing from the nose of cadavers, especially sheep. This is an indication of terminal pulmonary conges tion, edema, and hemorrhage. Hemorrhage originating within the nasal region is most commonly caused by traumatic, inflammatory, or neoplas-tic breakdown of vessels. It may also be part of any of the hemorrhagic diatheses (see The Hematopoietic System, Volume 3, Chapter 2). In some of the hemorrhagic diathe ses, such as those of thrombocytopenic origin, the bleed ing may be copious. Hemorrhage in rhinitis is associated with mucosal ulceration, a frequent feature of acute in flammation and some specific types of chronic inflamma tion. In most inflammatory hemorrhages, the extravasa tion is initially submucosal. Mycotic infections of the guttural pouches can cause epistaxis in horses. Rarely, nasal hemorrhage may be the result of hypertension or vascular aneurysms. The nasopharyngeal mucous membrane has a normal resident microbial flora established by specific adherence of bacteria via adhesins to sugar-containing surface bind ing sites on epithelial cells. An important role of the normal flora is to exclude adherence and subsequent colonization of the mucosa by more virulent organisms, particularly Gram-negative ones. Injury to the mucosal surface can lead to pathogenic activity by certain of the normal flora or, more importantly, affect surface binding sites so that adherence and colonization by pathogenic microorgan isms can occur. Similar changes can occur because of systemic immunodeficiency states or nonspecific stress situations such as occur postoperatively. Fungal and other opportunistic infections which commonly follow pro longed antibiotic therapy are probably also attributable to removal of the normal blocking bacterial flora. Primary injurious agents are usually viruses. Allergens are probably important in cattle and to a lesser extent in dogs, cats, and other species. Irritant volatile gases, dust, and excessive dryness of the atmosphere are occasional causes of injury to the nasal epithelium. Rhinitis usually results from the interaction between viruses, or other devi talizing influences, and bacteria or fungi. Rhinitis can be differentiated, according to its course, as acute or chronic. It can be differentiated morphologically, according to the nature of the response, into serous, ca tarrhal, purulent, ulcerative, pseudomembranous, hemor rhagic, or granulomatous inflammation. Most cases of acute rhinitis begin with a serous exudation, which changes in the course of the disease to a catarrhal and then purulent inflammation. Pseudomembranous, ulcerative, or hemorrhagic rhinitis is a sign of very severe damage. Chronic rhinitis is most commonly manifested by prolifer ative changes, but sometimes it causes atrophy, which affects mainly the nasal conchae in large breeds of dogs. During the initial serous stages of rhinitis, whether viral, allergic, or nonspecific, the mucosa is swollen and gray to red depending on the degree of hyperemia. Histologically, the epithelial cells show hydropic degeneration and loss of cilia. There is hyperactivity of the goblet cells and submucosal glands. The secretion is a thin, clear sero-mucin, which contains a few leukocytes and epithelial cells. The underlying lamina propria is edematous and sparsely infiltrated by inflammatory cells. The swelling of the mucous membrane tends to cause mild respiratory discomfort and the familiar sneezing and snuffling. Within hours or a few days, serous rhinitis is modified partly by changes in glandular secretion and partly by bacterial infection. The hyperemia, edema, and swelling are then aggravated, and the discharge becomes catarrhal (mucous) or frankly purulent because of the emigration of large numbers of leukocytes and desquamation of epithe lial cells. Regenerative hyperplasia of surviving epithelium can occur, but in purulent rhinitis, extensive ulcerations may be evident. In subacute to chronic rhinitis, diffuse or localized pol ypoid thickenings of the mucosa develop ( Fig. 6 .1A). The nasal polyps are initially sessile but can, when larger, be come pedunculated. The ease with which the nasal lamina propria becomes engorged and edematous, plus the ten dency of protruberances into the nasal meatus to compro mise venous and lymphatic drainage because of constric tion in their basal regions, are probable factors in the persistence or progression of inflammatory polyps. They occur occasionally in horses and cats, and less commonly in other species. Polyps are soft, pink-gray, irregularly nodular, pedunculated, or sessile masses. They have a chronically inflamed edematous core resembling myxoma tissue, covered by variously hyperplastic, metaplastic, or ulcerated epithelium. Old polyps can become more fi brous. Two special types of polyp deserve mention. One is the hemorrhagic nasal polyp (progressive hematoma) arising from the ethmoid region of the horse. This is a unilateral hemorrhagic mass, which can extend to the nostril or choanae. It tends to enlarge progressively and can recur after surgical excision. Histologically, it consists mostly of organizing hemorrhages of various ages with extensive siderosis and calcification of connective tissue fibers. The extent to which capillary angiomatous changes are the forerunners of hemorrhage and hematoma formation is uncertain. It has been suggested that equine paranasal sinus cysts have a common pathogenetic factor with hem orrhagic nasal polyps, namely repeated hemorrhages into submucosal tissues. The other special form of polyp affect ing the nasal region is the nasopharyngeal polyp of cats, which arises in the middle ear or Eustachian tube. Chronic catarrhal or suppurative rhinitis causes progres sive fibrosis of the lamina propria with atrophy of the glands and atrophy with focal squamous metaplasia of nasal epithelium. The atrophic epithelium is dry and shiny. Pseudomembranous rhinitis may be fibrinous or fibrino necrotic (diphtheritic), but it is usually the former, and the fibrinous membranes can be peeled off without leaving gross underlying defects. The deeper, fibrinonecrotic in flammations are associated with severe bacterial infec tions and frequently have a dry yellowish quality that indicates infection with Fusobacterium necrophorum. The fibrinonecrotic membrane is firmly adherent to the under- lying tissue a n d when removed leaves a r a w , ulcerated surface. Granulomatous rhinitis is a typical lesion in some spe cific diseases. T h e lesions are nodular and polypoid or b e c o m e large, space-occupying m a s s e s . T h e smaller ones are more firm, the larger o n e s , more friable or gelatinous. The histologic structure is specific for the disease. Rhinitis occurs commonly as part of a more generalized disease process. Important specific entities in which rhini tis is the sole or a major lesion will be covered subse quently. A chronic, nonspecific rhinitis is an important condition in the dog, and to a lesser extent in the cat. T h e term lymphoplasmacytic is sometimes applied because lymphocytes and plasma cells are the predominant in flammatory cell c o m p o n e n t s . There is a chronic unilateral or bilateral mucopurulent to hemorrhagic discharge, and the inflammatory proliferation leads to diffuse or polypoid thickening of the nasal m u c o s a and obstruction of nasal passages ( Fig. 6 .IB). T h e glandular elements are hyper plastic, the epithelium is variously ulcerated, hyperplastic, and metaplastic (squamous), and the e d e m a t o u s , fibrotic stroma is heavily infiltrated by lymphocytes and plasma cells. There is no sign of foreign bodies, at least in the chronic lesion, and bacterial cultures do not reveal signifi cant organisms. T h e pathogenesis is unclear, but following initial damage, which is no longer detectable, there is probably a vicious cycle involving impaired local de fenses, further infection, and damage by normally non pathogenic flora and self-sustaining inflammation. T h e last named is presumably associated with release of cytokines and inflammatory mediators generated by interaction of lymphocytes, plasma cells, and other elements. Pooling of exudate in obstructed portions of the lumen and com promised venous and lymphatic drainage in the hyperplas tic m u c o s a are also likely to b e factors leading to progres sion of the lesion. Rhinitis of itself can have unfortunate sequelae. Aspira tion of nasal exudate can lead to bronchopneumonia. T h e potential for reflux flow in the valveless veins of the head explains the occurrence of intracranial thrombophlebitis, abscess, or meningitis; these a r e , however, rare. Sinusitis probably is the most c o m m o n sequel to rhinitis. Inflammation of the paranasal sinuses often goes unde tected unless it has caused facial deformity or a fistula in the overlying skin. Sinusitis is of most significance in the horse because of the size and complexity of its paranasal sinuses and the compounding effects of limited drainage and tendency for periodontitis to extend to sinusitis. Si nusitis is very c o m m o n in sheep as a response to larvae of Oestrus ovis. It also follows penetration of infection in dehorning w o u n d s , fractures, and periodontitis. Seromucinous sinusitis of little significance occurs in viral infec tions of the upper respiratory tract. In acute catarrhal or purulent rhinitis, the mucosal swelling tends to occlude the orifices of the sinuses. T h e secretions a n d exudates then accumulate and render chronic purulent sinusitis al most inevitable. T h e histologic features of sinusitis are the same as those of rhinitis. T h e accumulation of seromucinous secretion is referred to as mucocele, a n d the accumu lation of purulent exudate is referred to as empyema of the sinus. Purulent inflammation of the sinuses is more significant than rhinitis because of proximity to the brain. It is also less likely to spontaneously drain a n d resolve and therefore more likely to cause epithelial atrophy a n d metaplasia, a n d distortion of the bony walls of the sinuses by pressure or osteomyelitis. [511] [512] [513] [514] [515] [516] [517] [518] [519] [520] [521] [522] 1981 . L a n e , J. G . , Longstaffe, J. A . , a n d Gibbs, C. Equine paranasal sinus cysts: A report of 15 c a s e s . Equine Vet J 19: [537] [538] [539] [540] [541] [542] [543] [544] 1987 . Leyland, A . , a n d Baker, J. R. Lesions of the nasal a n d paranasal sinuses of the horse causing d y s p n o e a . Br Vet J131: [339] [340] [341] [342] [343] [344] [345] [346] 1975 . N e g u s , V . " T h e C o m p a r a t i v e A n a t o m y a n d Physiology of t h e N o s e a n d Paranasal S i n u s e s . " Edinburgh a n d L o n d o n , Living stone, 1958. Piatt, H . H a e m o r r h a g i c nasal polyps of t h e h o r s e . J Pathol 115: 5 1 -5 5 , 1975. van Andel, A . C. J . , G r u y s , E . , a n d K r o n e m a n , J. Amyloid in the horse: A report of nine c a s e s . Equine Vet J 20: 2 7 7 -2 8 5 , 1988. In addition to t h e specific diseases t o b e discussed, rhinitis is a prominent feature of a variety of respiratory or more generalized infectious diseases. T h e nature, cause, a n d specificity of the various forms of rhinitis differ according t o species. Examples a r e canine distemper, t h e feline respiratory disease complex, t h e specific diseases of cattle described under ulcerative and erosive stomatitis, and equine influenza, equine rhinopneumonitis, and equine viral arteritis. This disease is widespread in E u r o p e . It also occurs in the United States and other major pig-raising areas of the world b u t appears to b e relatively unimportant. T h e disease is caused by a cytomegalovirus (family Herpesviridae, subfamily Betaherpesvirinae) which characteristically produces large ba sophilic intranuclear inclusions in swollen glandular epithelia of t h e nasal cavity. Inclusion-body rhinitis is most commonly an acute t o subacute disease of suckling piglets of ~ 1-5 w e e k s of age. The signs are those usual for rhinitis with modest fever. T h e early discharge is seromucinous, b u t it m a y b e c o m e catarrhal o r purulent if the course is prolonged, probably owing to secondary bacterial infection. T h e morbidity is high, b u t t h e mortality in t h e absence of suppurative com plications is low; the complications include sinusitis, otitis media, a n d pneumonia. T h e uncomplicated histologic changes in t h e m u c o s a are those of a nonsuppurative rhinitis, with a tendency to squamous metaplasia, a n d t h e p r e s e n c e of specific baso philic inclusions in t h e epithelial cells of t h e glands a n d their ducts (Fig. 6 .2). T h e inclusions a r e large a n d readily visible at low magnification. Affected glands occur in irreg ular clusters, and all their epithelial cells tend to contain inclusions. T h e inclusion bodies c a n persist for a month but b e c o m e less n u m e r o u s as t h e course of t h e disease a d v a n c e s . As the inclusion develops, t h e nucleus a n d cytoplasm of the affected cell e x p a n d . T h e cytoplasm b e c o m e s clear and finely granular, a n d cell borders b e c o m e indistinct. The inclusion body fills t h e nucleus except for small p e ripheral indentations, in which minute neutrophilic o r aci dophilic bodies m a y b e found. T h e affected nuclei con tinue to swell, a n d t h e nuclear m e m b r a n e loses its distinctiveness; by this time the inclusion bodies resemble bluish-gray smears among degenerating cytoplasm. Sloughing of the epithelium is followed by liquefaction and t h e accumulation of leukocytic debris. T h e necrotic glands a r e obliterated b y collapse of t h e lamina propria and infiltration by l y m p h o c y t e s . T h e r e is slight vascular reaction in this disease. T h e infiltrating cells a r e predomi- nantly lymphocytes and, although distributed diffusely, they tend to form more dense aggregates in the superficial layers of the lamina propria. Regeneration of glands may take place by downgrowth and differentiation from the superficial epithelium. Although rhinitis is the main manifestation of the infec tion, and dissemination is probably via the nasal route, the systemic clinical signs and presence of inclusion bodies in other epithelial tissues are indicative of a viremic phase. In addition to the nasal location, typical inclusion bodies can be found in lacrimal and Harderian glands, in glomeru lar and renal tubular epithelium, and, sparsely, in hepato cytes, lining cells of sinusoids in liver, adrenal glands and lymph nodes, and other secretory epithelia. The viremic phase may last for 2-3 weeks and is followed by persistent infection in pulmonary macrophages. Piglets which die of the disease do so in the period of generalization. Involvement of sinusoidal and endothelial cells produces petechial hemorrhages, and edema is pres ent in the subcutis and thorax. Focal necrosis occurs in parenchymal tissues, and in the liver it may become mas sive. The piglets are anemic; the presence of inclusion bodies in intravascular and splenic mononuclear cells sug gests that the anemia may be the result of bone marrow injury. Focal gliosis with intranuclear inclusions in scat tered glial cells occurs throughout the central nervous system. Infection in susceptible pregnant sows has been associ ated with fetal mummification, stillbirth, neonatal deaths, and failure of surviving piglets to thrive. Evidence for transplacental infection is, however, circumstantial. swine is characterized by moderate to severe atrophy of the nasal turbinates (conchae) associated with distortion or shortening of the snout in advanced cases. The turbinate atrophy is caused primarily by a protein toxin produced by toxigenic isolates of Pasteurella multocida. The toxin is lethal to mice on intraperitoneal inoculation and is dermonecrotic in guinea pigs following intradermal injection. Most toxigenic isolates of P. multocida are of capsular type D, but some are of capsular type A. Although the P. multocida toxin is the proximate cause of atro phy, colonization of respiratory mucosa by toxigenic P. multocida and its multiplication to produce damaging lev els of toxin require the presence of additional factors. Foremost among these is prior or concurrent infection by Bordetella bronchiseptica which, mainly through the action of its cytotoxin, acts synergistically to increase colonization by the toxigenic P. multocida. Bordetella bronchiseptica alone can experimentally cause only mild, clinically insignificant atrophy. Other factors known to be capable of enhancing the severity of the clinical disease, for instance cytomegalovi rus infection (inclusion body rhinitis) or adverse environ mental and nutritional circumstances, probably also act by facilitating colonization by toxigenic P. multocida. Nu tritional defects, particularly those involving calcium and phosphorus, can also interfere with metabolism of bone at the time when rapid growth and remodeling of turbinates in young pigs make them most susceptible to the effects of P. multocida toxin. Nutritional deficiencies alone, how ever, do not cause atrophic rhinitis. Turbinate atrophy can be caused by intranasal or parenteral injection of purified P. multocida toxin or of toxin produced by recombinant techniques in Escherichia coli. Antibody to toxin is protec tive and is cross-protective between capsular types D and A. The molecular mode of action of the toxin is not known but, by what appears to be receptor-mediated activity, it is capable of experimentally inducing progressive degener ation of conchal cartilage and of osteoblasts and increased osteoclastic bone resorption of turbinates. These are the key features of the naturally occurring disease. Atrophic rhinitis occurs with high incidence in most of the major pig-raising areas of the world. It is an important cause of economic loss because in young pigs, it causes decreased rate of growth and reduced efficiency of feed conversion. The endemic disease is insidious in onset and progression, but there can be acute episodes when a herd first becomes affected. Acute signs are observed in young piglets and consist of rhinitis with sneezing, coughing, and a serous or muco purulent nasal discharge. Large or small flecks of blood may be expelled by sneezing when damage is severe, and occasionally the hemorrhage is profuse. There is not a constant association between clinical signs of acute rhini tis and atrophic changes. Rhinitis occasionally is found not to have resulted in atrophy, at least of a permanent nature, and in some herds a high incidence of atrophy of the turbinates may be present in slaughtered pigs without there having been at any time clinical signs of rhinitis or facial deformity. Facial deformity, which is an expression of severe dis ease in the rapidly growing young pig, is seldom evident before 5-6 weeks of age. It consists of shortening and distortion of the snout and facial bones ( Fig. 6 .3) As a result of the shortening, the overlying skin forms thick transverse folds. Asymmetry of the disease process causes deviation of the snout toward the more severely affected side; when the intranasal lesions are symmetric, the nose may be shortened and turned upward. Characteristically, there is often patchy encrustation of dried tears and dirt just below the medial canthus of the e y e ; this is usually attributed to lacrimal spillage caused by obstruction of the nasolacrimal duct, but increased lacrimation may also play a role. The lesions of atrophic rhinitis range from indefinite to severe, and no clear dividing line separates the normal from the diseased. T h e lesions are most severe anterior to the nasofrontal suture. W h e n mild, they may be detectable only in the ventral scroll of the ventral turbinate, but with increasing severity, gross changes b e c o m e detectable in the entire ventral turbinate, in the dorsal turbinate, and farther back in the nasal cavity until even the ethmoids are involved. The nasal m u c o s a usually has fewer gross changes. It may be edematous and covered by a thin seromucinous exudate on the anterior portions and thick purulent exudate in posterior recesses and cells of the ethmoid, or it may be pale and dry. The grossly detectable changes in the conformation of bones are always of the same t y p e , but there are wide variations in the extent of the lesions. In the least-affected specimens, the ventral scrolls of the ventral turbinates are reduced in size, pliable, and soft. The width of the ventral meatus is increased. This is often accompanied by slight bulging of the nasal septum toward the less-affected side. With progression of the lesions in the turbinates, there is loss of scrolls of the ventral turbinate and then of the dorsal turbinate ( Fig. 6.4) . In extreme cases, nothing remains of the turbinates save for folds of m u c o s a on the lateral aspect of the empty nasal c h a m b e r . T h e b o n e s surrounding the nasal cavity are often thinned. In some animals, espe cially those whose general health is not significantly af fected by the disease and which continue to grow, hyper trophic changes frequently coexist with atrophic changes in the facial bones and rarely with hypertrophic changes in the turbinates. Combined hypertrophic and atrophic changes in the turbinates produce a series of longitudinal folds. H y p e r t r o p h y of the facial bones affects chiefly the dorsal part of the nasal bones so that the conformation is broad and flat rather than narrow and c o n v e x . T h e alveolar processes may also be thickened, although the lateral plates of the maxillae tend to be attenuated. Atrophy of turbinates in response to the toxin can occur at any age but is most severe w h e n it begins in young animals. At this early age, the anterior parts of the conchae still have a core of hyaline cartilage; growth is by endo chondral ossification on the inner or concentric side of the cartilage model and by m e m b r a n o u s b o n e apposition forming radiating trabeculae on the outer or eccentric side. Lamellar bone is present in the more caudal, earlierdeveloped parts of the c o n c h a e . E a c h of these tissues is affected by the toxin after intramuscular injection. It is assumed that the evolution of changes in these hard tissues is the same in the natural disease and in the atrophy pro duced by injected toxin, although the rate of change may be different according to toxin levels. The hyaline cartilage of the rostral extremity of the turbinates disappears quickly. Residual cartilage fails to undergo the hypertrophic sequence and is invaded by fibroblastlike cells and multinucleate cells. Endochondral ossification is suspended as both inner and outer surfaces of cartilage are eroded by chondroclasts. Trabecular bone on the outer surfaces is diminished or absent. The osteo blasts may be normal or show degenerative changes con sisting of aggregated chromatin, irregular folding of nu clear and plasma m e m b r a n e s , and dilation of cisternae of the endoplasmic reticulum. Osteoclast n u m b e r s are in creased, especially on the eccentric surface of the scroll. The inflammatory lesions in the nasal m u c o u s mem branes are usually non-specific and vary according to the stage of the disease. In early stages, there is loss of ciliated and goblet cells and proliferation of cuboidal cells to form layers one to several cells deep. Submucosal glands be come hyperactive and distended with mucus. Neutrophils infiltrate the superficial and glandular epithelium and occa sionally form microabscesses. Subsequently, there is in filtration of the lamina propria by lymphocytes and plasma cells. The only indication of a specific acute infection occurs in piglets from herds where cytomegalovirus infec tion is prevalent. There is no direct correlation between severity of the acute rhinitis and the later development of permanent atrophy of the turbinates. In established cases of atrophic rhinitis, there is chronic nonspecific mucosal inflammation with variation from epithelial ulceration to squamous metaplasia, and atrophy or cystic dilation of the glands within a fibrotic lamina propria. c. ATROPHIC RHINITIS IN OTHER SPECIES Chronic rhini tis with morphologic features similar to those of the por cine disease is occasionally observed in individuals of other species, mainly dogs, and as an endemic disease in some goat herds in Norway. Toxigenic strains of Pasteurella multocida do not readily colonize the normal nasal mucosa of pigs. The bacterial properties which allow colo nization are not known, although apparently they do not include adhesins. Until these properties are known, the different susceptibilities of host species will not be ex plained. The disease in goats closely resembles that in pigs, including a predominance of toxigenic strains in the nasal flora. All toxigenic strains were of capsular type D. Nota bly, there were no inflammatory lesions of significance in the nasal mucosa. 253-265, 1990. Chanter, N., Magyar, T., and Rutter, J. M Streptococcus equi in exudates is very resistant to the external environment and can survive for many months in stables. The initial source of infection, however, is usually a carrier animal or one with active but not necessarily clinically obvious disease. Outbreaks of the disease occur mainly in young animals under crowded conditions. Car rier horses are difficult to detect because shedding of or ganisms is intermittent, and the site of recovery can shift between nasal and pharyngeal regions in a single animal. The pathogenesis of the infection involves epithelial adherence, especially to soft palate and pharynx, and in ternalization of the organism into epithelial cells. There is intense chemotaxis of neutrophils to the mucosa and regional lymph nodes. Smears of pus show short chains of the organism, typically not in leukocytes. The intense chemotaxis is stimulated by factors derived from the alter native complement pathway, which is activated by peptidoglycan of the bacterial cell wall. Surface M protein and hyaluronic acid allow the organism to resist phagocytosis. Hemolysin production is not necessary for pathogenicity, but all strains produce a potent cytotoxin which allows the organism to resist intracellular digestion and to cause rapid degeneration of polymorphonuclear neutrophils. Recovery from strangles confers immunity to a second attack in -70% of horses, the acquired resistance appar ently due to IgA and IgG subclasses produced locally in the nasopharynx. The serum of recovered cases, and of some vaccinated with bacterin-type preparations, con tains complexes of IgA and bacterial M protein, which are probably responsible for the glomerulonephritis and the leukocytoclastic vasculitis which is the basis of complicat ing purpura hemorrhagica. The incubation period of strangles is 3-4 days, although it may be as short as 2 or as long as 15 days. Onset is indicated by fever, slight cough, and nasal discharge. The nasal discharge is bilateral, and in a few days it changes from serous to catarrhal and then purulent. Catarrhal con junctivitis occurs concurrently and, in cases which pursue a typical course, inflammatory swellings of the lymph nodes of the head and neck develop. The submandibular and retropharyngeal nodes are the first and usually the most severely affected. The acute inflammatory swelling is firm, but the nodes begin to fluctuate as liquefaction and suppuration develop. The typical and favorable outcome of the lymphadenitis is for the abscesses to rupture onto the skin 1-3 weeks after onset of infection. Rupture is preceded by depilation and oozing of serum. The dis charged pus is copious, creamy, and yellow-white. Abscessation of lymph nodes is not an invariable feature of strangles, but clinical diagnosis is seldom made in its absence. The nasal lesions are those of a purulent rhinitis but are otherwise nonspecific. Large amounts of creamy yellow pus collect in the folds of the turbinates and may produce temporary distortion. The mucosa is edematous, hyper emic, and occasionally ulcerated. In the typical course of strangles previously described, the outcome is favorable. The course, however, may be either milder or more severe with an unfavorable outcome. In herds of mixed ages, -20% of clinically affected animals will develop complications. In older horses, the course tends to be milder and confined to catarrhal rhinitis and pharyngitis without nodal abscessation, or the nodal ab scesses may become sterile and encapsulated. When the course is severe, infection may spread to the paranasal sinuses and by way of the Eustachian tubes to the guttural pouches to cause chronic empyema of these cavities. Ex tensive cellulitis may develop in the connective tissues of nose, pharynx, or throat. Retropharyngeal abscesses may discharge into the pharynx, allowing pus to be aspirated into the lungs. Metastatic abscesses (bastard strangles) occasionally form in the liver, kidneys, synovial struc tures, and brain. The internal organs most frequently af fected, however, are the mediastinal and mesenteric lymph nodes. Abscesses in mediastinal and mesenteric lymph nodes tend to be very large and, although frank rupture is unusual, the suppurative process can permeate to adjacent serous membranes and cause a purulent pleuritis or peritonitis. Two other important sequelae are pur pura hemorrhagica and local damage to cranial nerves, resulting in laryngeal paralysis (roaring), facial nerve pa ralysis, or Horner's syndrome. 1281-1286, 1989. e. GLANDERS Glanders is an infectious disease caused by a Gram-negative bacillus, Pseudomonas mallei. It is mainly an equine infection, but it does occur occasionally in humans, and it can be acquired naturally by carnivorous animals which eat diseased flesh of horses. Goats and sheep are susceptible to contract infection, but cattle and pigs are not. A variety of other generic names have been used for the organism, most commonly Loefflerella, Pfeif ferella, Malleomyces, and Actinobacillus. The disease in horses is characterized by nodular lesions in the lungs, and ulcerative and nodular lesions of the skin and respiratory mucosa. "Farcy" is the term often applied to the cutane ous lesions. Glanders is, historically, a very old disease and flour ished especially among cavalry horses. Since the advent of motorized vehicles and accurate serological diagnostic procedures, it has virtually or completely disappeared from many countries. It still exists, however, in some parts of eastern Europe and Asia. Pseudomonas mallei is sensitive to the external envi ronment, and infection is acquired directly or indirectly from excretions and discharges of affected animals. In horses, the disease is usually chronic, and the organisms are confined to the lesions and discharges, especially those of the skin and nasal mucosa. In the acute disease, which occurs in some horses and is the usual form in donkeys, the organism is distributed in most tissues and may be excreted in feces, urine, saliva, and tears. Although the most common form of the disease in horses is respiratory, the route of infection is probably oral, because this is the only experimental way to produce the typical chronic respiratory disease; intranasal or intratracheal inoculation reproduces the acute disease. Percutaneous infection can occur, but this is unusual. In the absence of definitive information, it is assumed that the organisms traverse the pharyngeal mucosa, and perhaps the intestinal mucosa, and are conveyed to the lungs where lesions almost always occur. From there, hematogenous spread is believed to result in the nasal, cutaneous, and nodal lesions. This sequence of events is speculative, however, and not entirely satisfying. The chronic syndrome of glanders is frequently divided into nasal, pulmonary, and cutaneous varieties. The division is convenient for description, but the varieties are not distinct. Emphasis may at any time change from one vari ety to another, and the same animal may suffer the three varieties at the same time. Involvement of all three sites is c o m m o n in the acute form of glanders in donkeys and in exacerbations of the chronic disease in horses. Rhinitis in glanders usually c o m m e n c e s as a unilateral nasal catarrh, but the inflammation may be bilateral and also involve the pharynx and larynx. The nasal excretion is copious, purulent, and greenish yellow. It is frequently flecked with blood and fragments of desquamated epithe lium. The typical nasal lesions are multiple small nodules lying in the submucosa and surrounded by a narrow hyper emic halo. E a c h nodule consists of a focus of intense cellular infiltration with an inner core of neutrophils and a periphery of macrophages. The core liquefies, and the overlying m u c o s a may slough. The nodules may be iso lated or semiconfluent with suppurative cores separated by granulation tissue. A discrete slough of the necrotic tissue over individual nodules can occur, leaving a crateriform ulcer which has a sharp margin and a smooth base. The ulcers sometimes perforate the septum in severe cases. N e w generations of nodules develop, ulcerate, and heal irregularly. It is usual to find nodules, ulcers, and white stellate scars mixed together in an affected horse. There is variation from case to case in the n u m b e r of lesions which can be found. In milder cases, a few discrete foci are present in the posterior portions of the nasal cav ity, and the anterior portions show only hyperemia and catarrh. Lymphadenitis of the submaxillary and retropha ryngeal nodes is regularly present. Depending on the age and activity, nodules or scars may be found. W h e n lesions occur on the larynx, they are of the same type as those occurring in the nose. Lesions in the tracheal m u c o s a are usually ulcerative but are occasionally pyogranulomatous nodules. Lesions of glanders can be found in lungs in all but a very small percentage of cases. T h e typical lesion is the nodule, but in some acute c a s e s , there may be a more diffuse pneumonia. The nodules have a miliary distribu tion throughout the lungs, but they are most visible be neath the pleura. They are basically pyogranulomatous lesions, but the relative proportion of exudative and prolif erative c o m p o n e n t s varies. T h e more exudative foci typi cally have necrotic centers composed of karyorrhectic neutrophils. In acute stages, there is hemorrhagic and fibrinous exudation. In more mature lesions, liquefied or caseonecrotic centers are surrounded by epithelioid cells, occasional giant cells, and lymphocytes, which blend with an outer layer of granulation tissue ( Fig. 6 .5A). T h e core may be gritty because of dystrophic calcification, but the salts are deposited irregularly and incompletely. In old lesions, the capsule is thin and fibrous ( Fig. 6 .5B). The more proliferative nodules develop a grayish semitranslucent core of granulomatous tissue consisting of epithelioid and giant cells with an admixture of leukocytes in a fibro blastic stroma. T h e more diffuse lobular pneumonia has In equine farcy, the cutaneous lesions of glanders, the cordlike thickening of the subcutaneous lymphatics has caused them to be referred to as farcy pipes. Chains of nodules (buds), which tend to ulcerate, are distributed along the corded lymphatics ( Fig. 6.6A,B) , and the re gional nodes are enlarged. T h e lymphangitis is purulent, and remarkable only for the unusual degree of leukocytic necrosis. Duval, C. W . , and White, P. C. T h e histological lesions of experi mental glanders. 7 Exp Med 9: 352-380, 1907. Hunting, W . " G l a n d e r s , a Clinical T r e a t i s e . " L o n d o n , H . & W . B r o w n , 1908. M c F a d y e a n , J. G l a n d e r s . 7 Comp Pathol 17: 295-317, 1904. f. MELIOIDOSIS Melioidosis is occasionally k n o w n as pseudoglanders. T h e causative organism is Pseudomonas (Malleomyces) pseudomallei, which is closely related to P. mallei. Geographic strains may differ in virulence, and there are breed differences in susceptibility of sheep and goats. Melioidosis is primarily a disease of rodents, but is occasionally a highly fatal disease of h u m a n s . All domestic species are occasionally infected, sometimes in small out breaks in regions where the infection is endemic. The principal occurrence has been in Southeast Asia, but it is also present in parts of western E u r o p e , the Caribbean, and Australia. Rats have been regarded as the usual source of infection but, since the organism can persist for as long as 30 m o n t h s in soil and water of endemic areas, it is probably an accidental pathogen. Infection can occur through cutaneous w o u n d s , and it can be transmitted by insects. Ingestion is probably the most important natural route of infection. Although the high incidence of disease in confined and intensively managed piggeries suggests respiratory transmission, the sources of infection are likely to be circumstantial, such as a contaminated water supply. The usual course following infection is pyemia followed by localization of the organism and abscessation in a wide variety of tissues, particularly lymph n o d e s , spleen, lung, liver, joints, and central nervous system. Depending on the severity of the p r o c e s s , there may be an acute disease associated with fulminating suppuration or a m o r e indolent one associated with chronic abscessation. Melioidosis in horses can resemble glanders. Melioidosis in dogs may cause dermal abscesses and epididymitis in addition to other organ involvement. In cattle, acute fatal infection, pneumonia, arthritis, placentitis, and endometritis are im portant variants of the disease. Assuming variations in virulence of the organism and of susceptibility of animals, unless localization involves a vital organ, the disease is most likely to be met as an incidental finding at autopsy or at slaughter. Outbreaks of melioidosis, as well as isolated cases, occur in sheep, goats, and pigs, and the infection can be transmitted to these species m o r e regularly than to other domestic animals. Pneumonia and arthritis are c o m m o n in the clinical course of the disease, which otherwise is nonspecific. Goats may develop a chronic infection or recover. T h e lesions are those of pyemia with multiple abscesses in the lungs, regional lymph n o d e s , and spleen and less often in other viscera and joints. T h e splenic abscesses are < 1 cm in diameter, and they project from the surface of the organ (Fig 6.7A ). Larger purulent cav ities, as well as multiple small a b s c e s s e s , occur in the lungs and are associated with focal adhesive pleuritis (Fig. 6.7B) . T h e abscesses are encapsulated and contain a creamy or c a s e o u s , yellow-green p u s . In some c a s e s , there is purulent exudate in the bronchi. E x c e p t for the lamina tion which occurs in old lesions of caseous lymphadenitis caused by Corynebacterium pseudotuberculosis, there is nothing in the morphology of the lesions to distinguish the t w o diseases in sheep and goats. Experimental infections in sheep can p r o d u c e , in addition to the lesions of the natural disease, microabscesses in the brain and lesions in the nasal m u c o s a similar to those of glanders. C o t t e w , G. S. Melioidosis in sheep in Q u e e n s l a n d . acute, contagious disease of cattle caused by bovine herpesvirus-1 (BHV-1) and is characterized by inflamma tory lesions in the upper respiratory tract, trachea, and conjunctiva. Serologically identical virus causes infec tious pustular vulvovaginitis (IPV) and balanoposthitis, but infectious bovine rhinotracheitis (IBR) isolates can be distinguished from those of IPV by molecular analysis. T h e standard method is by comparing D N A fragment pat terns after restriction endonuclease digestion. On this ba sis, IBR isolates are classified as BHV-1.1 and IPV iso lates, as BHV-1.2a or b . Both BHV-1.1 and BHV-2a have been shown capable of causing abortion. The herpesvirus isolates from meningoencephalitis and more generalized infections in young calves were also classified serologi cally as B H V -1 . H o w e v e r , restriction endonuclease D N A analysis and D N A : D N A hybridization have revealed sig nificant differences and led to the meningoencephalitis isolates being designated BHV-1.3 or as a separate vi rus, bovine encephalitis herpesvirus ( B E H V ) . Bovine herpesvirus-1 has also been implicated as a cause of vagini tis and balanitis in swine. On clinical and virologic evidence, IBR in cattle is widely distributed throughout the world, and on serologic evidence, the infection is more widespread than the dis ease. T h e disease occurs chiefly where cattle are crowded, and most outbreaks occur among animals kept in feedlots or indoor fattening p e n s . The disease in dairy cattle is usually milder. The onset in feedlots is usually preceded by introduction of animals from an outside source and, from there on, the pattern is typically that of an epidemic maintained by the continual m o v e m e n t of cattle into and out of the feedlots. The morbidity is high, but many cases are mild and unrecognized. T h e fatality rate is usually low, but it can exceed 30% in exceptional outbreaks. The clinical course is characterized by fever, increased respiratory rate, coughing, and serous nasal discharge. Lacrimation is c o m m o n . If the course is prolonged, the nasal discharge b e c o m e s mucopurulent, and inspiratory dyspnea develops. T h e lesions in typical and uncompli cated cases are those of seromucinous rhinotracheitis and possibly conjunctivitis. In cases of greater severity, which are usually associated with bacterial complications, there is a glairy or mucopurulent exudate with acute diffuse inflammation, and focal hemorrhages, erosions, and ulcer ations. In the most severe cases, and especially in fatal ones, there are widespread fibrinopurulent or fibrinonecrotic m e m b r a n e s on nasopharyngeal, laryngeal, and tra cheal surfaces (Fig. 6 .8A). T h e region of most severe damage varies, but in field outbreaks the necrotizing and diphtheritic inflammation is often most dramatic in the larynx and adjacent pharynx and trachea ( Fig. 6 .8B). Bac teria contribute to the severity of these lesions, particu larly Pasteurella spp., Mycoplasma spp., and Fusobacterium necrophorum. The histologic changes can be anticipated from the gross Infectious bovine rhinotracheitis. Inflamed mu cous m e m b r a n e s of nasal cavity partially covered by fibrinopuru lent e x u d a t e . appearance of the lesions. In mild cases, there is serous to mucopurulent inflammation with little epithelial necro sis. In fatal cases, the emphasis is on extensive epithelial necrosis and formation of a surface layer of admixed fibrin and necrotic debris ( Fig. 6.8C ). There is an intense vascu lar, neutrophilic, and mononuclear response in the under lying viable tissue. Acidophilic intranuclear viral inclusion bodies, best demonstrated after use of acid fixatives, can sometimes be found in infected cells. Because they appear for only a transient period -2-3 days after infection, they are mostly seen in experimental situations and are of little practical diagnostic value. They can rarely be detected in autopsy samples from field c a s e s , although they occasion ally persist long enough to be found in bronchial or alveolar epithelium. Assessment of the role of BHV-1 in causing pneumonia is complicated because in most descriptions of both the experimental and naturally occurring respiratory form of the disease, it is impossible to distinguish the effect of the virus itself, its role in predisposing to severe secondary bacterial pneumonia, and the confounding effect of preex isting pneumonic lesions which are c o m m o n in calves or feedlot animals. It seems fairly safe to conclude that the lung is not significantly affected in the mild viral disease. At the other end of the disease spectrum, severe viral infection seriously impairs pulmonary defenses and leads to the extensive secondary bacterial p n e u m o n i a usually present in fatal cases. T h e m e c h a n i s m s by which viral damage and its amplification by various mediator cascades predispose to secondary bacterial infection are not k n o w n in detail. S o m e idea of the complexity of factors is given subsequently in Section V I , F , 1 on b r o n c h o p n e u m o n i a . Pasteurella spp. are usually involved, and the lungs com monly show severe fibrinous p n e u m o n i a with or without pleuritis (see p n e u m o n i c pasteurellosis, in Section V I , H , 2 of this chapter). A n additional feature is interstitial e m p h y sema, which frequently follows the labored respiration caused by upper and lower airway obstruction. T h e most severe viral lesion, in which secondary organisms may not play a significant role, is in fulminating infections. In these instances, there is a severe, necrotizing bronchitis and bronchiolitis, and there is extensive serofibrinous flooding of alveoli. The pattern of generalized disease in newborn calves is spectacular. Affected calves are usually < 1 month of age and are part of a herd in which infectious bovine rhinotra cheitis affects all age groups. The calves are febrile and have serous ocular and nasal discharge, inspiratory diffi culty, anorexia, depression, and sometimes a laryngeal stertor suggesting laryngeal necrobacillosis. There is acute rhinitis and erosive pharyngitis, with intense hyperemia under the eroded areas and yellowish pellicles of epithe lium at the margin. The epiglottis may be similarly in volved, but the more distal parts of the respiratory tract remain unaffected. The most prominent changes are in the epithelium of the esophagus and forestomachs, which appear as if plastered with clumps of curdled milk. This caseous material is adherent necrotic epithelial debris. The necrosis involves the epithelium to its full depth, with intense neutrophil infiltration. Surviving epithelial cells and those at the margins of the lesions contain inclusion bodies in their vesicular nuclei. Additional lesions of sys temic viral action include acute lymphadenitis with focal cortical necrosis, especially in nodes draining the upper respiratory tract. Necrotic foci can also be seen in the kidney, spleen, and liver. Miliary white necrotic foci 1-2 mm in diameter are particularly prominent in the liver. They are either uniformly distributed or concentrated in the right lobe. When abortion is caused by the virus, the fetuses are edematous, and advanced autolysis indicates death of the fetus perhaps 2 days before abortion. There are no charac teristic gross lesions, but microscopic lesions occur in many parenchymatous organs and lymph nodes as well as in the placenta. They consist of foci of intense necrosis and leukocytic infiltration, and are most prominent and consistent in the liver, where they may be confused with lesions of listeriosis. Specific inclusion bodies often are not found in autolyzed fetuses. Vaccinal strains of virus produced in cell cultures are as effective as field virus in causing abortion, and the natural infections may not be preceded or accompanied by signs of rhinitis or other illness. It appears that cows pregnant <~5 months are less likely to abort following exposure to bovine herpesvirus-1. Feline viral rhinotracheitis is characterized by fever, sneezing, salivation, oral respiration, coughing, and se rous to mucopurulent nasal and conjunctival discharges. Most cats recover in 7-14 days, but mortality can be high in young kittens or debilitated animals, including those whose immune system is depressed by feline immunode ficiency virus or feline leukemia virus infection. The distribution of gross lesions corresponds to the predilection sites for viral replication, namely the epithe lium of nasal passages, pharynx, soft palate, conjunctivae, tonsils, and, to a lesser extent, trachea. The initial serous inflammation becomes mucopurulent or fibrinous within a few days. Lethal cases usually have extensive fibrinous rhinotracheitis, possibly with extension to an acute viral or secondary bacterial pneumonia. Tonsils are enlarged and often petechiated. The regional lymph nodes are also usually enlarged, reddened, and edematous. Ulcerations of the tongue are seen rarely and only in severely affected cats. This contrasts with the frequent finding of vesicular to ulcerative lesions on tongue, hard palate, or nostrils of cats with calicivirus infection. The ocular involvement is usually limited to purulent conjunctivitis, but it can pro gress to ulcerative keratitis. Microscopically, the respiratory and conjunctival le sions are associated with intranuclear viral replication causing epithelial cell death and the multifocal necrosis characteristic of active herpesvirus infection. The virus is virulent enough in its own right to cause extensive lesions, but mixed secondary bacterial infection by organisms such as Pasteurella multocida, Bordetella bronchiseptica, Streptococcus spp., and Mycoplasma felis enhance the suppurative response. Most active viral replication and cell necrosis occur from 2 to 7 days after infection, and during this period, herpesvirus inclusions are present in the nuclei of affected cells. They are typically large, acido philic, and surrounded by a clear halo (Cowdry type A). Fixation in acid fixative such as Bourn's solution is best for their demonstration. They may be found in lesions from cats dying of the disease, but they are rarely detected beyond 7 days after infection and cannot be relied on for diagnosis. Cells bearing inclusion bodies become large and pale with a perinuclear clear zone, or ballooned and granular. There is loss of epithelial organization, and the disrupted epithelium is soon eroded or ulcerated. An acute inflammatory reaction develops with exudation of fibrin and many neutrophils. Focal necrosis accompanied by acute inflammation may be found in tonsils and local lymph nodes. Necrosis and resorption of turbinates have also been described. Pulmonary involvement is uncommon except in fatal cases. In fulminating cases of viral infection, there is wide spread multifocal necrotizing bronchitis, bronchiolitis, and interstitial pneumonia, with extensive serofibrinous flooding of airspaces. In other instances, there is a second ary bacterial bronchopneumonia. Naturally occurring infection by feline herpesvirus-1 rarely causes manifestation of the wider tissue tropisms seen with other members of the family, such as BHV-1, but they occur occasionally. The virus is suspected of being a cause of abortion, but this has been difficult to prove in natural outbreaks. Experimentally, it has been possible to produce abortion and generalized neonatal in fection by intravenous or intravaginal inoculation of the virus into pregnant cats. Necrosis accompanied by inclu sion bodies has also been found in sites of osteogenesis in a wide variety of bones of kittens after intravenous inoculation. Degeneration of olfactory nerve fibers and focal lymphocytic infiltration of the olfactory bulbs have occurred in experimentally infected, germ-free cats, but the extent of lesions in the brain has not been properly documented. Feline calicivirus infection is the other main component of the feline respiratory disease complex. Although clini cal signs overlap with those of feline herpesvirus infection, and occasionally both viruses occur together, calcivirus has more affinity for epithelium of the mouth and lung than for that of the upper respiratory tract and conjunctiva. The tendency of virulent strains of calicivirus to affect lungs is discussed with pneumonia. The cat-adapted strain of Chlamydia psittaci (C. felis) is mostly a cause of persistent conjunctivitis analogous to trachoma in humans. The disease is misleadingly called feline pneumonitis, since mild or inapparent broncho-interstitial pneumonia is the only manifestation of pulmo nary infection. Sporadic instances of what probably is an allergic rhini tis are observed occasionally in dogs, cats, and horses. Clinically and in its response to treatment, the disease resembles hay fever in humans. It is diagnosed on the basis of oculonasal discharge, sneezing, nose rubbing, head shaking, and perhaps epistaxis, and the presence of eosinophils in nasal exudate or lavage fluid. There is no definitive information on either the pathologic or immuno logic basis of the condition. Frequently in cattle, and occasionally in sheep, there is a seasonal rhinitis, which in its clinicopathologic features is consistent with an allergic pathogenesis. Some evidence has been provided that affected cattle are allergic to pollen antigens. The disease has been reported mainly from Aus tralia, but it does occur elsewhere. It is more common in Channel Island breeds. A familial predisposition in cross bred cattle has also been reported. It occurs chiefly in the summertime when the pastures are in bloom and affects individuals or most of a herd or flock. Affected animals have nasal discharge, lacrimation, sneezing, and evidence of nasal itching. The nasal mucosa is pale and thick from edema fluid, and mucosal erosions may be visible in the anterior nares. The exudate is at first serous but later becomes mucopurulent or contains floccules of detritus and mucus. Eosinophils are a prominent component of the exudate. Histologically, the surviving nasal epithelium is hyper plastic or eroded and is infiltrated by eosinophils. The glandular epithelium can be hypertrophied, and mucus is produced in excess; if the orifices of excretory ducts are occluded by the superficial reaction, the mucus accumu lates in the ducts and eventually lifts off the debris on the surface. In more severe cases, in which there is extensive superficial diphtheresis, many of the small mucosal vessels show fibrinoid necrosis. Nasal granuloma is generally considered to be a more chronic form of allergic rhinitis. The affected mucosa is mainly in the posterior portion of the nasal vestibule and the anterior region of the nasal septum and ventral meatus. In long-standing cases, the lesions extend further caudally to involve the posterior nasal cavity and even the larynx and proximal trachea. The hyperplastic epithelium is gran ular or has multiple nodular projections covered by intact epithelium (Fig. 6 .9A). Histologically, the nodules typi cally consist of hyperplastic and metaplastic epithelium covering a superficial edematous lamina propria with a central core of inflammatory granulation tissue (Fig. 6.9B) . Nonkeratinizing squamous epithelium usually cov ers the surface of the nodules. Goblet cell hyperplasia is more pronounced in the terminal portions of nasal gland ducts, which often form the lateral boundaries of the nod ules. Active lesions have prominent eosinophil infiltration of the superficial lamina propria and epithelium. They are associated with increased n u m b e r s of submucosal mast cells. Vascular proliferation, fibroplasia, and accumula tion of mostly lymphocytes and plasma cells in the cores of nodules are features of chronicity. Correlation of acute inflammatory events with degranulation of mast cells and accumulation of eosinophils is strong evidence that an immediate (type I) hypersensitivity is involved. Further support for this hypothesis has been provided by experi mental production of closely similar lesions by repeated intranasal exposure of cattle to powdered ovalbumin. In view of the varied c o m p o n e n t s of chronic lesions, how ever, it is probable that other classes of hypersensitivity (types III and IV) also play some role. It is believed that the condition is due to hypersensitivity to a variety of plant pollens or fungal spores. Because there appears to be a familial predisposition in Jersey cattle and to a limited extent in other cattle, the existence of susceptible atopic animals has been proposed. T h e condition is therefore sometimes referred to as atopic rhinitis. L e s s c o m m o n l y , nasal granulomas in cattle are attribut able to fungal infection. They also occur mostly in the anterior portion of the nasal cavity but tend to be larger polypoid m a s s e s . They frequently have yellow-green cores associated with massive eosinophil accumulation. Histologically, c o m p o n e n t s of the lesions are similar to those previously described for the chronic allergic granu lomas, but hyphae and chlamydospores of fungi sur rounded by macrophages, giant cells, and eosinophils are present. Various fungi normally saprophytic on plants have been isolated. It is tempting to speculate that the mycotic granulomas represent the small proportion of the more nonspecific allergic granulomas in which the caus ative allergen is able to vegetate. Local damage to nasal m u c o s a or reduced defenses because of impaired immune responses or other systemic influences make the nasal cavity prey to occasional oppor tunistic fungal or yeast infections. T h e range of fungi var ies with species of animal affected. Aspergillus fumigatus is the c o m m o n e s t cause in the dog, but it is rare in other species. T h e usual lesion is a chronic, necrotizing to granulomatous reaction producing large amounts of friable exudate, which often consists mainly of necrotic fungal h y p h a e . Viable surface hyphae can sometimes be seen grossly as a blue-green mat. The lesion is slowly aggressive and causes destruction of turbi nates and sometimes the nasal septum, but it rarely erodes through the nasal, maxillary, or palatine bones. As with other fungal infections, there is usually suspicion of predis position by localized or generalized impairment of immu nity. Similar lesions can be caused by Penicillium spp. Cryptococcus neoformans is the most frequent cause of granulomatous rhinitis in cats and also occurs sporadi cally in horses and dogs and other species. T h e lesion in cats is more gelatinous than granulomatous, since it consists mainly of massed organisms with their abundant polysaccharide capsular material ( Fig. 6.10A ,B). Reaction by macrophages, epithelioid cells and lymphocytes is usu ally minor. Impaired immune responsiveness and ability of the capsular polysaccharide to cause antibody masking and immune paralysis are reasons for the lack of inflam matory response. T h e lesions are polypoid nodules or more widely space-occupying and slowly destructive masses. In cats, there is often facial swelling. Extension through the bony boundaries of the nasal cavity can in volve skin and possibly oral m u c o s a . Local extension occurs to eyes or brain, and occasionally there is wider dissemination to local lymph nodes and lung or a variety of visceral organs (see Pulmonary M y c o s e s , Section V I , H , 6 of this chapter). Actinomycosis and actinobacillosis, the latter in sheep especially, sometimes involve or are limited to the nasal cavities. The incidence of nasal and facial actinobacillosis in sheep is highest in drought-feeding conditions, probably as a result of injury to the lips. C a s e o u s fistulating tracts T h e y are limited to w a r m climates and are caused by fungi in the Conidiobolus or Basidiobolus genera. Conidiobolus incongruus, a c o m m o n soil saprophyte, is often responsible for destructive granu lomatous rhinitis in Australian sheep in seasons of unsea sonable s u m m e r rains. T h e r e is massive swelling and dis tortion, usually unilateral, of the maxillary region. There is extensive destruction of turbinates, palate, and facial bones by necrotizing and granulomatous inflammation in which the fungus is easily d e m o n s t r a t e d . T h e disease occurs in horses and cattle, and to a lesser extent in dogs, goats, and waterfowl. It also occurs in h u m a n s , sometimes in a more generalized form. T h e disease is endemic in India and Sri L a n k a , and it is sporadic in some other tropical and subtropical countries. Rhino sporidium seeberi grows in vitro only in cell cul tures. Its mode of transmission is u n k n o w n , and knowl edge of its life cycle is sketchy. The definitive stage is the sporangium, which has a diameter of 100-400 pm and is visible to the naked eye as a white spot in the lesions or squash preparations. T h e sporangia have thick, doublecontoured, chitinous walls and contain n u m e r o u s spheri cal sporangiospheres ~7 pm in diameter. T h e mature spo rangium releases the sporangiospheres into tissue or into the nasal discharge, and these in turn form new sporangia to complete the cycle. The source of the organism is u n k n o w n ; the only recog nized association of infection is with proximity to water. Initiation of the disease is thought to be influenced by local trauma to the nasal m u c o s a ; an association has been observed b e t w e e n rhinosporidiosis and the nasal lesions produced by Schistosoma nasalis, as well as with punc tures of the nasal septum for nose leads in draught oxen. T h e lesion is a polyp, usually single and unilateral. T h e polyps range from sessile to pedunculated and cauliflow erlike. They vary in size up to a diameter of 2 -3 cm. They are soft, pink, and bleed easily b e c a u s e of their insubstantial m y x o m a t o u s nature. On section, the sporan gia may be visible grossly. Histologically, the bulk of the polyp consists of a stroma of fibrous or fibromyxoid tissue covered by usually intact epithelium. T h e organisms are present in the stromal tissues as spherical bodies of various sizes. There is scant reaction to t h e m except w h e n sporan gia rupture. T h e n there is a granulomatous and occasion ally a neutrophilic r e s p o n s e . The larvae of a number of flies of the family Oestridae are parasites of nasal cavities of domestic animals. Cephalopina titillator deposits its larvae in the nasal passages of camels. Species of the genus Cephenomyia are the head bots of deer. Rhinoestrus purpureus, the Russian gadfly, is parasitic in horses. Its larvae can also be found in the conjunctival sac. The life cycles and effects of each of these parasites are similar to those of their most ubiquitous relative, the nasal bot of sheep, Oestrus ovis. The first-stage larvae of Oestrus ovis are deposited by the flies on the nares, and molt twice as they migrate through the nasal passages. Larvae which find their way through small openings into sinuses or recesses of turbi nates are unable to leave after they have grown, so they remain and eventually die there. Development in the nasal passages can take as long as 10 months, although larvae deposited early in summer are able to mature in that sea son. Pupation occurs on the ground. The larvae attach themselves to the mucous membrane by their mouth parts. They produce mucosal defects at the points of attachment and, since the cuticle is spinous, a more general irritation as they move about. Affected sheep develop a catarrhal rhinitis with a sometimes copi ous discharge. Irritation of the mucosa of the sinuses, especially the frontal, can cause a gelatinous hypertrophy of the mucous membrane, which may almost obliterate the sinus. Apart from persistent annoyance and the debil ity that this may cause, there are seldom untoward effects of the parasitism. Sometimes larvae penetrate the cranial cavity, and secondary bacterial infections spread from the olfactory mucosa to the meninges; such complications are rare. Mild infestations of Oestrus ovis occur in goats pastured with affected sheep. The cause is Linguatula serrata, a tongue-shaped para site considered by most to be a degenerate arthropod. Males are ~2 cm in length and females, 10-12 cm; the parasite has cosmopolitan distribution. The definitive hosts are carnivores, but in aberrant parasitisms, herbi vores and humans may be host to the final stage. Herbivo rous animals are the intermediate hosts, and the nymphs can be detected in their mesenteric lymph nodes. Carni vores are infected by eating the infected viscera of herbi vores, and the nymphs migrate to the nasal passages and mature. The parasites may be found anywhere in the nasal cavity, and occasionally they find their way into the para nasal sinuses or pass via the Eustachian tube to the inner ear. They lie on the surface of the nasal mucosa and produce, at most, nasal irritation and a catarrhal to lightly bloodstained exudate. The gravid females discharge a large number of eggs, which are removed by sneezing. The larvae develop in the alimentary tract of the intermediate host and migrate to the mesenteric nodes and other organs where they encyst and develop into the infective nymphs. The cysts are com mon in mesenteric nodes of cattle and sheep in some countries. They appear as small cysts containing brownish fluid; older lesions may calcify and resemble tubercles. Schistosoma nasalis, a cause of granulomatous rhinitis in cattle, goats, and horses in India, is described with other species of the genus in The Cardiovascular System (Volume 3, Chapter 1). The only other trematode that is normally parasitic in the upper respiratory tract of animals is Troglotrema acutum, a European parasite of mink, skunks, and foxes. The first and second intermediate hosts are snails and frogs, respectively. The adult parasites oc cur in the paranasal sinuses. In foxes, they are attached to the mucous membrane. In mink and skunks, however, they lie in cysts beneath the mucosa. The cysts, which also contain the eggs, are formed by suppurative granulation tissue. The reaction extends to cause a local rarefying osteomyelitis which may eventually perforate and release purulent discharge into the cranial cavity, into the nasal cavity, or to the exterior. The larvae of the genus Habronema may be deposited by flies in the anterior nares. The larvae subsequently burrow through the skin and produce granulomas similar to those of cutaneous habronemiasis. Capillaria aerophila, whose final habitat is the tracheobronchial system of carnivores, is found occasionally in the nasal passages and frontal sinuses. The leeches Limnatis nilotica and L. africana are taken in while drinking and attach to the mucosa of the pharynx and nasopharynx. They suck large quantities of blood, but the emergency caused by their presence depends on the development of large edematous swellings in the affected areas, which lead to dyspnea and, in severe cases, asphyxiation. The nematode Syngamus nasicola is found in the nasal passages of ruminants in tropical countries. The mite Pneumonyssoides (Pneumonyssus) caninum is occasionally found in the nasal passages and sinuses of dogs. It is usually an incidental finding not associated with signs or development of lesions, but there are occasional reports of the mites causing catarrhal rhinitis and sinusitis with sneezing, and one in which they were associated with bronchitis. With the exception of endemic ethmoidal tumors to be described subsequently, primary sinonasal tumors are uncommon. They occur frequently enough, however, to be an important entity in dogs and, to a lesser extent, in cats and horses. There is no clear relationship between frequency of nasal tumors in various breeds of dogs and lengths of their noses. The breeds with significantly in creased risk, such as collie and German shepherd, do have long noses, however, and this has led to the generalization that dolichocephalic breeds as a whole are at greater risk. Origin from the nasal cavity is usual in dogs and cats, but in horses tumors of the paranasal sinuses arise almost as frequently as those from the nasal cavity. Any of the tissues forming the lining or present in the boundaries of the nasal cavity and sinuses can give rise to either benign or malignant tumors. In general, most are carcinomas, followed in decreasing frequency by sarcomas of cartilage, fibrous tissue, or bone ( Fig. 6.11 ). The precise mix of types varies according to species. Squamous cell carcinomas predominate in the cat and horse. In the cat, a large proportion originate from the nasal vestibule, whereas in the horse the maxillary sinus is a common site ( Fig. 6.11 A) . It is speculated that the latter may arise from epithelial remnants in dental alveoli. Transitional carcinomas are the most common in dogs, with lower numbers of squamous cell carcinomas ( Fig. 6 .1 IB), adenocarcinomas, and undifferentiated carcino mas occurring in about equal frequency. Transitional carcinomas are so called because they as sume the stratified cuboidal appearance of transitional epithelium ( Fig. 6.11C ). Because of their characteristic appearance they are sometimes referred to as respiratory epithelial carcinomas and, in the literature on human nasal tumors, they are often classified as nonkeratinizing squa mous cell tumors. Transitional carcinomas typically con sist of thick stratified layers of mostly cuboidal cells with rounded nuclei, indistinct cell borders, and a distinct base ment membrane beneath the layer of neoplastic cells ( Fig. 6 .1 ID). Large transitional carcinomas have complex in folding or pleating of the thick epithelial bands separated by delicate fibrovascular septa. Small microcysts are sometimes present within the epithelial layers. Because the microcysts have a resemblance to glandular acini, their very obvious presence can lead to transitional carcinomas being classified as adenocarcinomas. Adenocarcinomas, however, have a predominance of papillary fronds and glandular acini formed by a single layer of cuboidal to tall columnar cells with a basement membrane, unlike the microcysts of the transitional tumor, which are within a thick layer of tumor cells. Mucin-filled acini are a fairly common feature of adenocarcinomas. Adenoid cystic carcinomas are rare tumors with a multi lobular organization and at least some lobules with a char acteristic striking cribriform pattern. Possibly these tu mors arise from salivary gland tissue in the soft palate rather than from nasal epithelial structures. Undifferentiated carcinomas are mostly solid tumors in which there are large packets or nodules of round to polygonal cells with no discernible pattern. Unless multi ple sampling reveals regions with a pattern resembling one of the more differentiated types of carcinoma, special methods are needed to separate these tumors from others such as olfactory neuroblastomas, amelanotic malignant melanomas, lymphoreticular tumors, and poorly differen tiated mast cell tumors. Carcinomas with mixed phenotypic expression are fairly common, especially if multiple sections are exam ined. Transitional carcinomas sometimes have scattered foci of squamous metaplasia or adenocarcinomatous re gions. Mucoepidermoid carcinomas have mucin-filled aci nar components and foci with usual features of squamous cell carcinoma. Both glandular and squamous elements must fulfill criteria for malignancy. The olfactory neuroblastoma (esthesioneuroblastoma, esthesioneuroepithelioma) is a rare tumor which mostly arises in the ethmoturbinate region of the caudal nasal cavity. Penetration of the cribriform plate and into the cerebral cortex is commonly observed. Most of the re ported tumors have occurred in cats. It is unclear whether they arise from one or more of olfactory neuroepithelial cells, remaining neural crest cells, or local c o m p o n e n t s of the dispersed neuroendocrine system. Despite some morphologic variation, the tumors are typically highly cel lular and consist of a uniform population of round to elon gated cells with moderately dense nuclei and small a m o u n t s of cytoplasm. An important diagnostic feature is the presence of palisading around vessels and rosette formation. In the absence of these features, the olfactory neuroblastoma is not distinguishable on routine examina tion from lymphoreticular tumors or undifferentiated tu mors of various origins. Definitive diagnosis, in any event, requires ultrastructural and immunocytochemical exami-nations. The presence of feline leukemia virus in feline olfactory neuroblastomas raises questions concerning the possible causative role of the virus. In dogs, paranasal meningiomas are uncommon tumors which develop as intranasal masses replacing ethmoturbinates and the crib riform plate and usually invading the olfactory region of the brain. The tendency of the stroma of large, more rapidly grow ing sinonasal tumors to become edematous can result in difficulty in distinguishing the more undifferentiated carci nomas and sarcomas. Regardless of histogenetic type, malignant nasal tumors tend to be soft, pale, and fleshy to friable masses which slowly invade and destroy adjacent structures but rarely metastasize. Endemic, or clustered, occurrence of tumors of the ethmoturbinate region in animals has been recognized in many countries for most of the century. Clustered cases have been reported in sheep from Germany, Spain, Can ada, France, and the United States of America; goats from India, Spain, and France; cattle from Scandinavia, Brazil, India, and South Africa; pigs from Brazil, India, and China; and horses from Scandinavia. The endemicity de pends on the observations that multiple cases occur in a few flocks and herds and may continue to occur over several years, and that more than one species can be affected on individual farms. The incidence patterns en courage the view that the neoplasms are caused by a virus, and success has been claimed for experimental transmis sion in sheep. Viral particles which structurally resemble retroviruses (type C particles) have been demonstrated electron-microscopically in the tumors from cattle, goats, and sheep, but a role for these viruses is not established. In view of the fact that jaagsiekte (pulmonary adeno matosis) in sheep is caused by a retrovirus, the virus must be considered a candidate. The tumors in sheep are adenopapillomas or adenocar cinomas, and arise from the olfactory mucosa of the turbi nate region. Ultrastructural evidence indicates their origin from sustentacular cells of olfactory mucosa or the dark cells of Bowman's glands. Histologic descriptions are con sistent for the several species. The tumors are locally aggressive and destructive space-occupying lesions. Me tastases to regional lymph nodes are reported in cattle. The pharynx, being common to upper respiratory and alimentary systems, shares the misfortunes of both. Be cause of the complicated organogenesis of the region, various congenital malformations are occasionally en countered. Most attention is drawn to defects in the dog and horse. In the dog, the excess of soft tissue over the skeletal framework, which occurs in brachycephalic breeds, leads to a variety of conditions of which excessive length of the soft palate, eversion of laryngeal saccules, and laryngeal collapse are most common. In the horse, complications are signaled by exercise intolerance and associated noisy respiration. Subepiglottic cysts, believed to arise from thyroglossal duct remnants, and entrapment of the epiglottis appear to be most frequent. Entrapment of the epiglottis below the aryepiglottic fold in horses is usually associated with congenital hypoplasia of the epiglottis or acquired shortening or distortion of the struc ture. A short epiglottis also predisposes to dorsal displace ment of the soft palate, and sometimes epiglottic entrap ment and dorsal displacement of the palate occur together. A posterior diverticulum of the pharynx lies immedi ately dorsal to the esophagus in pigs. In young pigs, awns of barley and similar foreign materials occasionally lodge in the diverticulum and cause inflammation. The local reaction may cause dysphagia and death from starvation. In some cases, the pharyngeal wall is perforated, and an ultimately fatal cellulitis spreads down the fascial planes of the neck. Perforation of the posterior dorsal wall of the pharynx by drenching guns occurs in sheep and is usually fatal. Pharyngeal inflammation is a part of inflammatory dis eases affecting the upper respiratory system, upper ali mentary system, or both. These have been covered else where. An entity deserving of brief mention here is equine chronic pharyngitis with lymphoid hyperplasia. It is de tected mostly by endoscopy in Thoroughbred race horses <5 years of age. In its most severe manifestation, there are polypoid projections in the dorsolateral boundaries of the pharynx with prominent white plaques or nodules representing lymphoid aggregates. The extent of lymphoid hyperplasia found in biopsies sometimes raises the suspi cion of neoplastic proliferation, but follicular structure is retained, and there is a predominance of mature lympho cytes. It is presumed to be due to continued lymphoproliferative stimulus by a combination of persistent bacterial agents, possibly aided by excessive drying or other fac tors, such as viral infections, leading to reduced local defenses. Streptococcus zooepidemicus and Moraxella spp. have been linked to severe grades of involvement. Equine lymphofollicular pharyngitis is the equine analog of adenoids in children. The guttural pouches of Equidae are ventral diverticula of the Eustachian tubes. They tend to become involved in inflammatory processes in analogous fashion to the para nasal sinuses. Complications differ, however, because se vere guttural pouch inflammation can extend to involve nearby cranial nerves (VII, IX, X, XI, XII), vessels, and the cranial sympathetic trunk, or even spread to adjacent bones, middle ear, brain, or atlanto-occipital joint. Suppu rative inflammation leading to empyema occurs mostly after upper respiratory infections, particularly with Strep tococcus equi or other streptococci. Fibrinous or fibrinonecrotic (diphtheritic) inflammation is usually associated with fungal infection, generally Aspergillus spp., particu larly Aspergillus nidulans, and hence is commonly re ferred to as guttural pouch mycosis. Fibrinonecrotic in flammation is highly suggestive of, but not pathognomonic for, fungal infection unless there is visible evidence of mycelial growth. Because the fibrinonecrotic inflamma tion extends deeply, and fungi when present can fre quently invade vessels and other structures, severe com plications are much more likely to follow than from guttural pouch empyema. Examples are thrombosis, aneu rysm formation, and rupture of the internal carotid artery with epistaxis, ischemic lesions, or osteitis, and fusion of stylohyoid and petrous temporal bones. A less common condition is guttural pouch tympany. This is seen mostly in young animals, and the accumulation of air is presumed to be due to valvular action of the nasopharyngeal orifice of the Eustachian tube. Tumors of the guttural pouches are rare, but when encountered are most likely to be squa mous cell carcinomas. Pharyngeal tumors are discussed with neoplasia of the mouth (The Alimentary System, Chapter 1 of this volume). Congenital anomalies of the larynx are rare. Hypoplasia of the epiglottis has been observed in horses and swine. Partial or complete agenesis of the trachea is a rare finding. Tracheal hypoplasia characterized by reduction in the lu minal diameter of the entire trachea, sometimes associated with bronchial hypoplasia, occurs in dogs. The higher frequency in English bulldogs indicates the possibility of an inherited basis. Malformations of the cross-sectional shape, mostly in the form of tracheal collapse, are im portant in the dog and occur in the horse, cow, and goat. Tracheal collapse in dogs occurs principally in miniature breeds. The trachea becomes flattened dorsoventrally. The cartilages form shallow arcs, and the dorsal tracheal membrane is widened and flaccid. The membrane is thin in uncomplicated cases but becomes thickened when there is chronic or periodic acute tracheitis. These are frequent complications of the mechanical obstruction. The nature of the basic defect is still unclear. It may be a manifestation of a more generalized chondrodysplasia in toy breeds. A major feature is focal hypocellularity of cartilage and areas of replacement by fibrous tissue. Reduction of chondroitin sulfate and calcium are associated with reduction in den sity of chondrocytes. Thus far, however, the basic defect has not been identified. In horses, lateral compression of the trachea produces the so-called ''scabbard'' trachea. In this species also, a scroll-like curling may affect the ends of the cartilages. Acquired malformations of the trachea are caused by external pressure, in most cases from enlarged thyroid glands or regional lymph nodes, or inflammatory or neo plastic lesions within the wall. Unilateral or bilateral paralysis of the larynx is the most c o m m o n cause of abnormal respiratory noise (roaring) in horses. T h e condition is almost always a left-sided hemi plegia and is due to degeneration of the left recurrent laryngeal nerve. Resulting denervation atrophy affects all intrinsic laryngeal muscles supplied by this nerve, but not all are affected equally. The most obvious atrophy occurs in the cricoarytenoid muscle, which may be reduced to fascial r e m n a n t s . Atrophy of the other muscles is less severe and is indicated by pallor and a reduction in size. T h e cricothyroid muscle, which is supplied by the cranial laryngeal n e r v e , is the only intrinsic muscle not affected. The cricoarytenoid muscle is the main abductor of the larynx. As a result of its paresis and atrophy, the left arytenoid cartilage sags into the lumen, thus interfering with airflow, particularly during the inspiration associated with severe exercise. In cases detected clinically, microscopic examination reveals severe loss of myelinated fibers in middle and distal portions of the left recurrent laryngeal nerve. Less obvious loss occurs in subclinical cases. Ultrastructural features indicate progressive loss of fibers in the left recur rent nerve accompanied by chronic demyelination, remyelination, and abortive regenerative attempts. Similar but milder changes can be detected electron-microscopically in the distal right recurrent nerve. The reasons for the axonal disease are still disputed. The axons in the left recurrent laryngeal nerve are much longer than those in the right recurrent nerve, and this presumably makes them more susceptible to damage. T h e extent to which damage is caused by traumatic interruption of axoplasmic flow, neuritis by extension from guttural pouch disease, vitamin deficiency, or neurotoxins has still to be established. It is unlikely that there is a single cause, as evidenced by the circumstantial implication of delayed neurotoxicity by oral haloxon administration as a cause in Arabian foals. An other organophosphate, trichlorfon, also is linked circum stantially with an incident of left recurrent laryngeal nerve degeneration in horses. Denervation atrophy of laryngeal muscles occurs occa sionally in dogs, mostly in old, large, or giant b r e e d s , and particularly in males. It is usually bilateral. T h e causes are not clear, but it can be associated with lesions in the recurrent laryngeal nerves or be part of generalized neuro muscular disease. Occasionally it is secondary to hypothy roidism. T h e condition appears to follow a hereditary de generation of the nucleus ambiguus in the Bouvier des Flandres. Laryngeal paralysis occurs rarely in the cat. Active hyperemia occurs in acute inflammation, which is c o m m o n . Laryngeal hemorrhages particularly affect the mucous m e m b r a n e on the dorsal surface of the epiglottis and occur in many septicemic diseases. They are of some diagnostic significance in salmonellosis of swine and hog cholera. The hemorrhagic speckling of the tracheal mu cosa in slaughtered cattle is produced by small extravasa tions in the submucosal lymphoid follicles. In cattle that die with severe dyspnea, and to a lesser extent in sheep, these follicular hemorrhages spread in a linear form. In severe c a s e s , the whole m u c o s a is red-black. T h e hemor rhages are reflected in the regional lymph n o d e s , which are also red-black, firm, and enlarged. E d e m a of the larynx is usually inflammatory and part of acute respiratory infections, or caused by inhalation of irritant materials, local t r a u m a , or inflammation (Fig. 6.12) . Mild e d e m a of the glottis is occasionally observed in e d e m a disease of swine. E d e m a occurs in cattle with acute interstitial pneumonia. It is also observed in cattle as part of a rapidly developing e d e m a of the face and throat; this latter s y n d r o m e is probably of allergic origin, and it responds well to antihistamines. If neglected, it leads to asphyxiation. Laryngeal e d e m a can also be part of the localized anaphylactic response to insect stings in most species. E d e m a of the fauces and larynx occurs in equine purpura hemorrhagica and in the same species as a response to the leech Limnatis nilotica or to lead poi soning. The amount of e d e m a varies, but in any case is most severe in the region of the epiglottis, the aryepiglottic folds, and the ventricles. inflammation and clear or pale yellow at other times. The fluid may disappear postmortem, but wrinkling of the mu cous m e m b r a n e remains to indicate the prior presence of fluid. Severe mucosal and submucosal e d e m a of the dorsal region of the distal half of the trachea occasionally causes death by asphyxiation in feedlot cattle. The loud inspira tory noise made by severely affected animals has given rise to the clinical term " h o n k e r s y n d r o m e . " There is correlation with increased respiratory m o v e m e n t s brought about by exercise or hot weather, usually in heavy cattle, but it is not known whether the condition is triggered by trauma, tracheal compression, inhalation of dusts, toxins in feed, or a combination of these. T h e location of the larynx and trachea is such that frequently they become inflamed as part of inflammatory diseases of either the upper or lower parts of the respira tory tract. Their involvement in major upper respiratory tract diseases has already been covered. Tracheitis fre quently accompanies bronchitis and is sometimes a minor c o m p o n e n t of pneumonias that do not arise by extension from severe upper respiratory disease. Laryngitis can, however, occur without wider involvement of the respira tory tract (Fig. 6 .13). Laryngitis can occur as a part of oral necrobacillosis (calf diphtheria) caused by Fusobacterium necrophorum in calves and swine, or it may occur without lesions elsewhere. Laryngeal ulcers or scarred sites of previous ulceration are found in a small proportion of slaughtered feedlot cattle. They occur mainly at points of apposition of vocal processes and medial angles of aryte noid cartilages. It is speculated that mucosal damage by the repeated trauma of laryngeal closure is the main predis- posing cause of ulceration. It has also been suggested that Haemophilus somnus infection is sometimes a factor. Lesions of acute or chronic diphtheria (F. necrophorum) and papillomatosis occur occasionally at the same sites and are believed to develop secondary to mucosal ulcer ation. Laryngeal chondritis occurs in sheep, calves, and young horses. It is characterized by necrosis and ulceration of laryngeal m u c o s a over or just caudal to the vocal cord and the presence of a purulent tract leading to abscessation within the arytenoid cartilage. There is usually a more generalized laryngeal e d e m a which is responsible for se vere clinical signs and possibly death. The disease appears to occur most frequently in sheep, particularly in young rams of Texel or S o u t h d o w n breeds. There is speculation that bulkiness of laryngeal and pharyngeal tissues in these animals predisposes to e d e m a and ulceration of apposing surfaces of vocal c o r d s , with subsequent activity of Acti nomyces pyogenes and other bacteria leading to arytenoid abscessation. Small foci of mineralization, often with accompanying granulomatous inflammation, occur in the lamina propria of the dorsal trachea and ventral turbinates of adult pigs, particularly males. A causal association with inhalation of dusty mineral-containing feed has been suggested, but this is unlikely. More widespread mineralization is frequently also present in severely affected pigs. A diphtheritic laryngotracheitis caused by untyped streptococci is occasion ally observed in pigs and may affect litters of piglets (Fig. 6.14) . A chronic and diffuse tracheitis can develop following tracheotomy. The reaction is most severe adjacent to the wound, the m u c o s a is swollen, and in the late stages, heavily scarred. Foci of chronic polypoid tracheitis are occasionally observed in dogs and cats. The thickening may be sufficient to cause significant stenosis and dys pnea. T h e cause is u n k n o w n , but the various pathogenetic factors involved are probably similar to those responsible for nasal polyps. S q u a m o u s metaplasia of tracheal epithe lium is a feature of vitamin A deficiency and severe iodide toxicosis. Syngamus laryngeus occurs in the larynx of cattle in tropical Asia and South America. The thin-walled eggs containing first-stage lar vae are coughed up and swallowed and hatch before being passed as infective larvae in the feces. Pups are infected by larvae in the saliva or feces of their d a m s . Filaroides osleri represents a special hazard to wild canids because infection of pups can readily occur during regurgitative feeding. L a r v a e migrate from gut to lung through the blood. The lesions vary in size from nodules that are barely visible to larger nodules or plaques which project 1 cm or more into the lumen of the trachea (Fig. 6 .15 A). The larger masses are oval with the long axis parallel to that of the trachea. The parasites do not typically incite acute bron chitis or tracheitis although they can provoke paroxysmal coughing and dyspnea. The nodules and nodes are gray or whitish, and the worms are visible through the intact overlying mucosa. The small nodules contain immature worms, and the larger ones contain a mass of tightly coiled adults ( Fig. 6 .15B). The worms lie in tissue spaces between the carti lage rings of the trachea and large bronchi and in the adventitia and lymphatics. The live worms provoke a mini mal reaction consisting of a thin capsule and infiltration of the lamina propria by lymphocytes and plasma cells. Superficially the nodules are covered by intact epithelium except for small pores through which female worms pro trude their tails to lay eggs. Dead worms provoke a foreignbody reaction with neutrophils and a few giant cells. Im mature worms without significant tissue reaction may be found in the pulmonary lymphatics and occasionally in the alveoli. These immature worms are probably still migrat ing toward the trachea. lupi occasionally forms nodules in the tra chea or bronchi as an example of aberrant localization. Neoplasms of the larynx and trachea are rare, and infor mation about them is fragmentary. Any tissue in or adja cent to the wall of these structures can give rise to tumors, so a variety of epithelial and mesenchymal tumors have been found. Epithelial tumors are most likely to be papillo mas or squamous cell carcinomas. Adenocarcinomas are exceedingly rare. Leiomyomas and rhabdomyosarcomas can arise in or close to the wall. Chondromas or osteochon dromas occasionally originate from the laryngeal or tra cheal cartilages. The osteochondromas are usually carti laginous nodules with central endochondral ossification. They are derived from perichondrial proliferation of devel opmental, inflammatory, or neoplastic basis. It is difficult or impossible to decide what the basic process is in any one tumor. Although it has been argued that the lesions should be classified as osteochondral dysplasias, the term osteochondroma is well established and can be understood to embrace the full range of pathogenetic possibilities. Chondrosarcomas and osteosarcomas are also rare find ings. Mucosal involvement in lymphosarcoma or malig nant mast cell tumor is an uncommon occurrence in cats and dogs, and deformation or invasion by adjacent neo plasms in the thyroid or lymph nodes has been mentioned. Oncocytomas are rare benign tumors arising as solitary projecting nodules in or close to the lateral ventricle of the canine larynx, particularly in young dogs. They consist of lobular masses of pleomorphic cells with abundant, deeply eosinophilic, granular or foamy cytoplasm. Ultrastructurally there are numerous mitochondria and intermitochon-drial glycogen granules. Oncocytes (oxyphil cells) occur in a variety of endocrine glands and epithelial tissues of humans, and occasionally give rise to tumors. Evidence indicates that they are atypical neuroendocrine cells; hence, oncocytomas are related to carcinoids and other tumors of the dispersed neuroendocrine system. Granular cell tumors and rhabdomyomas also arise in the laryngo pharyngeal region of dogs with presentation similar to that of oncocytoma. The distinction between the three tumor types may not be possible by light microscopy; myotubes and cross-striations may not be demonstrable in the rhab domyomas. Histochemical methods to demonstrate myo globin and desmin and ultrastructural identification of my ofibrils or Z lines distinguish the rhabdomyomas. The granular cell tumors are arranged in strands or clusters insinuated in stroma that may contain amyloid. The gran ules which are densely packed lysosomes stain with Schiff reagent and Sudan black. Bronchi and bronchioles form the transitional zone be tween the upper and lower respiratory tract and therefore are often involved either as an extension of severe upper respiratory tract disease or as part of pulmonary disease. Congenital malformations are included with malforma tions of the lungs, and tumors arising in bronchi are consid ered with neoplasms of the lung. Agents inducing acute bronchitis and bronchiolitis usu ally do so by interacting initially with airway epithelial cells and inducing the stereotypic pattern of injury, sloughing, and epithelial repair (see General Considera tions, Section I of this chapter). The most significant im mediate pathophysiologic consequence of bronchial and bronchiolar inflammation is airway obstruction. This can result from one or more of intraluminal blockage by infil tration and accumulation of inflammatory exudate, bronchoconstrictive contraction of airway smooth muscle, and thickening of the wall by accumulation of cells and edema in the submucosa. Morphologic manifestations of acute bronchitis include the same range of inflammation described for upper air ways. The exudates may be catarrhal, mucopurulent, fi brinous, fibrinopurulent, or purulent. Epithelial necrosis is often a concurrent finding. Catarrhal bronchitis is the simplest form of inflamma tion. Acute, mild irritation of the bronchial mucosa causes discharge of secretion from goblet and serous cells and from such seromucinous glands as are present. Since the types, relative numbers of epithelial secretory cells, and density of the glands differ from species to species, fine details of the response vary accordingly. Hyperemia and edema of the lamina propria accompany the secretory discharge. Ciliated epithelial cells are most sensitive to a wide array of injurious agents and are often the first to undergo necrosis and slough. The usual traffic of leuko cytes through the epithelium becomes exaggerated. If the inflammation is transient, the integrity of the epithelium is restored rapidly by proliferation of nonciliated secretory cells and basal cells. The course of bronchitis after the initial catarrhal phase depends on the nature of the irritant and the duration and severity of exposure. In common bacterial infections, purulent or suppurative bronchitis occurs, and the exudate in the bronchi becomes characteristically yellowish and viscid. The exuded dead and dying neutrophils collect in the lumen together with mucus and sloughed epithelial cells. Ulcerative bronchitis occurs in severe viral or bacte rial infections during which large areas of epithelium are destroyed. In bacterial infections, there is often intercur rent purulent bronchitis. Fibrinonecrotic bronchitis is char acterized by exudate forming a thick, yellow membrane which is firmly attached to many points. Reactions of this severity usually also involve the larynx, trachea, and cranioventral portions of the lungs and are typified by severe cases of infectious bovine rhinotracheitis, but can also be seen in mycotic bronchitis in cattle. Severe necro tizing bronchitis can occur in bronchiectasis or as a result of aspiration of foreign materials. In such lesions, the microflora is mixed, and the greenish or brown putrid debris is characteristic. Severe bronchitis can resolve following removal or neu tralization of the offending agent. Repair characterized by complete bronchial epithelial regeneration and only mild fibrosis of the bronchial lamina propria may often follow. In instances of severe or more prolonged injury to epithe lium, fibrosis in the lamina propria becomes more promi nent with time. Aggregates of lymphocytes, macrophages, and plasma cells in the lamina propria are common se quelae as acute bronchitis progresses through subacute to chronic duration. Prominent lymphofollicular hyperplasia of the bronchial and bronchiolar mucosa is a common feature of chronic mycoplasmal infections. Epithelial hy perplasia may also become prominent with prolonged mu cosal injury of any cause. With more severe injury to the mucosa, especially in chronic suppurative reactions, bronchial wall destruction often results (see Bronchiecta sis, Section V,B of this chapter). Fibrous polyps obstruct ing the bronchial lumen are an extremely rare response to severe bronchial mucosal injury. Mild and limited bronchitis or tracheobronchitis rarely causes death a n d is observed mainly as a clinical problem. Infectious tracheobronchitis (kennel cough) in dogs is an example of persistent, tracheobronchial inflammation that is characterized clinically by a hard, persistent, and usu ally nonproductive cough, which can b e c o m e paroxysmal. Affected dogs usually recover, although signs can persist for 3 w e e k s or longer. Available evidence indicates that clinical signs are accompanied either by no significant gross lesions or, with about equal frequency, by catarrhal or mucopurulent tracheobronchitis. There is sometimes extension to a cranioventral bronchopneumonia and occa sionally serous t o mucopurulent rhinitis. Palatine tonsils and tracheobronchial and retropharyngeal lymph nodes are usually enlarged and reddened. Microscopically, vari ous degrees of tracheobronchitis and bronchiolitis are usu ally present. These range from a focal, superficially necro tizing tracheobronchitis and bronchiolitis t o a m o r e severe process characterized by mucopurulent inflammation. There is epithelial degeneration and necrosis with disorga nization of the normal pseudostratified pattern in the nec rotizing lesions. T h e response in the underlying lamina propria is limited. T h e lesion is associated mainly with viral and bacterial infection. Viral infections contributing to this syndrome include parainfluenza type 2, canine ade novirus-2, a n d canine distemper virus. Extensive infiltra tion by neutrophils is characteristic of mucopurulent tra cheobronchitis associated with Bordetella bronchiseptica infection. These bacteria attach to cilia and can induce ciliostasis within hours of attachment. Bacteria are often attached to cilia in sufficient numbers to be visible by light microscopy after staining for Gram-negative bacteria. My coplasma cynos h a s also been implicated in t h e complex etiology of infectious tracheobronchitis in dogs. Severe bronchitis usually develops as a result of infec tion descending, usually aerogenously, from the upper respiratory system. Ascending infections can be im portant, particularly those involving verminous a n d granu lomatous pneumonias. F o r instance, metastatic tubercles frequently erode into the airways to produce tuberculous bronchitis with subsequent spread as tuberculous bron chopneumonia. In a similar manner, pulmonary abscesses of caseous lymphadenitis can evacuate into bronchi, re sulting in persistent caseous bronchitis. The consequences of inflammation that are limited to larger bronchi are much less serious than t h e conse quences of inflammation of small bronchi a n d especially of bronchioles. T h e larger bronchi lie in interstitial tissue outside the pulmonary lobules, and infectious processes are less likely to spread directly into surrounding paren c h y m a from bronchi than from bronchioles. Chronic bronchitis is usually of bacterial, parasitic, or presumed allergic cause. T h e relative importance of these causes varies according to species. Chronic catarrhal or mucopurulent bronchitis is most important in dogs, where bronchial irritation a n d hyperse cretion of m u c u s causes a chronic intractable cough. T h e condition is seen mostly in small breeds, particularly in obese animals. At p o s t m o r t e m , t h e major finding is excess mucus or mucopurulent exudate in the tracheobronchial tree. This ranges from pooling of turbid viscous fluid at the tracheobronchial junction to large amounts of tenacious, white or green to b r o w n exudate in all airways. Sometimes the exudate is profuse enough to cause terminal foamy filling of the airways. T h e bronchial m u c o s a is thickened, often hyperemic, and e d e m a t o u s . Occasional polypoid projections into the lumen c a n be seen grossly in advanced cases, as can pale foci representing lymphoid nodules. Microscopically, t h e mucosal thickening and folding is caused mostly by increase in n u m b e r and size of the muco sal glands and extensive infiltration of the lamina propria by lymphocytes, plasma cells, and occasional macro phages and neutrophils ( Fig. 6 .16). T h e superficial epithe lium h a s prominent hyperplasia of goblet cells and usually has foci of ulceration or squamous metaplasia. Histochem ical techniques reveal a shift in the character of secretions from sulfomucins to more viscous sialomucins. T h e intra luminal mucus is commonly mixed with abundant neutro phils. T h e amount of fibrosis, hyperemia, and edema in the bronchial wall depends on t h e age and severity of the lesion a n d whether there has been recent acute exacerba tion. T h e airway involvement extends to involve bronchi oles a n d , in -25% of cases, there is a usually small area of associated bronchopneumonia. H y p e r t r o p h y of the smooth muscle in t h e wall of medium-and small-sized pulmonary arteries accompanies severe chronic bronchi- The pathogenesis of the chronic bronchitis in dogs is uncertain. It m a y occur in those dogs which fail to recover from a syndrome similar to infectious tracheobronchitis. W h a t e v e r the reasons for failure of the acute episode to resolve, eventually there occurs a vicious cycle of disrup tion of normal defense mechanisms and persistent interac tion of bacteria and leukocytes capable of mediating con tinued inflammation. T h e most important infectious agent in dogs is Bordetella bronchiseptica. Chronic suppurative bronchitis is a frequent sequel to b r o n c h o p n e u m o n i a in cattle and is usually associated with bronchiectasis. A variety of bacteria can be isolated from the suppurative lesions, with Actinomyces (Corynebacterium) pyogenes and Pasteurella s p p . being the most im portant. Although there is circumstantial evidence that allergens can be an important cause of bronchitis, rigorous proof is still lacking in most instances. T h e role of allergens in causing the chronic b r o n c h i o l i t i s -e m p h y s e m a complex in the horse and the airway lesions associated with hypersen sitivity pneumonitis are dealt with later. There remains a broad clinical syndrome, mostly in cats and dogs, which is commonly referred to as asthma, allergic bronchitis, or allergic pneumonia. Diagnosis is usually made on the basis of coughing, wheezing, respiratory distress, eosinophilia in blood or tracheobronchial lavage fluid, and alleviation of signs by sympathomimetic drugs and corticosteroids. There have been limited studies of the lesions associated with the clinical s y n d r o m e . Bronchial biopsies have dem onstrated an edematous and hyperemic lamina propria with infiltration of eosinophils and fewer plasma cells and lymphocytes. T h e epithelium is highly susceptible to sloughing, which is exaggerated by sampling and pro cessing artefacts. T h e lesions found p o s t m o r t e m usually are in an animal which h a s h a d repeated episodes or chronic involvement and therefore have features of a chronic bronchitis in which eosinophils are the predomi nant inflammatory cell. In the cat, there is narrowing of bronchial lumina because of extensive hyperplasia of the submucosal glands which are a prominent feature of nor mal cats in contrast to other species of domestic animals. mon but not always present. Bronchioles are affected in severe cases ( Fig. 6 .17). Occasionally t h e lesion extends into peribronchiolar alveoli. Since lesions seen at postmor tem a r e usually from an animal dying as a result of acute exacerbation, there is also a widespread patchy alveolar and interstitial e d e m a . S o m e t i m e s , particularly in dogs, the n u m b e r s of eosinophils m a y be low relative to those of the other inflammatory cells. Bronchiectasis is defined as p e r m a n e n t , abnormal dila tion of bronchi. It most frequently o c c u r s a s an acquired lesion secondary to some form of bronchitis. T h e bronchi tis m a y be of infective etiology or secondary to aspiration or another abnormality such as immotile cilia s y n d r o m e . It rarely occurs as a congenital malformation. T h e r e are two main anatomic varieties of bronchiectasis, saccular and cylindrical. Saccular bronchiectasis is less c o m m o n and consists of thin-walled, circumscribed outpouchings of bronchial or bronchiolar walls. It is m u c h m o r e easily detected in lungs fixed b y intratracheal infusion of fixative under pressure. This type of bronchiectasis c a n result from focal necrotizing bronchitis a n d bronchiolitis and occurs occasionally in sheep a n d cattle. It c a n also be found to a mild degree in t h e small airways of horses with the bronchiolitis-emphysema complex to be described later. Cylindrical bronchiectasis affects bronchi partially or along their entire length ( Fig. 6 .18). In cattle, it is almost always a sequel to chronic suppurative bronchitis, which is in turn a frequent aftermath of bronchopneumonia. It therefore affects airways in cranioventral portions of the lung where bronchopneumonia occurs. Several pathoge netic events contribute to the development of bronchiecta sis associated with bronchopneumonia. One is severe sup purative bronchitis with damage to and weakening of the bronchial wall by neutrophil lysosomal e n z y m e s and asso ciated oxygen radicals. This leads to pooling of exudate in the lumen. Secondly, inflammatory processes in more distal airways and alveolar p a r e n c h y m a contribute to lower airway obstruction and atelectasis. The loss of alve olar tissue volume leads to traction on the walls of the airways during inspiration, which contributes to airway expansion over time. With lower airway obstruction and atelectasis, there is less-rapid airflow in the bronchial lu men, even during coughing efforts, to help maintain lumi nal patency. Mucociliary clearance is less effective be cause of damage to ciliated cells. This contributes further to mucus and inflammatory exudate accumulation in the bronchi. In cattle, the complete lobular septation and lack of collateral ventilation both lessen the effectiveness of resolution of bronchopneumonia and lead to m o r e exten sive atelectasis because of airway blockage. On both ac- Affected lungs have irregularly dilated bronchi in crani oventral regions. They are filled with viscous to caseous, yellow-green pus. The intervening p a r e n c h y m a is atelec tatic and sometimes fibrotic. In the cranial lobes the atelec tasis tends to be complete, but in the caudal lobe there is often a mixture of areas of bronchopneumonia, hyperinflated lung, and atelectasis. In the bovine lung, in which the demarcation of lobules is distinct, dilation of the cen tral bronchiole and alveolar collapse make a small hillock of each lobule, resembling the surface of a pineapple ( Fig. 6 .19A). The superficial appearance is often obscured by fibrous pleural adhesions, so the induration of the paren c h y m a and the dilated thin-walled bronchi filled with exu date are best appreciated when the lobe is sliced so that the bronchi are sectioned transversely. In severe cases, the dilated bronchi give a h o n e y c o m b e d or cystic appear ance to the lobe ( Fig. 6 .19B). Microscopically, depending on the severity and chro nicity of the lesion, there are various degrees of recon struction of the wall of the bronchus by granulation tissue. The lumen contains m u c u s , detritus, large collections of inflammatory cells, and frequently some blood. The mu cosa may be destroyed by ulceration almost to the muscu laris, or it may show a combination of ulcerative, atrophic, metaplastic, and hyperplastic changes. T h e bronchial walls are densely infiltrated with all types of leukocytes, and the lamina propria takes on the histologic properties of granulation tissue with progressive fibrosis. The necro tizing process can extend more deeply than the mucosa and destroy cartilage and submucosal glands. T h e destruc tive and suppurative process can involve the full width of the bronchial wall and some of the adjacent alveolar tissue and become equivalent to a lung abscess. Cylindrical bronchiectasis in the dog ( Fig. 6 .18) arises against the background of severe chronic bronchitis but, in contrast to that in the cow, it is not so consistent a sequel. A major factor is probably the less frequent occur rence of alveolar atelectasis in the dog. Since there is very effective collateral ventilation in dogs, atelectasis is less likely to follow airway obstruction. This could be the reason bronchitis is less likely to cause bronchiectasis in this species. In addition to generalized bronchiectasis associated with severe, diffuse, chronic, mucopurulent bronchitis, the condition sometimes is limited to only one or two lobes, more often the middle lobes. Whether local ized or generalized, the greatly dilated bronchi often con tain casts of either crumbly or tenacious and rubbery, partially dehydrated exudate. Chronic mucopurulent bronchitis with bronchiectasis and bronchiolectasis is rare in cats. Occasionally there is accompanying miliary broncholithiasis. In pigs, sheep, and goats, bronchiectasis is usually associated with severe parasitic bronchitis. Occasionally in all species, localized bronchiectasis follows obstruction by a foreign body, granuloma, or tumor. The course of widespread bronchiectasis is chronic and unfavorable. Complications, other than bronchopneumo nia, include bronchopleural fistula, septic thrombosis, and hemorrhage, or production of septic emboli with meta static abscess formation, and secondary amyloidosis. Although bronchiectasis occurs infrequently in dogs, dogs with immotile cilia syndrome usually develop bron chiectasis as part of a constellation of abnormalities asso ciated with a basic ciliary defect. Kartagener's syndrome was the eponym applied to a congenital and often familial disorder in infants in which there was coexisting situs inversus, sinusitis, and bronchiectasis. The triad of Karta gener's syndrome is recognized in dogs. Only -50% of the dogs with immotile cilia syndrome develop situs inversus. Abnormalities are referable to improper function of cili ated cells, particularly of respiratory and reproductive organs. The basic defect is usually associated with one of several ultrastructural abnormalities of cilia throughout the body, including absence of one or both of the inner and outer dynein arms, microtubular transposition, random microtubular orientation, and partial microtubular defi ciency. Ciliary basal body abnormalities have also been described. Some dogs with the syndrome do not have ultrastructural changes in cilia. Littermates with the condi tion have been recognized in English pointers, English springer spaniels, and Old English sheepdogs. Breeding studies confirm the heritable nature of the disease in dogs and suggest that it is an autosomal recessive condition. Inflammation of bronchioles commonly occurs as an extension of bronchitis or concurrently with bronchitis and pneumonia. Bronchiolitis as a distinct pathologic en tity occurs under several specific forms of pulmonary in jury, with viral infection and pulmonary toxicity being the two most common forms in domestic animals. A notable example of viral bronchiolitis occurs with respiratory syn cytial virus infection in cattle, where viral replication oc curs in bronchiolar epithelial cells, in addition to bronchial and alveolar epithelial cells, to induce both airway in flammation and interstitial pneumonia. Bronchiolitis and bronchiolar obstruction can become a prominent feature of the disease, leading to severe hypoxemia due to ventilation/perfusion inequality, and forced expiratory efforts with obstructed airways leading to interstitial emphysema. Airway obstruction in viral bronchiolitis occurs by pro cesses similar to those described for bronchitis, but hyper plasia of nonciliated bronchiolar epithelial cells often is much more pronounced in bronchiolitis. The epithelial hy perplasia and other viral cytopathic effects together cause severe narrowing or obstruction of the airway lumen. Exposure to xenobiotic compounds, such as 4-ipomeanol, 3-methylindole and perilla ketone, can lead to severe bronchiolar injury as a result of necrosis of nonciliated bronchiolar epithelial cells, which possess high concentra tions of cytochrome P-450-monooxygenase enzymes. Relatively mild inflammatory lesions in bronchioles that result in thickening of the wall, if diffusely distributed, can lead to significant increases in respiratory resistance. According to Poiseuille's law, narrowing of the airway will increase resistance to the fourth power of the reduction in radius. Acute inflammatory conditions characterized by edema and infiltration or chronic conditions associated with fibrosis that reduce the bronchiolar lumen radius by half will increase resistance 16-fold. Physical airway obstruction occurs more readily in bronchioles than in bronchi. This is partly explained by the ease with which bronchiolar walls collapse and by their small luminal size readily permitting occlusion by exudate. For these reasons, severe bronchiolitis charac terized by accumulation of exudate and delayed epithelial repair is likely to lead to obliteration by organizing fibrous connective tissue. Bronchiolitis fibrosa obliterans or organizing bronchio litis is a nonspecific response to a variety of severe forms of damage to bronchioles and adjacent alveoli. It can fol low viral infections such as influenza, inhalation of toxic gases (including 100% oxygen), or damage by lungworms or pneumotoxins such as those associated with acute inter stitial pneumonia in cattle. Prerequisites are necrosis of epithelium at the bronchiolar-alveolar junction and the presence of an inflammatory exudate that may be rich in fibrin and chemotaxins for macrophages, fibroblasts, and endothelial cells. Fibroblast migration into the exudate and phagocytosis of debris and/or lysis of the fibrin are accompanied by collagen synthesis to lead to a perma nently obstructive lesion in the bronchiolar lumen. The lesion is typically a polypoid projection of fibroblastic tissue partially or completely obliterating the bronchiolar lumen ( Fig. 6 .20A,B,C). In species with well-developed respiratory bronchioles (for instance, the dog), organiza- The main histologic features are dilated bronchiolar struc tures, hypoplastic bronchi, a n d various degrees of devel opment of alveolar ducts and alveoli. Bronchial hypoplasia also appears to b e the basic defect in what is usually referred to as congenital adenomatoid malformation o r adenomatoid hamartoma. In this condition, o n e or more lobes of the normal lung are replaced by swollen, spongy or cystic, lobulated tissue. Histologically, as in accessory lungs, dilated bronchioles sometimes a r e large enough to be noted grossly as cystic spaces. Bronchi are hypoplastic and lack cartilage and smooth muscle in their walls. Alveo lar structures m a y be more normal. H o w e v e r , if there is airway collapse a n d obstruction with secondary hyperin flation of the lung, enlarged alveoli may result (congenital lobar e m p h y s e m a ) . Other anomalies include chondromatous h a m a r t o m a s a n d pulmonary epidermoid cysts. a c c o m p a n y congenital diaphragmatic hernia. Congenital cysts a n d congenital bronchiectasis a r e localized varia tions on t h e same t h e m e . Congenital alveolar dysplasia has been observed in p u p s . The gross form of the lungs is regular, but they retain a fetal appearance a n d b e c o m e poorly aerated and poorly crepitant. The distribution, size, and shape of the alveoli a r e uneven. Alveoli a r e reduced in number, a n d there is excessive interstitial tissue that contains many dilated capillaries. The formed alveoli a r e lined by mature alveolar epithelium. In such c a s e s , it is difficult o r impossible to determine whether infection of the fetal lung played a pathogenetic role. Abnormal lobulations a n d Atelectasis means incomplete expansion of the lung and was originally applied t o defective aeration of fetal lung at the time of birth. It is n o w also applied t o collapse of previously air-filled pulmonary p a r e n c h y m a . Atelectasis is therefore divided into congenital a n d acquired forms. In congenital ( n e o n a t a l ) atelectasis, the lungs range from those of the stillborn animal which have never been aer ated (fetal atelectasis) t o minor degrees of incomplete expansion. In fetal atelectasis, t h e lungs appear as in t h e fetus b u t a r e dark reddish blue because of dilation of alveolar capillaries. They are of fleshy consistency and d o not float. The alveoli are partially distended with fluid, and the epithelial cells a r e rounded. Sloughed epithelial cells (squames) from t h e oronasal regions a n d amniotic fluid are usually present in the alveolar fluid, possibly with bright yellow particles of meconium. Small numbers of squames can be present in the lungs of normal term fetuses but large n u m b e r s , especially if meconium is also present, indicate aspiration of amniotic fluid during the exaggerated respiratory m o v e m e n t s of the asphyxiated fetus in utero. Patchy congenital atelectasis d u e to incomplete expansion is usually d u e to w e a k respiratory m o v e m e n t s caused by general debilitation or damage to respiratory centers in the brainstem. Laryngeal dysfunction, obstruction of air w a y s , and abnormalities of the lung or related thoracic structures are other possible causes. In the neonatal pe riod, it is often not possible to distinguish atelectasis of incomplete expansion a n d acquired atelectasis of briefly aerated lung. T h e atelectasis is frequently seen affecting groups of lobules or occasionally more widespread regions during the first week of life. T h e larger zones are more likely to occur in weak, recumbent animals and mostly affect the lowermost region of the d o w n side ( Fig. 6 .22). T h e atelectatic lobules are distinct because they are dark red, depressed below the surface of the surrounding aer ated lung, a n d , in contrast to pneumonic lung, have a flabby consistency. T h e sectioned surface is homoge n e o u s , dark red, and free blood is easily expressed from it. Microscopically, the alveolar walls are in close apposition. Only small amounts of fluid, epithelial debris (including squames from the upper oronasal regions or amniotic fluid), and alveolar macrophages are present. Extensive neonatal atelectasis is a feature of neonatal hyaline membrane disease (neonatal respiratory distress syndrome). This is a c o m m o n disease in h u m a n infants, particularly in premature babies and those born to diabetic mothers. A similar condition in animals is best recognized in foals, but has been reported in lambs, pigs, puppies, and a calf. Foals a n d pigs have been called barkers because of the doglike sound made during forced expiration. Foals which show evidence of presumed hypoxic brain damage are sometimes referred to as w a n d e r e r s . Affected lungs are extensively atelectatic, although the borders of the lobes m a y be spared. They are heavy, fleshy, and often e d e m a t o u s . Cream-colored or bloodstained foam fre quently exudes from cut surfaces and is present in large airways. T h e lungs sink or almost submerge in fixative. The main microscopic abnormalities are alveolar septal congestion, variably collapsed or edema-containing alve oli, and presence of acidophilic hyaline m e m b r a n e s lining alveolar ducts and distal portions of bronchioles. Focal hemorrhages and interstitial e d e m a are c o m m o n . There is general agreement that lack of normal surfacetension-reducing capacity of t h e alveolar lining liquid plays the central pathogenetic role. This in turn is linked to defective production by alveolar type II epithelial cells of the phospholipid surfactant material. There is still de bate, however, as to the extent to which decreased surfac tant activity is d u e to immaturity of type II cells o r to a more specific metabolic derangement of their surfactant synthesis. Fetal hypothyroidism and possibly hypoadre nocorticism also play a role in the condition in piglets by being responsible for delayed maturation of type II cells. Other pathogenetic factors are fetal asphyxia, aspiration of amniotic fluid, reduction in pulmonary arteriolar blood flow, and inhibition of surfactant by fibrinogen, other se rum constituents in e d e m a fluid, or by c o m p o n e n t s in aspirated amniotic fluid. Acquired atelectasis and alveolar collapse are used syn onymously. Acquired atelectasis is most commonly the obstructive type, which is caused by complete airway ob struction. W h e t h e r atelectasis follows obstruction de pends on the size of airway obstructed and the degree of collateral ventilation. Complete blockage of lobar or segmental bronchi is necessary for atelectasis in the dog and cat, where collateral ventilation is extensive. Blockage of small bronchi o r even bronchioles c a n result in atelectasis in bovine lungs where there is insignificant collateral ventilation. L u n g s of sheep are also prone to atelectasis, pigs less s o , and the horse is intermediate between ruminants and dogs. Atelectasis is more likely to develop in dependent lung regions where alveoli are smallest and airways, most easily compressed. Atelectatic lung caused by obstruction has the appearance of other forms of atelectasis. It is sunken relative to aerated lung, homogeneously dark r e d , and flabby. Evidence of bron chial obstruction by e x u d a t e , parasites, aspirated foreign material, granulomas, or tumors can often be seen grossly. Resorption of oxygen from nonventilated lung occurs quickly, but nitrogen is resorbed very slowly. Obstruction of airways by aspirated material or foamy exudate shortly before death does not, therefore, produce atelectasis in animals breathing air. Microscopically, simple atelectasis appears as slightly congested alveolar walls lying in close apposition with slitlike residual lumina having sharp angular ends ( Fig. 6 .23). Atelectasis which is sometimes seen preceding the development of bronchopneumonia, or during the final phase of its resolution, is usually associated with small a m o u n t s of e d e m a fluid and excess alveolar macrophages in the alveolar lumina. T h e e d e m a accompanying large zones of atelectasis is due partly to leakage because of hypoxic damage and partly to the hypoxic vasoconstric tion of vessels in the affected region. Reduced surfactant activity also plays a role. Microatelectasis of small groups of alveoli is often an artefact of immersion fixation, and the apparent blending of several alveolar septa is easily mistaken for interstitial pneumonia. pleural or intrapulmonary space-occupying lesions. Ex amples are hydrothorax, h e m o t h o r a x , exudative pleuritis, and mediastinal and pulmonary t u m o r s . In large animals, the atelectasis caused by pleural effusions often occurs below a sharply demarcated fluid line. Abdominal disten sion, as in severe ascites and ruminal t y m p a n y , may cause partial atelectasis, typically in the cranial regions where ventilatory m o v e m e n t s are most easily compromised by intra-abdominal pressure. What may be termed hypostatic atelectasis occurs in the lowermost zone of the lung of the d o w n side in recumbent large animals. This is a hazard of prolonged anesthesia or of weakened animals, particularly if there is a condition causing chest pain. The contributing factors are shallow amplitude of respiration causing impaired ventilation of dependent lung, gradual loss of surfactant activity, and pooling of secretions in the lower airways. Sharp-bordered, ribbon-shaped, or lobular zones of at electasis are present to some extent in the cranioventral regions of the lungs of slaughtered sheep. Although many of these are associated with blockage of bronchioles and small bronchi with purulent e x u d a t e , some have no detect able blockage of airways, and the reason for the atelectasis is not k n o w n . M a s s i v e atelectasis is seen mostly as a sequel to p n e u m o thorax. What appears to be total atelectasis is seen in animals, usually dogs and cats, which die during the course of breathing 8 0 -1 0 0 % oxygen as part of intensive care. Because of the speed with which the oxygen is resorbed into the tissues, the lungs are usually completely devoid of gas by the time they are examined p o s t m o r t e m . They are uniformly shrunken, dark red, flabby, and ooze blood on cut section. E m p h y s e m a in its widest sense refers to tissue puffed up by air or other gas. In the lung there are two major forms. Alveolar (vesicular) emphysema is excessive a m o u n t s of air within airspaces of the lung. Interstitial emphysema is the presence of air within interlobular, subpleural, and other major interstitial zones of the lung. Emphysema, unless otherwise qualified, should be used only for alveolar e m p h y s e m a . The most widely accepted current definition of human e m p h y s e m a is abnormal en largement of air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and an absence of obvious fibrosis. Some broaden the definition to include abnormal enlargement of airspaces, with or without evi dence of destruction. The advantage of requiring evidence of destruction of walls of the airspaces is that it enables more precise recognition of an irreversible, functionally significant lesion. Simple enlargement, or hyperinflation, can be a temporary and relatively insignificant lesion. An example of this is the so-called compensatory e m p h y s e m a which occurs along the margin of a consolidated lung (Fig. 6.24A) . What appear to be e m p h y s e m a t o u s lesions in lungs removed postmortem are often not significant antemortem changes but mostly result from failure of the lung to deflate normally (Figs. 6.19A, 6.24B). This is caused by air trap ping, usually by blockage or spasm of airways. Accurate assessment of e m p h y s e m a therefore can be obtained only in lungs inflated with fixative to a volume approximating the in vivo state. In the following discussion, e m p h y s e m a will refer to abnormal enlargement of air spaces distal to terminal bronchioles with evidence of destruction of their walls. Several morphologic types of e m p h y s e m a are recog nized in h u m a n lungs according to the distribution of the enlarged airspaces. Centriacinar (centrilobular) emphy sema principally affects respiratory bronchioles and adja cent central portions of the respiratory acini, an acinus being defined as the terminal unit of lung supplied by a single terminal (nonrespiratory) bronchiole. Panacinar (panlobular) emphysema more uniformly involves all por tions of acini. T h e s e t w o major anatomic types of emphy sema in h u m a n s also differ with regard to other clinicopathologic features. L e s s important forms of e m p h y s e m a are paraseptal emphysema, which affects distal alveoli bordering interlobular septa or pleura, and irregular or paracicatricial emphysema, which results from distortion of airspaces by adjacent contracted scar tissue. Regardless of distribution, severely e m p h y s e m a t o u s lung is grossly voluminous, pale, and puffy. W h e n the lesion is diffuse, the lungs fill the thoracic cavity even after the chest has been opened, and sometimes they bear imprints of the ribs. The enlarged air spaces are often visible as small vesicles, and in severe cases coalescence of air spaces can p r o d u c e large air-filled bullae one to several centimeters in diameter. Histologically, enlarge- ment and coalescence of air spaces in inflation-fixed lungs can readily be detected in moderate to severe cases. Scan ning electron microscopy, which dramatically reveals the moth-eaten appearance ( Fig. 6 .25A,B), is best for visual ization of early lesions. With the exception of the chronic bronchiolitise m p h y s e m a complex in the horse and congenital lobar or bullous e m p h y s e m a in dogs (see the following para graphs), naturally occurring e m p h y s e m a is of little clinical significance in animals. It can be found p o s t m o r t e m in the apices and along the sharp ventral border of the lungs of old animals and is therefore seen mostly in dogs, (Fig. 6 .26A,B) cats, and horses. E m p h y s e m a t o u s bullae also occasionally occur in these regions and in rare instances rupture to cause fatal p n e u m o t h o r a x . E v e n w h e n not noted grossly, subpleural air spaces, particularly along cranio ventral margins of the lung, are often shown to be larger than more central ones at microscopic examination. In contrast to that in animals, e m p h y s e m a is an ex tremely important condition in h u m a n s , where it fre quently coexists with chronic bronchitis and bronchiolitis in causing chronic obstructive pulmonary disease. Most of what is known about the pathogenesis of e m p h y s e m a is therefore derived from the h u m a n condition or, more recently, from experimental animal models. With regard to pathogenetic factors in e m p h y s e m a , there has been considerable speculation over the years concerning the relative importance of genetic factors, inflammatory alve olar destruction, atrophy of alveolar septa due to ischemic or u n k n o w n c a u s e , and mechanical factors leading to wid ening and rupture of air spaces. T w o important findings led to convergence of these ideas. One was the discovery that h u m a n s deficient in a r a n t i t r y p s i n (now referred to commonly as a : r p r o t e a s e inhibitor) have increased inci dence and earlier onset of e m p h y s e m a . T h e other was that intratracheal injection of papain in hamsters produced an e m p h y s e m a t o u s lesion. F u r t h e r developments led to the current basic hypothesis that e m p h y s e m a is caused by excessive proteolysis in the lung because of p r o t e a s eantiprotease imbalance. T h e critical structural c o m p o n e n t undergoing lysis is elastin, because experimentally the development of e m p h y s e m a is correlated well only with elastolytic activity and evidence of elastin b r e a k d o w n . The neutrophil elastase (a serine protease) from lysosomal granules is believed to be the main source of elastolytic activity. In h o m o z y g o u s ^-a n t i t r y p s i n (a,-antiprotease) inhibitor deficiency, the e m p h y s e m a is panacinar in distri bution and the p r o t e a s e -a n t i p r o t e a s e imbalance is pre sumed to be due mainly to genetically controlled reduction in the antiprotease. In h u m a n centriacinar e m p h y s e m a , such as associated with cigarette smoking, slowly smol dering inflammation at the bronchiolar-alveolar junctions (respiratory bronchiolitis) appears to be the forerunner of the e m p h y s e m a t o u s lesion. An important feature, how ever, is that although the respiratory bronchiolitis is gener alized, the e m p h y s e m a is mainly in the u p p e r lobes. Cur rently, centriacinar e m p h y s e m a in cigarette-smoking h u m a n s is considered to be basically due to an excess of elastase from neutrophils recruited to the inflamed sites. This is c o m p o u n d e d by a lack of antiprotease activity caused by oxidative inactivation of antiproteases by com ponents in cigarette smoke and by neutrophil-derived ac tive oxygen species. It h a s been hypothesized that the preferential distribution of e m p h y s e m a in upper lobes is associated with slower neutrophil traffic through capillar ies in these regions of the lung. in excised lungs the alveoli m a y appear hyperinflated be cause of air trapping. Rarely, e m p h y s e m a is present with out significant bronchiolitis. T h e e m p h y s e m a is mostly in cranial regions, even when it accompanies a more general ized bronchiolitis. Constant features of the chronic bronchiolitis are epi thelial hyperplasia, goblet cell metaplasia, peribronchiolar fibrosis, and infiltration by lymphocytes and plasma cells. Lumina of bronchioles are narrowed by accumulation of exudate and peribronchiolar fibrosis. M u c u s is usually a major c o m p o n e n t of the exudate and sometimes occurs in such large quantities that reflux into adjacent alveolar ducts and alveoli occurs ( Fig. 6 .28A,B). T h e major vari able c o m p o n e n t of the bronchiolitis is the eosinophil. This is sometimes the most obvious feature, both of the intra luminal exudate and of the intraepithelial and peribronchi olar sites. At other times, relatively few eosinophils are scattered within the m u c u s and the bronchiolar wall. There often seems to b e an inverse relationship between the amount of mucus and t h e n u m b e r of eosinophils. There are usually increased n u m b e r s of mast cells surrounding the bronchioles. Neutrophils are less c o m m o n than eosin ophils, but sometimes the lesion h a s the characteristics of a mucopurulent bronchiolitis. T h e relative importance of allergy, infection, and toxic ity in causing the bronchiolitis is not established-it al most certainly can differ across a series of cases. T h e frequent presence of eosinophils, circumstantial evidence of clinical exacerbation on exposure to moldy hay, bed ding, or stable dust, and limited information from aerosol challenges using suspect fungal antigens all indicate that an allergic response to inhaled allergens (e.g., Micropolyspora faeni, Aspergillus fumigatus, and hay dust) is an important mechanism. Infection probably plays some part in a proportion of cases. Experimental evidence that blood-borne toxins, specifically 3-methylindole in the horse, can selectively damage bronchiolar epithelium in troduces a further possible set of c a u s e s . F r o m the point of view of the characteristic goblet cell metaplasia and mucus hypersecretion, there is evidence that histamine, prostaglandins, and leukotrienes released during type I allergic responses (anaphylaxis) have a stimulatory effect on mucus secretion. This could explain the association of goblet cell increases, mucus hypersecretion, eosinophils, and mast cells. As mentioned under allergic bronchitis, asthma and chronic allergic bronchitis and bronchiolitis are not clearly separable in animals. Interstitial emphysema is distinguished from alveolar e m p h y s e m a by the presence of air in the connective tissues and lymphatics of the lung, chiefly the interlobular septa but also beneath the pleura and around vessels and airways ( Fig. 6 .29A,B). Interstitial e m p h y s e m a occurs mainly in lungs with well-developed interlobular septa. Lungs of the cow, sheep, and pig have this feature, but only the cow is readily susceptible to the lesion. Any condition causing forced expiratory m a n e u v e r s , even agonally, can cause the condition in the cow. It is c o m m o n in slaughtered cattle. It occurs in most dramatic form as a prominent feature of acute interstitial p n e u m o n i a in cattle (acute bo vine pulmonary e m p h y s e m a and edema). A point to be emphasized is that there is no connection w h a t s o e v e r be tween the pathogenesis of alveolar e m p h y s e m a , as de scribed previously, and interstitial e m p h y s e m a in the cow. Although there is as yet no proof, it is p r e s u m e d that air is forced into the complete but delicate interlobular septa because bronchioles are collapsed or otherwise blocked during forced expiration. F o r this to occur there has to be a lack of collateral ventilation and highly u n e v e n deflation among neighboring lobules. In c o w s surviving a sufficient time with severe interstitial e m p h y s e m a , the air can extend along lymphatics to the bronchial and mediastinal lymph nodes or along fascial planes of the mediastinum to be neath the skin of the back. T h e lungs are affected by a large variety of circulatory disturbances. They are caused by abnormalities princi pally involving the pulmonary vessels a n d heart or by vascular changes secondary to pulmonary disease. T h e most important functional c o n s e q u e n c e is hypoxemia d u e to mismatching of ventilation and perfusion or shunting of blood through nonventilated regions of lung. Pulmonary ischemia occurs following e m p h y s e m a t o u s or fibrotic attenuation of alveolar capillaries, and can be associated with severe reduction in blood volume. Be cause of the dual blood supply from pulmonary and bron chial arteries, and the extensive collateral circulation, con gestion rather than ischemia is the usual sequel to arterial obstruction. Active hyperemia is part of the acute inflam matory response and is a feature of acute pulmonary injury of many types (see pneumonia, Section V I , F of this chap ter). Pulmonary congestion is most commonly caused by left-sided or bilateral cardiac failure. It can also be d u e to changes in vascular tone causing redistribution of blood from the systemic to the pulmonary circulation. Such shifts commonly occur terminally or can b e caused by autonomic disturbances, such as those produced by trau matic or other acutely damaging lesions in the hypothala mic region of the brain. T h e main importance of pulmonary congestion is that it leads to pulmonary edema. Starling's equation for flow of liquid across a capillary m e m b r a n e applies in general to pulmonary capillaries; that is, flow is dependent o n the surface area and permeability characteristics of t h e vascular wall a n d o n the balance of hydrostatic and osmotic pressures between the intravas cular a n d interstitial c o m p a r t m e n t s . T h e situation is more complicated in the lung, however, because the set of fac tors involved in the pathogenesis of alveolar e d e m a also includes the permeability characteristics of the alveolar epithelium, air pressure, a n d surface tension acting o n the alveolar surfaces, the role of alveolar oxygen in main taining the permeability characteristics of alveolar capil laries, a n d preferential drainage of liquid through the pul monary interstitium a n d possibly into t h e pleural space. Uncertainty exists about the exact magnitude of some of the factors and t h e routes by which water, solutes, and macromolecular substances cross endothelial and epithe lial boundaries but the capacity of the pulmonary intersti-tium to act as a sink for excess fluid is critical to the maintenance of fluid balance. Despite the low capillary hydrostatic pressure in the pulmonary circulation, there is a slow but steady flow of liquid from the alveolar interstitium into pulmonary lymphatics. Two factors are important in ensuring that alveoli do not become flooded under normal circum stances. One is that alveolar epithelium and its intercellu lar junctions are much less permeable than endothelial structures and therefore effectively seal off the alveolar lumen. The other is that the interstitial space is at lower pressure than intra-alveolar pressure. The interstitial pres sure in the loose fascia surrounding vessels and airways where lymphatics are situated becomes increasingly subatmospheric (negative) toward the pulmonary hilus. The net effect is that liquid is drained from alveolar interstitium to lymphatics and to the loose connective tissue sur rounding major vessels and airways, separating lobules, and in subpleural zones. The liquid then moves to the hilus of the lung and mediastinum. The broncho vascular interstitium and lymphatics therefore constitute a highly compliant sump. Provided the alveolar epithelium remains undamaged, alveolar edema does not occur until the ca pacity of the sump is overwhelmed. In slowly developing cardiogenic edema, the volume of interstitial liquid can be increased severalfold before alveolar flooding occurs. This explains why the first morphologic evidence of edema due to cardiac insufficiency is excess liquid in interstitium and lymphatics, particularly in the more compliant hilar re gions. The increased capillary hydrostatic pressure and higher interstitial pressures caused by gravitational effects in dependent regions of the lungs predispose these sites to edema in large animals. Physiological studies indicating different rates of move ment of water and molecules of various size ranges and polarity have led to the development of mathematical mod els postulating the presence of pores of differing size ranges in the air-blood barrier. There is as yet no good correlation between the mathematical pore concept and ultrastructural evidence of sites of the pores. Probably water and small solutes pass through the endothelium by a transcellular route, and larger solutes, by way of intercel lular junctions. Macromolecules appear to be largely transported by pinocytotic vesicles. Under some circum stances, water and protein are also actively transported across the alveolar epithelium. It is usually assumed that alveolar edema occurs by passage of edema fluid locally from interstitium to lumen. This is unquestionably the case for edema associated with increased capillary and type I epithelial permeability. It is not necessarily true for edema caused by increased capillary hydrostatic pressure (cardiogenic edema). There is the possibility that in this form of edema, excess fluid accumulates in the perivascu lar and peribronchiolar interstitium before overflowing into the alveoli through an as yet unidentified pathway close to the bronchiolar-alveolar junction. Although there is experimental evidence supporting this mechanism, its importance in naturally occurring, clinically significant cardiogenic edema remains to be established. Pulmonary edema is a frequent complication of many diseases and is therefore one of the most commonly en countered pulmonary abnormalities. Most causes of edema act by increasing capillary hydrostatic (microvas cular) pressure, by increasing permeability of the air-blood barrier, or by a combination of both factors. The total microvascular surface area is now recognized to be an important determinant, particularly in edema caused by increase in hydrostatic pressure. Decreased plasma oncotic pressure, such as occurs in hypoalbuminemia and lymphatic obstruction, caused for instance by widespread tumor infiltration of lymphatics and pulmonary lymph nodes, are less important. Edema due to increased microvascular hydrostatic pressure is commonly the result of increased left atrial pressure in left-sided or bilateral cardiac failure and is commonly referred to as cardiogenic edema. The conges tion and edema are important parts of the pulmonary com plications of congestive heart failure (see The Cardiovas cular System, Volume 3, Chapter 1). Increased capillary hydrostatic pressure is also the basis for the edema of hypervolemia developing in some cases of excessive fluid transfusion. Edema secondary to acute brain injury (neu rogenic edema) appears to be due to both hemodynamic and capillary permeability changes. The immediate effect is increase in microvascular pressure associated with pul monary hypertension, probably because of catecholamine release. Increase in capillary permeability occurs later. Many agents cause pulmonary edema by damaging alve olar type I epithelium and capillary endothelium. The in crease in permeability leads to edema of more rapid onset and of higher protein concentration than in cardiogenic forms. Inhaled corrosive gases (including 80-100% oxy gen), systemic toxins, anaphylaxis in certain species such as the cow and horse, endotoxins, and shocklike states all can cause acute pulmonary edema. Reperfusion injury is now also recognized as a cause. As in edema elsewhere, there is no clear dividing line between these inflammatory edemas and serous exudates. Many of the toxic or shock like states causing the edema accompanying acute pulmo nary injury may be sufficiently severe to cause the set of abnormalities characterizing acute interstitial pneumo nia. They will be considered further under that heading (Section VI,F,3 of this chapter). Loss or inhibition of phospholipid-rich surfactant in the alveolar lining layer can enhance edema formation because high surface ten sion at the air-liquid interface tends to draw fluid into the alveolus. This is probably not of primary importance except in neonatal hyaline membrane disease (respiratory distress syndrome) and perhaps in loss of surfactant activ ity accompanying prolonged shallow respiration. Clinically evident pulmonary edema is a sign of serious underlying disturbance. Cardiogenic edema is not fatal if the cardiac insufficiency can be controlled, but pulmonary edema is often the cause of death from sudden cardiac decompensation. Whether other forms of pulmonary e d e m a cause death depends on the severity and speed of onset of the underlying disease process and the e d e m a it produces. Alveolar e d e m a prevents ventilation of flooded alveoli. In the presence of surfactant material, it b e c o m e s stable foam by mixing with air in small airways, and the foam further compromises ventilation. As stated pre viously, clearance of interstitial e d e m a fluid is through the compliant interstitial and lymphatic routes to the hilus of the lung and then into the mediastinum. Passage into the pleural space may also be important. Clearance of e d e m a fluid from alveoli depends on protein content. Liquid (not protein) can be cleared rapidly by active metabolic trans port of sodium across the alveolar epithelium into blood or interstitial spaces. Protein removal is slow, possibly by transcytosis (via pinocytotic vesicles) across the alveolar epithelium. The color of e d e m a fluid and foam depends on the amount of hemorrhage. If absent, the interstitial edema is clear, colorless to slightly yellow, and the foam is white. Various a m o u n t s of hemorrhage cause corresponding de grees of bloodstaining of fluid and foam. The pulmonary p a r e n c h y m a varies from the dusky hue of cyanosis to reddish black according to the amount of congestion or hyperemia. W h e n severe, the distinction between acute pulmonary e d e m a and peracute pneumonia, especially in terstitial pneumonia, is not possible grossly and can be blurred even on microscopic examination. Histologically, e d e m a fluid is acidophilic, homoge neous, or faintly granular material filling alveoli except for occasional discrete holes which represent trapped air bubbles. The same material is usually present in interstitial tissue and lymphatics around vessels and airways and in interlobular septa and subpleural zones in those species in which these are well developed. The amount of protein present in cardiogenic e d e m a is small enough, particularly in dogs and cats, that it does not stain well after the leaching that occurs in formalin fixative. It can therefore easily be overlooked. Noting the presence of foam or fluid at gross examination, and distension of interstitial tissue and lymphatics microscopically, then takes on added im portance. Coagulant fixatives containing mercury are best for demonstration of protein in e d e m a fluid. E d e m a due to permeability defects is more acidophilic than cardiogenic e d e m a , even after formalin fixation, and frequently con tains strands or clumps of fibrin. The postmortem seepage of fluid into the alveoli of animals killed by barbiturate euthanasia solutions can easily be mistaken for edema. This artefact usually prevents detection of any antemortem e d e m a unless the latter is revealed by dilation of interstitial lymphatics. W h e n the lungs are congested, the capillaries are dis tended and intra-alveolar hemorrhages are c o m m o n . Alve olar macrophages containing erythrocytes or hemosiderin are present and increase in n u m b e r with duration of the congestion. These cells are k n o w n as heart failure cells ( Fig. 6 .31); they are not usually a prominent feature of congestive heart failure in animals, however. This is at least partly because of the shorter time animals with severe failure are kept alive c o m p a r e d to h u m a n s . A more usual feature accompanying the pulmonary hypertension of chronic cardiogenic e d e m a in the dog and cat is hypertro phy of the muscular walls of small pulmonary vessels and thickening of pulmonary capillary walls by fibrous tissue, resulting in prominent circular profiles of capillaries with thickened walls within alveolar septa ( Fig. 6 .31). Occa sionally, in terminal cardiac failure in the dog and cat, there is accumulation of leukocytes in pulmonary capillar ies, severe damage to endothelium and alveolar type I epithelium, and filling of alveoli with fibrin-rich fluid. The cause is not established, but the morphologic evidence indicates acute pulmonary injury of shocklike antecedents (see acute interstitial pneumonia, in Section V I , F , 3 of this chapter). H e m o r r h a g e s occur frequently in the lung and beneath the pleura in the hemorrhagic diatheses, septicemias, dis seminated intravascular coagulation (DIC), and severe congestion. They can also be caused by infarction, rup tured a n e u r y s m s , and t r a u m a . H e m o r r h a g e s vary from petechiation to massive filling of large regions by blood. Aspiration of blood is frequent at slaughter. It has a char acteristic pattern of multiple, small, bright red foci with feathery or indistinct b o r d e r s . Massive hemorrhage suffi cient to cause hemoptysis or exsanguination is occasion ally observed in cattle. It is caused by erosion of a large vessel and rupture into a b r o n c h u s . It can be a complica tion of a bronchogenic abscess but is m o r e often the sequel to septic thromboembolism and arteritis, usually caused by embolism from a septic t h r o m b u s in a large hepatic vein or the posterior vena cava. Clotted blood will be found in the forestomachs. currently used for hemorrhage occurring in horses during racing or training. It used to be referred to as epistaxis, but with endoscopic examination it has been shown that most horses (75% or more) examined soon after strenuous exertion have detectable h e m o r r h a g e , but only 1-10% have blood at the nostrils. T h e frequency of exerciseinduced hemorrhage increases with age and severity of exertion. Bronchoscopic examinations reveal that the hemorrhage occurs in dorsocaudal lung regions. This is confirmed on p o s t m o r t e m examination of severely af fected horses by finding grossly visible, patchy, bluishbrown discolored subpleural foci in the dorsocaudal portions of both caudal lobes. Histologically, the main features in affected regions are multifocal bronchiolitis, fibrosis, hemosiderophages in airspaces and interstitium, and extensive proliferation (neovascularization) of bron chial arteries. H o w these morphologic findings translate into pulmonary hemorrhage during exercise is debated. Current speculations favor increased microvascular pres sure because of b r o n c h o p u l m o n a r y a n a s t o m o s e s and he modynamic changes of severe exercise, and exaggerated forces acting on the alveolar septa b e c a u s e of u n e v e n ventilation of neighboring lung lobules. T h e latter would be exaggerated during increased respiratory rate and am plitude in the presence of small airway disease and fibrosis. The lungs are strategically situated to catch emboli car ried in venous blood. In a c c o r d a n c e with the general pa thology of e m b o l i s m , the o u t c o m e will depend on the nature of the embolic material and on the features of the pulmonary circulation. B e c a u s e the lung is supplied by both pulmonary and bronchial arteries and has extensive collateral channels, infarction usually does not follow em bolism and thrombosis unless the pulmonary circulation is already c o m p r o m i s e d . It is possible, for instance, to find a major pulmonary artery occluded by large, pale, friable thromboembolic material without gross abnormality of the pulmonary p a r e n c h y m a . Bacterial emboli are associated with fulminating bacteremias and cause acute pulmonary e d e m a or interstitial pneumonia. Septic emboli arising from infected thrombi cause t h r o m b o e m b o l i s m , arteritis, usually multiple abscessation, and sometimes m o r e exten-sive chronic suppurative pneumonia. In the cow, septic emboli arise mainly from thrombosis of the posterior vena cava due to local spread of a hepatic abscess. They can also originate in uterine and pelvic veins. Emboli arise mainly from mesenteric veins in horses, and they can originate from vegetative endocarditis in any species. Tumor emboli vary in number from a few widely sepa rated foci to extensive showering of capillaries and larger vessels with neoplastic cells. The latter is more common with highly invasive, anaplastic carcinomas such as some types of mammary carcinomas in bitches. An unusual form of embolism occurs where carcinoma cells lodge and proliferate within vessels to produce multiple discrete foci surrounded by smooth muscle and collagen. In some foci, there is thrombosis which stimulates organization by gran ulation tissue and frequently leads to death of the neoplas tic cells and obliteration of the vascular lumen. Malignant cells usually proliferate more in perivascular lymphatics than in the vessels themselves. Fat embolism is only occasionally important in animals. The fat can originate from bone marrow at sites of fracture and from severe hepatic lipidosis when the hepatocytes rupture. The emboli lodge in alveolar capillaries and pro duce sausage-shaped distensions, which are empty in rou tine paraffin sections. Megakaryocytes are frequently found in pulmonary capillaries, particularly in dogs. A small number of megakaryocytes derived from bone mar row are present in circulating blood and lodge in the lungs where they continue to produce platelets. This is a normal occurrence, but may be accentuated when there is com pensatory extramedullary hematopoiesis in spleen and liver. Pulmonary thrombosis can be triggered, as elsewhere, when there is hypercoagulability, stasis of blood, or vascu lar endothelial damage, as well as by embolism and endo arteritis. There is an association between pulmonary thrombosis and renal amyloidosis in dogs because of the loss of antithrombin III as part of the protein-losing ne phropathy. The endoarteritis caused by Dirofilaria immitis or Angiostrongylus vasorum is also a cause of thrombosis in dogs; less commonly, thrombosis is secondary to ulcer ation of intimal atherosclerotic plaques. Disseminated in travascular coagulation in septicemic, toxic, and advanced neoplastic states is also an important cause (see The Car diovascular System, Volume 3, Chapter 1). Pulmonary thrombosis of unexplained cause is found occasionally in all species. Pulmonary infarction is an unlikely event unless the pulmonary circulation is already compromised. Thrombo sis of large vessels is more likely to lead to congestion, edema, and atelectasis of the affected regions. Most in farcts occur in lungs which have generalized passive con gestion. Thrombi occurring in conditions associated with general circulatory collapse, such as disseminated intra vascular coagulation, are therefore particularly likely to cause infarction. All recent infarcts are hemorrhagic. They occur most frequently in the caudal lobes ( Fig. 6 .32). They usually extend to the pleura and are particularly prone to affect the sharp costophrenic borders of the lung. At the costophrenic margin, they are wedge shaped with the broad base toward the hilus of the lung. When they involve only one pleural surface, they are cone shaped with the base at the pleura. The shape is difficult to appreciate when they are small because their margins blend laterally with adja cent congested parenchyma. Infarcted areas bulge on the pleural aspect and are red-blue to black. They are firm, and the overlying pleura becomes roughened, opaque, and covered by bloodstained exudate if the infarct is more than a few hours old. When the infarct is large, the occluded vessel can usually be detected at or near its apex. Histolog ically, an early infarct has extensive hemorrhage against a background of necrotic parenchyma. If the animal sur vives, there is lysis of red cells and a border of neutrophils and macrophages appears within 1-2 days. Organization by peripheral encroachment of granulation tissue occurs subsequently and eventually results in scar formation. The sequelae to septic infarction consist of the more severe changes described previously for septic thromboem bolism. Pulmonary hypertension can be initiated by high-pres sure flow of blood in the pulmonary artery, as occurs in congenital left-to-right shunts, or by increased resistance in the pulmonary vascular system. The increased resis tance to flow may be the result of left-sided heart failure, as occurs with mitral incompetence, luminal narrowing of vessels by arteriosclerotic changes, or by hypoxic vaso constriction as seen in high-altitude disease of cattle (see The Cardiovascular System, Volume 3, Chapter 1). Re gardless of initial cause, there occurs a vicious cycle of hypertension causing arteriosclerosis, which in turn leads to more hypertension. Probably the most common cause of hypertension is functional resistance to flow due to hypoxemia. The hypoxemia may reflect the low ambient oxygen tensions of high altitudes, the various forms of hypoventilation, or the various causes of abnormal ventilation/perfusion ratios. The histologic changes in the pul monary vasculature may be minimal, consisting of muscularization and intimal thickening of small arteries, but in cattle, and to a lesser extent in sheep, muscular thickening in veins is prominent and develops rapidly. Any subacute or chronic lesion causing narrowing or obliteration of pulmonary vessels can cause pulmonary hypertension. Thromboembolic situations may therefore produce hypertension and cor pulmonale. Widespread fi brosis in chronic interstitial pneumonias can also cause pulmonary hypertension by occluding small vessels. There is frequently hyperplasia of smooth muscle of bron chioles, alveolar ducts, and small vessels accompanying fibrosis, particularly in cattle. It is possibly caused by stimulation of smooth muscle cells by platelet-derived and other growth factors, which also stimulate the fibroblasts. The increase in smooth muscle tends to exacerbate the Alveolitis is a n o t h e r term used to describe acute exudative inflammation of alveolar tissue. Separate and sometimes conflicting use of pneumonia, pneumonitis, and alveolitis has more potential for confusion than clarification, however, so the term pneumonia will be used for pulmonary inflammation throughout this chapter. Salient morphologic and pathoge netic features of the various types of pneumonia are con veyed by additional descriptive terms. The susceptibility of alveolar cells to injury and their capacity for regeneration have been briefly outlined in the first section of this chapter. When considering the response of alveolar tissue to injury, a brief review of alveolar cell responses and a few of the major regulatory molecules involved is warranted. Type I alveolar epithelial cells are among the most sensi tive cells to injury in the lung. The usual pattern of alveolar response to injury is for necrosis and sloughing of type I cells to occur during the acute exudative phase of inflam mation. Provided the severity of the process is not suffi cient to cause necrosis of type II cells and other compo nents of the alveolar septa, the type II cells begin to proliferate within 24 hr and eventually completely line the previously denuded alveolar wall. Histologically, small clusters of alveolar cells can be detected 2-3 days after loss of type I cells, and by 6 days there can be complete lining of alveoli by cuboidal type II cells. Alveoli com pletely lined by type II cells give the appearance com monly referred to as epithelialization. In some instances, exaggerated proliferation of type II cells in dogs accompa nied by variability of nuclear/cytoplasmic ratios is erro neously interpreted as a neoplastic process. The complete lining of alveoli by type II cells, which is a common re sponse to injury, has also misleadingly been referred to as adenomatosis. Proliferation of type II cells marks the shift from the exudative to the proliferative stage of pneumonia and is usually accompanied by an alveolar exudate in creasingly composed of macrophages and other mononu clear cells. Resolution of the epithelial lesion, once in flammation has subsided and provided there has not been scarring of the alveolar wall, is accomplished by transfor mation of type II cells into type I epithelium. The character of alveolar exudate depends on its cause. In general, it changes with time from serous fluid (inflam matory edema) containing various quantities of fibrin, through a neutrophil phase that predominates in most bac terial infections, to an accumulation mostly consisting of alveolar macrophages. Both the dominant features and the rate of change vary according to cause of the inflammation. The degree of neutrophil infiltration into alveolar spaces and the amount of fibrin deposition and persistence are determined by a complex network of interactions at the alveolar level involving alveolar macrophages, capillary endothelial cells, circulating neutrophils, and serum com ponents, as well as the nature and severity of the inciting agent. Neutrophil movement and function in the alveolar space involve the classical processes of margination and adher ence to endothelial cells, chemotaxis across the endothe lial and epithelial barriers into the lung, and stimulation (up-regulation) of phagocytic and secretory functions. De pending on the nature of the inciting stimulus, various celland serum-derived inflammatory mediators are released to activate neutrophil adherence to capillary endothelial cells. Factors such as leukotriene B 4 , platelet activating factor, and C5a can stimulate expression of integrin recep tors on neutrophil surfaces. Interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a), which are also produced by activated macrophages, can act on endothelial cells to stimulate expression of endothelial leukocyte adhesion molecules and other adhesion molecules. These promote neutrophil-endothelial adherence prior to migration of the neutrophil into the alveolus along chemotactic concentra tion gradients. Chemotactic factors for neutrophil move ment into the lung are well characterized and include IL-8, C5a, leukotriene B 4 and fibrin-degradation products. Interleukin-8 (neutrophil attractant/activation protein-1) is a 8400-dalton protein, which is released by many pulmo nary cells including macrophages, type II cells, endothelial cells, and fibroblasts following exposure to a number of stimulants including IL-1 and TNF. Clearly, cytokines released from macrophages following a number of pertur bations, including particulate and antigen exposure and stimulation by gamma interferon, play a major role in neutrophil recruitment into the lung. The quantity of fibrin in alveolar exudate is an index of the amount of damage to the alveolar-capillary membrane because it reveals leakage of its precursor fibrinogen. Fi brin, together with other serum constituents and cell de bris, forms the hyaline membranes found in conditions involving severe damage to the alveolar wall. The amount of fibrin deposited within and persisting in the alveolus is an important determinant of loss of alveolar function and repair by alveolar fibrosis. When alveolar epithelium is denuded, fibrinous membranes or plugs are infiltrated by macrophages, fibroblasts, and endothelial cells from the alveolar wall. Macrophages promote fibrosis by releasing fibronectin, which is chemotactic for fibroblasts, and by release of cytokines and growth factors including trans forming growth factor-beta (TGF£), platelet derived growth factor (PDGF), and insulinlike growth factors, all of which stimulate collagen synthesis and synthesis of glycosaminoglycans. Collagen-containing fibrous tissue can be detected as early as 7 days after initial fibrinous exudation. Chronic inflammation of the alveolar septa is the major feature of chronic interstitial pneumonias and will be dis cussed more fully under that heading. Chronic broncho pneumonia, on the other hand, is much more likely to lead to destruction of alveolar walls and abscessation because of persistent suppuration caused by pyogenic bacteria. An aspect of the response of alveolar type II cells to chronic injury is their potential for undergoing metaplasia to squa mous, ciliated, or fetal-type, glycogen-containing cells. One of the most important general features of the response of pulmonary epithelial cells to both acute and chronic injury is the extent to which transdifferentiation (metapla-sia of one cell type to another) can occur in airways and alveoli. Persistent irritation or disruption of the normal epithelial interaction with basement membrane and alveo lar stroma leads to persistence of atypical alveolar type II cells and the possibility that they will occasionally give rise to bronchioloalveolar tumors, as sometimes seems to occur in dogs and rodents. The pulmonary inflammatory response varies according to the nature of the causative agents, their distribution (particularly the route by which they reach the lung), and their persistence. Pneumonia can be classified on a tempo ral basis as acute, subacute, or chronic, on an etiologic basis by major categories of causative agent, or according to morphologic features. Morphologically, there are two approaches. One approach is to classify according to the type of inflammation. Here there are two main subcatego ries: exudative pneumonias, in which the emphasis is on filling of alveoli by exudate with predominant catarrhal, fibrinous, suppurative, hemorrhagic, or necrotizing charac teristics, and proliferative pneumonias in which the em phasis is on proliferation of alveolar type II cells, fibro blasts, macrophages, and possibly additional elements. The second, and more useful, morphologic approach is to classify pneumonias according to initial site of involve ment and the pattern of spread of the lesion. On this basis, most pneumonias fall into three main categories: bronchopneumonia, lobar pneumonia, and interstitial pneumonia. The importance of this classification lies in the provision of clues regarding pathogenesis and possible causes. There is often good linkage between the various classi fications. For example, acute pneumonias are commonly of infectious cause, exudative in nature, and of bronchopneumonic pattern. Chronic pneumonias are of highly var ied cause, proliferative in nature, and often of interstitial pattern. Other correlations, and exceptions to these gener alizations, are identified in following sections. The hallmark of bronchopneumonia is the origin of in flammation in the bronchioloalveolar junction, as an ex tension of bronchial inflammation. This is correlated with a predominantly aerogenous portal of entry of the caus ative agents, involvement usually of cranio ventral regions of the lungs, and a patchy or variegated gross appearance. The irregular lobular involvement is reflected in the older term lobular pneumonia. The defenses of the healthy lung are remarkably effec tive. Whether inflammation results from the constant bom bardment of the lung by inhaled irritants depends on the balance between the intensity of the insult and the effec tiveness of local defense mechanisms at each structural level of airways and parenchyma. In the distal respiratory tract, the bronchiolar-alveolar junctions are the sites of greatest vulnerability to damage by many types of inhaled particles and vapors, including droplet nuclei carrying in fectious agents. There are three main reasons for the vul nerability of these regions. First, they are the major site of deposition of small particles (0.5-3.0 pm in diameter) capable of reaching deep lung. Second, the epithelium of bronchioles is probably susceptible to damage because it is not protected by the mucous blanket of larger airways or by an effective alveolar macrophage system. Third, the cellular (mostly macrophage) and noncellular material cleared from large volumes of alveolar parenchyma has to pass through the narrow lumen of its parent bronchiole, an easily plugged funnel or bottleneck, especially where lack of collateral ventilation hampers expulsion of ex udate. Epidemiologic and experimental evidence indicates that the important infectious bronchopneumonias of animals usually develop only when the balance is tipped in favor of disease by an increase in numbers of pathogenic micro organisms reaching vulnerable bronchioloalveolar regions of the lung or when pulmonary defenses are underdevel oped or impaired. In most situations, both of these circum stances are present. Increased exposure to pathogenic microorganisms is particularly likely to occur when ani mals from a variety of sources are congregated. This is often associated with lack of immune experience with the organisms involved. An important aspect of increased exposure of pulmonary parenchyma to pathogenic micro organisms at times of environmental stress is the concur rent increased colonization of upper respiratory mucosa by agents such as Pasteurella spp. Reduced effectiveness of pulmonary defense mechanisms occurs in congenital and acquired immunodeficiency states and can also be caused by a variety of factors impairing the mucociliary blanket, alveolar macrophage defense systems, or both. Dehydration, extreme chilling, viral infection, inhalation of toxic gases and particles, certain anesthetics, and ciliary abnormalities inhibit mucociliary clearance and can pre dispose to bacterial colonization. Functions of alveolar macrophages and reinforcing activities of lymphoid cells are impaired by severe chilling, starvation, viral infection (including immunodeficiency viruses), toxic gases, meta bolic disorders such as uremia and acidosis, and immuno suppressants such as corticosteroids. Chronic disease of heart or lungs also reduces pulmonary defensive capa bility. Various combinations of these factors exist in circum stances recognized as predisposing to a high risk of bron chopneumonia and also the more aggressive lobar pneu monias. Most outbreaks are in young, intensively managed animals, especially soon after stresses associated with transport. Mixing of animals with different microbial floras and levels of acquired immunity is often involved as well. Sporadic cases of bronchopneumonia in individual animals are likely to be associated with interactive predis posing causes such as debility, immunodeficiency, preex isting cardiopulmonary disease, and prolonged anesthesia or recumbency of illness. Aspiration of foreign material can cause bronchopneumonia, but because of its severity, the inflammation more commonly has a lobar distribution. The characteristic cranioventral distribution of infec tious bronchopneumonias in animals indicates that in these regions the balance between insult and defense is most precarious. This is supported by the fact that pneu monia caused by inhalation of acutely irritant particles or gases does not have a cranioventral distribution. All the reasons for the cranioventral involvement have not been determined. It is reasonable to hypothesize that there is increased deposition of infectious particles in these re gions, that defenses are more easily compromised, or both. There is slightly increased deposition of particles in cranial regions. This is believed to be due to the shorter and more abruptly branching airways. Gravitational in fluences impeding clearance of cranioventral regions, and possibly leading to pooling or reflux of secretions, are probably more important contributory factors. The smaller size of ventral airspaces and their greater vulnera bility to collapse or blockage may also be involved. The possible roles of different rates of leukocyte traffic through the pulmonary capillary bed and different densities of in tercellular adhesion molecules or other receptors have not been explored. There is evidence that P. haemolytica reaching the lungs in the blood also causes pneumonia in cranioventral regions. Since this is an unusual location for hematogenous injury, it supports the hypothesis that bacterial infection can become established and develop further in the cranioventral lung because local defense mechanisms are less effective there. Bacteria are the main causes of clinically significant bronchopneumonia, most commonly after pulmonary de fenses have been lowered by viral infection, severe stress, or other predisposing factors. Many species of bacteria are involved, the particular set of agents varying with animal species and sometimes geographic location. In sheep and cattle, Pasteur ella spp. and Actinomyces pyo genes are common. In swine, P. multocida, Actinobacillus pleuropneumoniae, Haemophilus spp., A. pyogenes, Bordetella bronchiseptica, and Salmonella choleraesuis are often involved. In horses, the chief offenders are Strepto coccus spp. and Rhodococcus equi. In dogs, B. bronchi septica, Klebsiella spp., streptococci, staphylococci, and Escherichia coli are important. In cats, in which the dis ease is less common, P. multocida and a variety of other Gram-negative organisms are most often found. Bacteria tend to cause suppurative pneumonia. Exceptions, such as the fulminating fibrinonecrotic pneumonias that can be caused by Pasteurella and Haemophilus spp., will be addressed later. The involvement of viruses, mycoplas mas, and chlamydiae will also be considered further under specific pneumonias, as will their roles in causing the enzootic pneumonias of cattle, sheep, and swine. The typical gross appearance of bronchopneumonia is of irregular consolidation in cranioventral regions. The cranial and middle lobes are most often affected in those species having well-defined lobation. Consolidated lung varies from dark red, through gray-pink to more gray, depending on the age and nature of the process. Palpable firmness (consolidation) of the tissue is the single most important gross criterion of pneumonia. The extent to which there is a lobular or sublobular mosaic of consoli dated, atelectatic, congested, and more normal lung tissue depends partly on the severity and rate of spread of the pneumonia and partly on the degree of septation. It is most common in relatively slow-spreading bronchopneumonias of ruminants and swine which have well-developed septa tion ( Fig. 6.33) . The more uniform and rapidly spreading the pneumonia, the more homogeneous and extensive the consolidation. Even where complete lobes become in volved, however, the bronchopneumonia pattern can of ten be detected on careful gross examination by the pres ence of multiple, small, evenly spaced, gray-white, bulging foci separated by narrow deep red zones. The bulging pale foci denote areas of exudation centered on bronchioles, and the deeper red zones represent more congested, edem atous, and atelectatic alveolar p a r e n c h y m a in peripheral acinar regions. This gross pattern is m o r e usual in bron chopneumonia of dogs and cats, which have rudimentary interlobular septa, and in the enzootic b r o n c h o p n e u m o nias of ruminants and swine. T h e pleura overlying mild to moderately inflamed pulmonary p a r e n c h y m a usually has its normal smooth, glistening sheen. Where the inflamma tory process is severe, h o w e v e r , it extends to the pleura to produce reddening, roughening, and superficial accu mulation of yellow-gray fibrinous or fibrinopurulent exu date indicating pleuritis. The cut surface of affected lung reflects the variability of involvement seen on the pleural surface. In catarrhal or suppurative b r o n c h o p n e u m o n i a s , consolidated lobules are moist on cut section; mucopuru lent or purulent material can be expressed from small airways and can be seen in fluid or foamy state in the large airways. Frank abscesses can be present in severe suppurative inflammation ( Fig. 6 .34A). The cut surface of fibrinous inflammation, in contrast, has a dull, dryish appearance ( Fig. 6 .34B). Histologically, the nidus of inflammation in broncho pneumonia is in the bronchioloalveolar junctions ( The spread of infection after its initial foothold in the bronchiolo-alveolar regions is mostly by airways, both proximally through bronchioles and bronchi and distally through alveolar ducts and alveoli within a respiratory acinus ( Fig. 6 .37). T h e rate and extent of spread depends mainly on the balance between virulence of the causative agent and host defense. Rapid bacterial proliferation leads to severe suppurative pneumonia if pyogenic bacteria are involved, and fibrinous through hemorrhagic and necrotiz ing pneumonia if highly toxigenic bacteria such as P. haemolytica and A. pleuropneumoniae are the cause. In the latter instances, the pneumonia is likely to take on lobar characteristics, and spread of infection across edem atous interlobular septa can b e c o m e important. The time sequence of inflammatory events varies with the severity and speed of onset, which in turn depend on the balance between the virulence of the agent and host defense. The red stage of consolidation is present for only 2 -3 days in a typical bacterial pneumonia. T h e increasing amount of leukocytic or fibrinous exudation reduces capil lary volume and results in a gray appearance within 5 -7 days. Proliferation of alveolar type II cells can also occur during this period unless there is severe purulent or fibrin onecrotic inflammation. Variations on this theme will be dealt with under the heading of the special types of pneu monia or under specific etiologic agents. Just as the rate at which b r o n c h o p n e u m o n i a reaches maturity and the type of inflammation vary greatly, so the rate and degree of resolution vary. A catarrhal or mild purulent b r o n c h o p n e u m o n i a can begin to resolve within 7 -1 0 days and the lung return to normal within 3 -4 w e e k s . Once the agent has been o v e r c o m e by the cellular and humoral defenses, m a c r o p h a g e s b e c o m e the predominant cell and phagocytose debris and aid in lysis of fibrin. T h e macrophages and extracellular debris are mostly cleared through the airways with the aid of coughing and collateral ventilation. This milder inflammation is not associated with significant damage to alveolar b a s e m e n t m e m b r a n e s or capillaries, and resolution can occur without recogniz able trace. In these c a s e s , there is a stage as the inflamma tion begins to wane w h e n the alveoli are lined by alveolar type II cells. Transformation to type I cells occurs as the inflammatory exudate is cleared. A transitory stage of partial atelectasis is usually present b e t w e e n clearance of exudate and regeneration of the pulmonary p a r e n c h y m a . If there is a residual bronchiolitis or bronchitis, h o w e v e r , and especially if the lack of collateral ventilation impedes expulsion of exudate from small airways, the atelectasis, bronchiolitis, and bronchitis persist. This probably ex plains why resolution of b r o n c h o p n e u m o n i a is frequently incomplete in ruminants and swine, and w h y cattle in particular tend to develop chronic suppurative bronchiec tasis and b r o n c h o p n e u m o n i a . Severe b r o n c h o p n e u m o n i a causes death mostly by a combination of hypoxemia and toxemia. Complete resolu tion can occur, but requires integrity of alveolar basement m e m b r a n e s , readily cleared e x u d a t e , and rapid killing of the infectious agent. Necrosis of alveolar septa, intracta ble e x u d a t e , or persistence of the agent therefore preclude complete resolution, even if the animal survives. Often all three conditions occur together. T h e resulting complica tions range from healing with scarring, through atelectasis, chronic b r o n c h o p n e u m o n i a , and bronchiectasis, to ab scessation or necrosis with sequestration. Atelectasis is both a prelude and a sequel to broncho pneumonia. As a complication of b r o n c h o p n e u m o n i a , it follows resolution of parenchymal inflammation with per sistence of obstructive bronchiolitis and bronchitis. Ob structive bronchiolitis can occur in three w a y s . In the simplest form, there is a chronic bronchiolitis with persis tent plugging of the lumen by e x u d a t e . T h e second form occurs w h e n there is necrosis of bronchiolar epithelium, presence of fibrin-rich e x u d a t e , and development of plugs or polypoid projections of granulation tissue (Fig. 6 .20A). These can cause complete obliteration of the bronchiole if epithelial necrosis is total. A n alternative finding is that re-epithelialization of incompletely obliterating granula tion tissue can occur to p r o d u c e multiple, small, rudimen tary lumina analogous to a recanalized t h r o m b u s ( chiolar origin. This can be caused by constricting fibrous tissue, in which case it denotes a preceding severe acute inflammation and usually occurs with obliterative bronchi olitis, or by lymphoid proliferations such as occur in myco plasmal pneumonias. Bronchopneumonia may b e c o m e chronic. This is seen most commonly in cattle and to a lesser extent in sheep and swine. It is reasonable to associate the tendency for poor resolution of b r o n c h o p n e u m o n i a with complete lobu lar septation and lack of collateral ventilation. T h e viru lence of the bacteria involved also undoubtedly plays some part. T h e lesions of chronic b r o n c h o p n e u m o n i a are those of chronic suppuration with fibrosis. The suppurative le sions in ruminants and swine tend to involve mostly the airways ( Fig. 6.38A ,B) and, in cattle especially, there is bronchiectasis and abscessation. Alveolar p a r e n c h y m a is mainly atelectatic and fibrotic. Severe acute exudative pneumonias cause prominent widening of interlobular, subpleural, and peribronchial zones by accumulation of serofibrinous or fibrinopurulent exudate in the loose fascia and lymphatics. T h e exudate b e c o m e s organized and visi ble as broad seams of moist fibrous tissues, most fre quently seen as an aftermath of lobar pneumonia in rumi nants and swine. Similar changes occur in subpleural regions and as irregular interlobular septa in the horse as a sequel to severe exudative pneumonia. Organization of fibrin-containing pleural exudate often produces pleural adhesions. Severe suppuration and abscessation of pulmonary pa r e n c h y m a can be caused by pyogenic organisms. Suppura tion is c o m m o n in dogs w h e n pneumonia is caused by Bordetella bronchiseptica and in foals w h e n it is part of the pyogranulomatous response to Rhodococcus equi. In both cases, the exudate has a gray ish-yellow slimy quality. B r o n c h o p n e u m o n i a in the horse commonly causes ab scessation because the organisms are usually pyogenic streptococci (Figs. 6.34A, 6.39). The suppuration usually begins deep in the consolidated areas. The alveolar tissues undergo necrosis in volumes large enough to be visible as many gray nodules, around each of which is a narrow hyperemic zone. T h e s e nodules coalesce, and most of the lobe may be converted to a fragile mass of dull gray detritus. Some of this can liquefy and be discharged into a b r o n c h u s so that a cavity remains. Actinomyces pyogenes causes pulmonary abscesses in sheep, cattle, and swine. The abscesses sometimes develop in the alveolar tissue, or they may be associated with chronic suppurative bron chitis, bronchiolitis, and bronchiectasis. The abscesses vary in size and n u m b e r , and the purulent reaction usually extends to the pleura to produce dense adhesive pleuritis, or an abscess may fistulate to produce pleural e m p y e m a . Metastatic abscessation can occur in other organs. E r o sion of a blood vessel occasionally leads to fatal pulmonary hemorrhage. A variety of other bacteria occasionally cause abscesses, the set of possible agents varying ac cording to species of animal affected. L o b a r pneumonia, as the term implies, is one in which entire pulmonary lobes, or major portions of lobes, are diffusely and uniformly consolidated. Pathogenetically, lobar pneumonias are rapidly confluent, fulminating bron chopneumonias in which gross evidence of bronchiolar orientation and spread is not evident. Since lobar p n e u m o nias have this close relationship to b r o n c h o p n e u m o n i a s , it is not surprising that separation of the t w o is difficult and often arbitrary. This is further complicated by the fact that even though large areas of uniform consolidation may be seen on gross examination, microscopic evidence often reveals orientation of the inflammation about bronchioles and hence basically a b r o n c h o p n e u m o n i c pathogenesis. The term lobar is entrenched, however, and is useful to indicate a fulminating or highly aggressive bronchopneu monia. T o use this term with as little confusion as possible, it is best applied as a gross designation of extensive pneu monic consolidation in which the parenchymal involve ment appears uniform ( Fig. 6 .40). Exceptions to the uni form appearance are the necrotic foci which develop, for example, in pneumonic pasteurellosis of cattle or conta gious bovine pleuropneumonia ( Fig. 6 .34B) and the exuda tive distension of interlobular septa in ruminants and swine. Since lobar pneumonia can be regarded as a fulminating bronchopneumonia, it follows that similar pathogenetic factors are involved. L o b a r pneumonia is the result of overwhelming spread of the inflammatory p r o c e s s , and is usually caused by the action of a virulent organism in an animal with severely impaired pulmonary defense. T h e prototype in animals is lobar p n e u m o n i a caused by P. haemolytica in cattle that have recently been stressed by transportation and frequently have a predisposing respira tory viral infection. A strong correlation exists b e t w e e n a fulminating pulmonary inflammation and production of profuse fibrinous e x u d a t e , as exemplified by the condition in cattle. Therefore a t e n d e n c y has arisen to use the terms lobar and fibrinous interchangeably. This is u n w a r r a n t e d , however, b e c a u s e , although there is considerable overlap, not all lobar pneumonias are fibrinous and vice versa. Because of the p r e d o m i n a n c e of p n e u m o n i c pasteurellosis as a cause of lobar p n e u m o n i a in cattle and other animals, details of the typical lesions will be presented under that heading. Other than by overwhelming Pasteurella infec tion, lobar p n e u m o n i a is sometimes caused by Haemophi lus somnus in ruminants and Haemophilus spp. and Acti nobacillus pleuropneumoniae in swine. Mycoplasma mycoides is incriminated in cattle and goats. L o b a r pneu monia can occasionally be caused by P. multocida in cats and pigs. In horses, massive proliferation of streptococci or occasionally Rhodococcus equi can be responsible. A n o t h e r cause in all species is the aspiration of foreign fluids or gastric contents. Infectious lobar p n e u m o n i a s diffusely affect large por tions of cranioventral lung ( Fig. 6 .40). T h o s e caused by aspiration affect portions of lung lowermost at the time of aspiration and therefore, in a r e c u m b e n t animal, may involve the lateral zones of the caudal lobe of one side or the dorsal zones of both sides. As would be expected from their peracute or acute nature, lobar pneumonias are hemorrhagic, fibrinous, fibrinopurulent, or necrotizing and sometimes gangrenous (the latter usually caused by aspiration). The gross a p p e a r a n c e varies with the age of the lesion from reddish black through d e e p red, to reddish brown or gray. In all but the peracute hemorrhagic c a s e s , there is usually roughening of the overlying pleura and a coating of fibrin. Two additional features are often seen in ruminants and swine and less often in horses. One is the prominent distension of interlobular septa by serofibrinous exudate, and the other is the development of irregular, discrete zones of necrosis with swollen, pale margins ( Fig. 6 .34B). The cut surface in early cases exudes bloody fluid and later, in the fibrinous lobar pneumonias, becomes grayish brown, finely granular, dry, and friable. Necrotic areas sometimes become crumbly and cavitated. The initial stage of red consolidation (hepatization) is characterized by hyperemia of alveolar capillaries and flooding of alveoli with serofibrinous exudate admixed with various amounts of hemorrhage, small numbers of alveolar macrophages, and neutrophils ( Fig. 6 .41A). The amount of fibrin precipitated in alveoli as dense pink fibril lar or more homogeneous clumps rapidly increases. It is accompanied by neutrophils, which predominate in some regions. The capillaries are compressed by pressure of exudate, and many become occluded by thrombi. This is the stage of red-brown or gray consolidation, depending on the degree of ischemia and extent of hemorrhage and lysis of extravasated red cells. During this time, the inter lobular septa (when present) and perivascular, peribron chiolar, and subpleural sheaths become widely distended by serofibrinous or fibrinous exudate within the loose con nective tissue and especially in the lymphatics. The latter often become greatly distended by fibrin thrombi (Fig. 6 .4IB). Small airways in affected regions are filled with either a purulent exudate or a more fibrinous exudate similar to that filling alveoli. Arteries, and especially veins, passing through severely inflamed regions can develop vasculitis by local extension across their walls, and occa sional thrombi are formed. There is a tendency for leuko cytic aggregates in alveoli to become condensed or spindle shaped (oat shaped) under the influence of toxins from Gram-negative bacteria such as Pasteur ella spp. (Fig. 6 .41C); necrotic foci can also develop ( Fig. 6 .41D). A feature common to most lobar pneumonias is massive proliferation of bacteria, which can be readily detected even in sections stained by hematoxylin and eosin. They are especially prominent within developing necrotic foci and tend to be concentrated close to the leukocytic bound ary zones. This description of lobar pneumonia has drawn heavily on the fibrinous lobar pneumonias best exemplified by pneumonic pasteurellosis in cattle. However, the features of predominantly fibrinous pneumonia in a series of af fected cattle are often a mix of lobar and bronchopneumonic patterns. The complications of lobar pneumonia are more fre quent and serious than those of the less severe broncho pneumonias. Death is frequent, usually with accompa nying pleuritis and sometimes with pericarditis. If the animal survives, resolution without some degree of scar ring is virtually impossible. Extensive organization by granulation tissue leading to fleshy fibrous tissue (carnification) is likely, as is chronic abscessation. Peritonitis may arise by hematogenous spread of the infection or direct extension from the pleura through the diaphrag matic lymphatics. Additional complications include toxe mic degeneration of parenchymatous organs, endocardi tis, fibrinous polyarthritis, meningitis, and hemolytic icterus. A late complication may be empyema of the pleu ral cavity following rupture of a subpleural abscess. Ero sion and rupture of an abscess into a bronchus can cause a rapid onset of purulent bronchopneumonia or fatal hem orrhage if an artery is affected. Diffuse or patchy damage to alveolar septa is the essen tial feature of interstitial pneumonia. It can be caused by many forms of pulmonary injury. The lack of a completely satisfactory morphologic designation embracing the vari ants of interstitial pulmonary disease has led to a confusing array of terms. Two terms are most commonly used: inter stitial pneumonia and diffuse fibrosing alveolitis. The for mer is preferred because it more appropriately covers the broad range of morphologic, etiologic, and pathogenetic aspects. Other relevant terms, with emphasis on more chronic diseases, are chronic diffuse infiltrative lung dis ease and diffuse interstitial pulmonary fibrosis. Interstitial pneumonias are inflammatory conditions in which there are predominantly exudative and proliferative responses involving alveolar walls. A variety of agents produce acute, diffuse damage to alveolar walls, causing an early intra-alveolar exudative phase that is quickly followed by proliferative and fibrotic responses. The acute pulmonary injury can be caused by, or associated with, conditions such as severe viral pneumonia, chemical lung injury, acute pancreatitis, shock, and septicemia. Often there is superimposed toxicity caused by the high concen trations of oxygen used therapeutically. Terms which refer to the various circumstances under which such acute dam age occurs in humans include shock lung, respirator lung, and traumatic wet lung. Clinically, however, the common feature is acute respiratory distress and the collective term adult respiratory distress syndrome is generally used. The syndrome was originally called acute respiratory distress syndrome in adults to distinguish it from neonatal respira tory distress syndrome in human infants. For veterinary medicine, it is sufficient to refer to acute respiratory dis tress syndrome because there is no need to distinguish the adult and the less common neonatal forms. The clinician evaluating a patient with acute respiratory distress and the pathologist interpreting an acute interstitial pneumonia (alveolitis) are both dealing with acute pulmonary injury and therefore need to consider the same differential diag noses. Pathogenetically, interstitial pneumonia results from diffuse or patchy damage to alveolar septa. The absence of obvious orientation of the lesions in and around small airways differentiates interstitial pneumonia from bron chopneumonia. Grossly, the lesions are distributed widely throughout the lungs, often with greater involvement of dorsocaudal regions (Fig. 6.42A,B ). This pattern is in T h e alveolar septal damage is caused by a blood-borne insult in most instances. This accounts for the widespread or r a n d o m distribution of lesions within affected acini as opposed to the centriacinar localization of damage caused by most inhaled irritants. There are t w o notable excep tions to the generalization that deeply penetrating airborne lung irritants cause mainly centriacinar damage, and blood-borne irritants cause diffuse or r a n d o m damage. One is that some blood-borne chemicals exert their toxic effect only after they are metabolized to reactive interme diates by microsomal enzyme systems, particularly monooxygenases. Depending on the chemical and the species of animal affected, damage can be limited to nonciliated bronchiolar epithelial (Clara) cells and the pulmonary alve olar p a r e n c h y m a , spared, even through the parent chemi cal is in the blood. Necrosis of equine Clara cells by 3-methylindole is the best known example in domestic animals. The second exception to the generalization is that inhalation of irritants which b e c o m e widely distributed in the lung causes sufficiently diffuse damage to present as interstitial pneumonias. Severe, acute, diffuse damage is associated with inhalation of very high concentrations of toxic gases or fumes because there is not an appreciable concentration gradient of the toxic substance between small airways and distal portions of the pulmonary acini. Inhalation of 100% oxygen is the best example. The pneu moconioses, on the other hand, are chronic progressive lesions caused by inhalation of inorganic dusts. H e r e , although there may initially be a greater tendency for the granulomatous or fibrotic foci to be located close to termi nal airways, this often b e c o m e s obscured by the time the lesions progress to the point of causing clinical pulmonary dysfunction. There is no explanation for the tendency of interstitial pneumonias, whether of hematogenous or aerogenous origin, to be more severe in dorsocaudal re gions of the lung. Histologically, the interstitial pneumonias as defined here can range from acute to chronic. Although the term implies that the inflammatory response takes place pre dominantly within the alveolar walls and the interstitial tissues of the lung, interstitial pneumonias of acute onset have an initial phase in which the most obvious feature is exudation into alveolar lumina. T h e interstitial compo nents soon predominate, however, if the animal survives. T h e apparent paradox that some interstitial pneumonias have an acute exudative phase is the principal reason for the alternative term of diffuse alveolitis. It is also the reason that acute interstitial pneumonia in cattle was ini tially called atypical interstitial pneumonia. As in other organs, the morphologic responses of the lung following damage by a large variety of agents have many features in c o m m o n , and the lesions often lack etiologic specificity. Acute injury, whether of toxic, meta bolic, or infectious origin, causes damage principally to alveolar capillary endothelial cells and type I epithelial cells. W h e t h e r the endothelium or epithelium is damaged first depends on the nature, portal of entry, and intensity of the insult and, to some extent, the species affected. Usually, however, the alveolar type I epithelial cells even tually suffer most damage because of their poor reparative capacity and inability to regenerate. During this acute phase, the most dramatic features of the lesion are flooding of alveoli with serofibrinous exudate and congestion and e d e m a of alveolar walls. Fibrin, other serum proteins, and cell debris frequently condense to form hyaline mem branes lining airspaces or aggregates plugging their lumina ( Fig. 6.42C ). There is usually some admixture of leuko cytes and erythrocytes in the alveolar exudate and an initial accumulation of mixed leukocytes within the alveo lar interstitium. Mononuclear cells predominate if the in flammation persists. Replacement of degenerate type I epithelium takes place on intact basement m e m b r a n e s by proliferation of type II epithelium, as described under patterns of alveolar response to injury. T h e resulting lining of alveoli by cuboi dal cells (epithelialization) is a c o m m o n feature of sub- acute to chronic interstitial pneumonias (Figs. 6.42D, 6.43A,B). Once the inflammation has subsided, and if there is not severe scarring of the alveolar wall, complete resolution can be effected by differentiation of type II cells into type I epithelium. Proliferation of alveolar type II cells marks the shift from the exudative to the proliferative stage of interstitial pneumonia. Onset of fibrosis is a critical feature of the proliferative phase because it is irreversible, at least in its mature form. Fibroblast proliferation can occur as early as 72 hr after severe alveolar d a m a g e . It is most evident when alveoli are filled with fibrinous exudate. Immature or profibroblasts can appear within alveoli in the lungs by 3 days after severe fibrinous exudation such as that caused by paraquat toxicity. Mature fibroblasts can be seen by 4 days, and collagen fibers can be detected histologically by 5 -7 days. Interstitial fibrosis also occurs in such instances, though not to such a dramatic degree. It occurs more rapidly when there is considerable interstitial e d e m a or serofibrinous exudation. Both intra-alveolar and interalveolar (interstitial) fibrosis, therefore, are sequelae to severe exudative lesions and can be a striking feature by 14 days after initial onset. If the animal survives and residual scar ring is present, it is no longer possible to determine the relative contributions of intra-and interalveolar fibrosis (Fig. 6.44) . Chronic, smoldering lesions in which there are prominent interstitial cellular accumulations, mostly of mononuclear cells, cause fibrosis within the alveolar walls. T h e rate of fibrosis is therefore heavily d e p e n d e n t on the intensity of inflammation. Studies on mechanisms un derlying fibrosis focus on t w o major areas. One is the biochemistry of collagen; the other, the nature of factors influencing collagen synthesis and degradation. A relative increase of type I collagen (dense fibers of high tensile strength) over type III (reticulin-type fibers) occurs wher ever active fibroplasia can be recognized histologically or where there is extensive scarring. There may be an early, transient increase in type III collagen in conditions where the rate of accumulation of fibrous tissue is slow. Factors influencing the balance of synthesis and degra dation of collagen are extremely complex. Potentially any of the cellular and biochemical alterations in an inflamma tory site can have an influence, and presumably most of them d o . Stimulation (up-regulation) of fibroblast prolifer ation and synthesis of collagen are believed to be induced by macrophage-derived cytokines. Important a m o n g these are alveolar-macrophage-derived and platelet-derived growth factors ( A M D G F and P D G F ) , interleukin-1, trans forming growth factor-a, fibroblast growth factor, and granulocyte/macrophage colony stimulating factor (GM-C S F ) . Collagen synthesis can also be stimulated by factors such as fibronectin and laminin. Inhibition of fibroblasts and collagen synthesis (down-regulation) is even less well understood, but collagen can be degraded, before becom ing heavily cross-linked to form scar tissue, by plasmino gen activation, cysteine p r o t e a s e , and collagenase. Cell-cell and c e l l -m a t r i x interactions are also im- portant in maintenance of normal structure and prevention of fibroplasia. Ultrastructurally, alveolar type II epithelial cells can be seen to be in contact with plasma m e m b r a n e s of fibroblasts by means of foot processes, which pass through gaps in basement m e m b r a n e . It is thought that the type II cells inhibit fibroblasts through these contacts, possibly with the aid of local production of factors such as prostaglandin E 2 ( P G E 2 ) . T h e type of collagen present in basement m e m b r a n e is also important because there is evidence that type IV collagen promotes spreading of type II cells and conversion to type I epithelium. T h e presence of types I and III collagen leads to the persistence of type II cells. This could account, at least in part, for the presence of cuboidal type II cells lining airspaces with fibrotic walls. If the animal survives, most acute interstitial p n e u m o nias resolve with various amounts of residual scarring (Fig. 6.44) . Chronic, progressive inflammation is not often encountered but, where a specific cause can be identified, is usually associated with persistence of, or repeated expo sure t o , the causative agent (e.g., dusts, drugs, or infec tious agents). Often immunologic processes are known or suspected to be at least partly involved in t h e pathogene sis, even where a specific cause cannot be identified. The central features of chronic interstitial pneumonia are intra-alveolar accumulation of various mononuclear cells (mostly macrophages), proliferation and persistence of alveolar type II cells, and interstitial thickening by accumulations of lymphoid cells and fibrous tissue. Granu lomatous interstitial pneumonia is probably the most com mon chronic form ( Fig. 6.45A ,B,C). Hyperplasia of smooth muscle and distortion of airspaces (honey combing) are sometimes present in more advanced cases, not necessarily in proportion to o n e another. Hyperplasia of smooth muscle, for instance, is a prominent feature of chronic progressive pneumonia (maedi) in sheep. A large variety of agents representing all major etiologic categories of disease can cause interstitial pneumonia. T h e list of recognized causes or associations is much larger for h u m a n s than for animals. Most of t h e recognized sponta neous interstitial pneumonias in animals are caused by infectious or parasitic agents or by toxins entering via the digestive tract. Hypersensitivity pneumonitis (extrinsic allergic alveolitis) and pneumoconiosis occur occasion ally. Occupational exposure to dusts, gases, fumes, and vapors, which c o m p o s e the largest group of causative agents in h u m a n s , is essentially lacking in animals. Other important categories of interstitial pneumonia in humans for which there is little or no definitive information con cerning analogous spontaneous conditions in animals are those caused by adverse drug reactions a n d those associ ated with collagen-vascular disorders such as systemic lupus erythematosus and rheumatoid arthritis. Most interstitial pneumonias in animals are infectious Fig. 6 .44 Aftermath of acute interstitial pneumonia. O x . Fi brosis of alveolar walls a n d persistence of type II cells. in origin a n d a r e c a u s e d by viral, bacterial, f u n g a l , o r parasitic diseases (Table 6 .1). Many agents a r e involved; most produce pulmonary lesions as the result of systemic or blood-borne infection, for example, toxoplasmosis ( Fig. 6.46A,B) . Most inhaled viruses, particularly myxoviruses, can in fect both airway and alveolar epithelium. When uncompli cated viral pneumonia occurs, t h e lesion is centered o n bronchioles a n d adjacent alveolar p a r e n c h y m a a n d is therefore a bronchopneumonia by pathogenetic pattern. Because interstitial accumulation of leukocytes rapidly becomes t h e dominant feature of the lesions, these viral pneumonias are often termed interstitial. Since the inter stitial response in most instances is clearly associated with bronchioles a n d adjacent alveoli, such cases c a n be distin guished from the more characteristic interstitial pneumo nias not associated with bronchioles. F o r these viral bron chopneumonias, a combined morphologic designation of bronchointerstitial p n e u m o n i a is preferable. The pattern of viral pneumonia resulting from aerogenous exposure is affected by t h e extent to which viral prolif eration is limited by t h e immune system and b y t h e cell tropism of the virus. With influenza virus infection in mice, limitation of viral proliferation t o airways is a n important determinant in minimizing the severity of the disease. Cell tropism is important in pneumonia such as that caused by certain virulent strains of feline calicivirus in which type I alveolar epithelial cells are principally affected following aerosol infection. Although early lesions a r e in regions adjacent t o bronchioles, this orientation b e c o m e s o b scured by 4 days postinfection w h e n t h e damage is more widespread. Severe, diffuse pulmonary parenchymal damage caused by inhaled gases, fumes, o r vapors is rarely encountered in animals because they d o n o t have t h e occupational exposures that are usually responsible in h u m a n s . Occa sional poisoning of cattle, pigs, a n d chickens by nitrogen dioxide generated in corn silos h a s been suspected b u t never proven. Acute pulmonary injury is occasionally seen in animals trapped in burning buildings. W h e n a s phyxiation is not immediate, t h e combined chemical and heat effects of smoke can cause widespread epithelial ne crosis and exudation, a n d death within a few days. With the advent of increased attention to intensive care units in veterinary hospitals, oxygen toxicity is emerging as an important form of inhaled chemical injury in animals. Most cases of oxygen toxicity a r e superimposed o n t h e preexisting pulmonary abnormality which necessitated oxygen therapy. Susceptibility t o oxygen toxicity varies with species, previous exposure history, metabolic state, and w h e t h e r there is preexisting pulmonary damage. Con centrations over 50%, particularly in the 8 0 -1 0 0 % range, can produce damage in already compromised lungs after 2 -3 days of exposure. The lesion is nonspecific, consisting of damage t o alveolar-capillary endothelium, necrosis of bronchiolar epithelium a n d of alveolar type I cells, a n d serofibrinous exudation. T h e relative proportion of these changes also varies with species. Reactive oxygen species (superoxide, hydroxyl radicals, a n d hydrogen peroxide) are currently favored as t h e active metabolites. These are believed, in turn, t o damage cell m e m b r a n e s by lipid peroxidation, t o inactivate sulfhydryl-containing en z y m e s , a n d to damage a variety of macromolecules includ ing D N A . T h e enhanced toxic effect of oxygen in t h e period shortly after acute pulmonary injury of some other cause suggests that alveolar epithelial cells exert some controlling influence o n proliferating fibroblasts a n d h a s important implications for therapeutic u s e of high oxygen concentrations. I n g e s t e d toxins o r precursors a r e second in importance to infections as causes of interstitial p n e u m o n i a in animals generally. In cattle, they are probably the most important cause. Several plant-or feed-related substances can cause a nonspecific a c u t e interstitial p n e u m o n i a i n c a t t l e . L-Tryptophan and 3-methylindole a r e implicated in causing t h e pasture-related form in cattle (commonly referred t o as acute bovine pulmonary e m p h y s e m a a n d e d e m a , o r fog fever). Similar pulmonary damage in cattle is caused by perilla mint ketone, toxin from moldy sweet potato (4ipomeanol), stinkwood poisoning, a n d toxin from moldy garden b e a n s . Pulmonary lesions a r e also produced in horses, pigs, sheep, and cattle b y pyrrolizidine alkaloids from a variety of plants (mostly genera Crotalaria, Trichodesma, a n d Senecio). Crofton weed (Eupatorium adenophorum) is another poisonous plant that produces chronic interstitial pneumonia in horses. Toxicity is asso- 6 . T V I . T A B L E 6.1 Acute Principally systemic viral, bacterial, o r parasitic involvement, e.g., canine distemper, feline infectious peritonitis, septicemic salmonellosis in calves a n d pigs, toxoplasmosis, a n d acute parasitism by lungworm o r migrating ascarid larvae dosage, whereas in accidental poisonings, there is more often time for hyperplasia of alveolar type II cells and fibroplasia to be superimposed on the earlier exudative changes. In the acute intoxication with survival as long as 2-3 days, the lungs are heavy, dark, and rubbery, and the alveolar spaces are filled with fluid and blood, with much fluid in the hilar connective tissue. Thin hyaline mem branes are present in alveolar ducts. With longer survival, profuse fibroplasia thickens the alveolar septa. The alveo lar lining cells which are destroyed in the acute phase are replaced from the peribronchial region by the epithelialization of type II cells. The extrapulmonary lesions which are almost consistent include patchy necrosis of the adrenal glomerulosa and of renal tubular epithelium. Affected ani mals are often placed on oxygen therapy, but it is difficult or impossible to determine whether oxygen has exacer bated the lesions because of the severity of the preexisting damage caused by paraquat. Poisoning by the rodenticide a-naphthylthiourea (ANTU) also causes respiratory dis tress, but it causes pulmonary edema and pleural effusion without the tendency to epithelial hyperplasia and fibro plasia if the animal survives. There is insufficient damage to components of the alveolar wall for it to be included as a cause of interstitial pneumonia as defined here. Little is known concerning pulmonary damage caused by therapeutic use of drugs in animals. Development of acute pulmonary edema as part of the anaphylactic or anaphylactoid shock caused by drugs such as penicillin is widely recognized but not well documented. Inhaled inorganic dusts (pneumoconioses) are uncom mon in animals because they lack occupational exposures to dusts, which are the basis for pneumoconioses in hu mans. There are old reports of asbestosis in animals with industrially related exposure. A very mild form of pneu moconiosis was found in ponies used in coal mines. There were multiple compact aggregates of coal dust, particu larly around small vessels adjacent to terminal and respira tory bronchioles. The amount of fibrosis was minimal. There have been reports of silicate pneumoconiosis or diatomaceous pneumoconiosis in animals kept in zoos. The minimal to mild, clinically insignificant lesions mostly consist of focal dust granulomas associated with lymphat ics in perivascular, peribronchiolar, and other interstitial sites. Similar foci can be seen in the lungs of many animals living in a dusty environment, but the amount of dust retention appears to be greater in birds. Silicate pneumoconiosis in horses is the only reported clinically important pneumoconiosis in animals. Multifo cal granulomatous interstitial pneumonia with interstitial fibrosis (Fig. 6 .47A) is associated with exercise intoler ance of various degrees. Necrosis and mineralization are frequently present in the centers of granulomas in the most severely affected lungs (Fig. 6.47B ). Small crystalline par ticles are difficult to detect in the macrophages by light microscopy but are plentiful when examined electron mi croscopically. The type of silicate responsible is cristobalite, one of the highly fibrogenic species. In its most specific sense, hypersensitivity pneumonitis (extrinsic allergic alveolitis) refers to pulmonary disease caused by inhalation of organic antigens. Naturally oc curring hypersensitivity pneumonitis in animals occurs in cattle and to a lesser extent in horses. Lesions are those of a lymphocytic interstitial pneumonia. Noncaseating granulomas can be found in the farmer's lung analog in cattle caused by spores of thermophilic actinomycetes (especially Micropolyspora faeni) from moldy hay. A lymphocytic and plasmacytic bronchitis and bronchiolitis is frequently a prominent feature of the disease in cattle and horses. There is probably some degree of mixed immediate and delayed-type hypersensitivity in many infectious and parasitic conditions. An example of the latter is the inter stitial pneumonia associated with microfilaria of Dirofilaria immitis in dogs with both occult and nonoccult heartworm disease. Immunologic mechanisms will un doubtedly be found to play some part in the pathogenesis of virtually all chronic interstitial pneumonias. This is a convenient place to consider eosinophilic syn dromes involving the lung. As would be expected of any set of diseases grouped on the basis of the presence of a particular inflammatory cell, these represent an ill-defined, poorly understood mixture. Little is known of the range of eosinophilic involvement of animal lungs, though their presence in helminth infections and presumed allergic bronchitis is well recognized. The term pulmonary infil trates with eosinophilia has come into use to include all cases in which, as the name implies, there is radiologic evidence of interstitial pulmonary infiltrates together with a blood eosinophilia. Eosinophils may be present in bronchoalveolar lavage fluid with or without the blood eosino philia. Since affected animals usually recover with cortico steroid treatment, the precise nature of the pulmonary lesion and the etiology often remain uncertain. The best known causes of pulmonary infiltrates with eosinophilia are dirofilariasis in dogs and migrating helminth larvae in many species. Involvement in hypersensitivity pneumoni tis, allergic bronchitis and asthmatic states is more often suggested than clearly proven. Whether pulmonary infil trates with eosinophilia can be part of adverse drug re sponses or immune-mediated disorders can be determined only by extensive, careful studies. Pulmonary infiltrates with eosinophilia is not a diagnosis, and there should be concerted efforts to make the term redundant by identifi cation of the specific disease responsible in each case. can cause acute pulmonary injury leading to inflammatory edema or more severe alveolar wall damage and serofibri nous exudation as described for an acute interstitial pneu monia. Acute uremia frequently causes severe pulmonary edema. Acute pancreatitis in dogs is occasionally associ ated with radiologic evidence of pulmonary edema. Shock like states, massive burns and trauma, and prolonged sur gery can also produce acute pulmonary injury, and these are also a major cause of the acute respiratory distress syndrome in humans. Endotoxin is suspected to play an important role in many instances, for example, shock asso- ciated with severe enteric diseases in horses. But the situa tion is extremely complex because essentially all media tors implicated in any form of acute inflammation have to be considered. T h e complete range of possible factors involves the clotting cascade starting with activation of H a g e m a n factor, the alternate pathway of comple ment activation, the arachidonic acid c a s c a d e , plateletactivating factor, interactive cytokines, lysosomal prote ases, reactive oxygen species, and cationic proteins from neutrophil or eosinophil granules. T h e roles of tumor ne crosis factor-a (TNFo:) and lysosomal elastase are a partic ular focus of attention at the m o m e n t . Acute and chronic interstitial pneumonias of u n k n o w n cause are encountered in all species, but the sporadic reports do not enable assessment of their prevalence. Since the clinicopathologic picture of interstitial p n e u m o nias is often nonspecific, many are not identified by a specific cause, and go unreported. In cattle, acute intersti tial pneumonia occurs in calves and feedlot cattle. Chronic interstitial pneumonia (diffuse fibrosing alveolitis) of adult cattle has been described. In pet animals, particularly dogs, acute interstitial pneumonia is occasionally seen where there is no evidence of access to a pneumotoxin such as paraquat. There seems sometimes to be an associa tion with cardiac insufficiency. An acute shocklike pulmo nary injury occurs in terminal cardiovascular collapse. Similar lesions, often with superimposed oxygen toxicity, are seen in animals which have been treated in intensive care units. Acute to subacute interstitial pneumonia oc curs in horses of various ages, and thus far the causes are not k n o w n . The most important attribute of a classification scheme in pathology is that it provides an effective framework for diagnosing, interpreting, and conveying information about disease processes. From this point of view, the designation of certain pneumonias as bronchointerstitial is justified. Bronchointerstitial pneumonia is commonly caused by aerogenous viral infections, particularly by myxoviruses. Pulmonary abscesses usually arise either from focal residues of severe, suppurative lobar or bronchopneumo- nia or from septic emboli lodging in the pulmonary vascu lar bed (Fig. 6.49 ). Cranio ventral location and associated scarring or bronchiectasis are evidence of origin from a suppurative pneumonia. Multiple, widely distributed ab scesses indicate hematogenous origin and are usually asso ciated with an obvious source of septic emboli elsewhere in the body, for example, septic thrombosis of the poste rior vena cava in cattle. Isolated abscesses in dorsocaudal regions are more likely to have arisen from septic emboli, but in the absence of a pattern of abscesses in other organs, the origin remains uncertain. Difficulty is encountered in interpreting the pathogenesis of pulmonary abscesses in horses; they are relatively frequent and can arise by either major route. It is often impossible to determine the patho genesis of isolated old abscesses. T w o less-common causes of pulmonary abscesses are aspirated foreign bodies, such as a plant a w n , or direct traumatic penetration of the lung. Complications of ab scessation include pleural fistulation and e m p y e m a , hem orrhage from a ruptured blood vessel, and fulminating suppurative b r o n c h o p n e u m o n i a subsequent to rupture into a b r o n c h u s . The term embolic pneumonia could be extended to in clude pneumonias caused by any circulating particulates, including bacteria and parasites, but it is preferable to consider pneumonia caused by hematogenous infectious agents under the general heading of interstitial pneumonia, as was discussed earlier. Embolic pneumonias can be con sidered as a special category of interstitial pneumonia in which there are focally discrete lesions with clear relation ship to the vascular bed. In addition to the abscesses caused by septic emboli mentioned previously, other ex amples are the hematogenous abscesses which are an inte gral part of specific diseases such as caseous lymphadeni tis and melioidosis. Gangrene can be a complication of other forms of pneu monia in which there is extensive necrosis of pulmonary p a r e n c h y m a . It is occasionally seen in cattle as a result of penetration of a foreign body from the reticulum, but mostly it is a result of aspiration of foreign material and associated saprophytic, putrefactive bacteria. The yellowish-to greenish-black color and foul odor are char acteristic. Extensive ragged cavitation rapidly develops. If a gangrenous cavity extends to the pleura, afoul e m p y e m a results with putrefactive pneumothorax. Aspiration pneumonia refers to pneumonia caused by aspiration of foreign material, often in liquid form, reach ing the lungs through the airways. This distinguishes it from pneumonias caused by inhalation of small respirable particles, which includes the bulk of aerogenous p n e u m o nias. T h e response to the aspirated material depends on three factors: the nature of the material, the bacteria which are carried with it, and the distribution of the material in the lungs. Widespread distribution of inhaled milk or combination of milk and gruel is observed occasionally in pail-fed calves. The course of the disease in these cases can be as short as 1 day. The gross appearance is not characteristic. The lungs remain inflated; they are hyperemic, and small amounts of exudate can be expressed from the small air w a y s . Histologically, there is an acute bronchiolitis with various degrees of acute alveolar inflammation. Lipids, and sometimes plant material, can be seen in the lesions. Aspiration of ruminal contents can produce a similar pic ture in recumbent cattle, but in these cases the aspirated material is usually obvious, and there is often a hemor rhagic tracheobronchitis. W h e n the distribution of foreign material is more local ized, either discrete foreign-body granulomas, broncho p n e u m o n i a (Fig. 6 .50), lobar pneumonia, or gangrene of the lungs occurs. Cattle and lambs frequently aspirate inflammatory exudate from necrotic laryngitis. L a m b s with nutritional myopathy affecting the muscles of degluti tion aspirate milk and plant material, including whole grain. Pigs in dry, dusty environments and fed on dry, finely particulate food can aspirate starch granules and particles of plants from the feed. Any cause of dysphagia, pharyngeal paralysis in particular, is likely to lead to aspi ration pneumonia. It is also a hazard of anesthesia. Aspira tion of vomitus and medications occurs in all species. T h e aspiration of vomitus in a simple stomached animal is often rapidly disastrous, and death can occur from laryn geal spasm or acute pulmonary edema before there is time for much inflammation to develop. The possibility of aspirated material's being responsible must always be considered in any case of fulminating lobar or broncho pneumonia, especially one with a history of one of the predisposing conditions just mentioned. Careful search will usually reveal evidence of foreign material, but this is not the case when the material is largely or entirely liquid. This is a special form of aspiration pneumonia in which droplets of oil are inhaled. It used to be fairly c o m m o n in cats and other species given mineral oil (liquid paraffin) as a laxative, or cod-liver oil for its antirachitic properties. The reaction is typically macrophagic and proliferative, with some qualitative differences depending on the nature of the oil. In general, vegetable oils, such as olive oil, are not irritating, and they are eventually resorbed with little reaction or fibrosis. Oils of animal origin are irritants and provoke an early exudation of serofibrinous fluid and leu kocytes. This is replaced later principally by macro phages, among which giant cells can be n u m e r o u s . F o a m y macrophages fill the alveoli, and the alveolar walls are thickened by infiltrated mononuclear cells and fibrosis. The oil is ultimately resorbed. T h e purest cellular response occurs to mineral oil, which is the usual offender in ani mals. T h e nature of the oil can be distinguished by its p e r m a n e n c e and by its failure to stain with osmic acid. The lipid is both extracellular and intracellular. Lipidladen macrophages tend to fill the alveoli, and in time, they accumulate in the lymphatics which surround the bronchi and blood vessels (Fig. 6.5IB ). Fibrosis of alveo lar walls and proliferation of alveolar type II epithelial cells are conspicuous, and the foamy macrophages tend to be incorporated into the alveolar septa by extension of the fibroplasia. Unless complicated by secondary bacterial infection, the lesions have a characteristic yellowish, ho mogeneous, or finely mottled appearance (Fig. 6 .51 A). They vary from multiple small nodules to complete consol idation of a lobe. Involvement is usually bilateral and tends to be in ventral regions. The bronchial lymph nodes are grossly normal, but histologically often contain droplets of oil. Pneumonias caused by aspiration of foreign (exoge nous) lipid must be differentiated from the so-called endog enous lipid pneumonias. Accumulation of lipid-filled mac rophages and various a m o u n t s of interstitial response are c o m m o n to both conditions. The most important dis tinguishing feature is that in lipid aspiration pneumonias there are large discrete extracellular globules of lipid. In paraffin-embedded sections these appear as clear spherical spaces with distinct borders formed by the compressed cytoplasm of macrophages and giant cells. Severe uremia causes increased permeability of the al veolar a i r -b l o o d barrier and is therefore a cause of pulmo nary edema. The usual form of uremic p n e u m o n o p a t h y occurs in dogs with chronic uremia in which, in addition to edema, the principal lesion is degeneration and calcifi cation of smooth muscle and connective tissue fibers (see The Urinary System, Chapter 5 of this volume). This oc curs mainly in the walls of respiratory bronchioles and alveolar ducts in mild c a s e s . Severe involvement results in extensive mineralization of alveolar septa, which can be recognized grossly by the gritty, porous texture of the lung. Inflammatory cell c o m p o n e n t s are not usually a significant feature of uremic p n e u m o n o p a t h y in dogs. This is a convenient term for lumping together an illdefined group of conditions with overlapping morphologic features. They are usually found as incidental lesions in which alveoli are filled by one or m o r e of (1) (1) their clearance is impeded by obstructed airways; (2) they are produced in e x c e s s ; or (3) their mobility is impaired by increased adhesiveness or metabolic abnor mality. These conditions are included here because some have obvious inflammatory c o m p o n e n t s , especially the so-called endogenous lipid p n e u m o n i a , and inflammation plays a part in the pathogenesis of most of the conditions. countered mostly in laboratory rodents and fur-bearing animals. It is seen occasionally in cats and rarely in dogs. Grossly, the lungs have irregularly distributed, yellowishwhite, firm foci. Most of foci are subpleural and appear as sharply defined small flecks or bulging nodules as much as a centimeter or more in width (Fig. 6.52A ). T h e overlying pleura is often thickened, and the adjacent lymphatics may be prominent because of accumulations of macrophages and lipid. Histologically, the bulk of the lesion in many instances is c o m p o s e d of distended alveoli filled with foamy macro phages ( Fig. 6 .52B), and the term alveolar histiocytosis is commonly applied. There is a small amount of interstitial fibrosis and accumulation of lymphocytes and plasma cells. In more severe cases, there are intracellular and extracellular cholesterol crystals, more severe interstitial fibrosis, accumulation of small numbers of neutrophils and mononuclear cells, and regions of alveolar type II cell proliferation. The large cholesterol crystals stimulate de velopment of giant cells and intra-alveolar fibroplasia. The term e n d o g e n o u s lipid p n e u m o n i a (cholesterol p n e u m o nia) is sometimes applied to these more severe mixed inflammatory and fibrotic lesions. T h e causes of alveolar histiocytosis and endogenous lipid pneumonia are not clearly defined. In some instances, the accumulation of alveolar macrophages is associated with localized bronchitis and bronchiolitis and is therefore attributed to obstruction of alveolar clearance. In other instances there is no evident obstruction of clearance path w a y s , although initial sites of accumulation are in subpleu ral or paraseptal locations where clearance deficits are more likely to result in stasis of macrophages. It is proba ble that alveolar histiocytosis and endogenous lipid pneu monia are nonspecific responses to mild injury com pounded by as yet u n k n o w n inherent species-dependent factors. T h e transition from histiocytosis to endogenous lipid pneumonia is gradual. Admixtures of neutrophils and small mononuclear cells, and evidence of macrophage b r e a k d o w n , a c c o m p a n y the cholesterol formation and fi brosis of endogenous lipid pneumonia. The latter is there fore probably initiated by b r e a k d o w n of macrophages, which sets in train a sequence of proinflammatory events involving neutrophils and lymphocytes. are characterized by accumulation of acellular acidophilic material within alveoli. Knowledge about the pathogenesis of these conditions is derived mostly from t w o types of experimental models, one induced by crystalline silica and the other by amphophilic drugs. T h e condition caused by high concentrations of inhaled silica or similar irritants is conventionally called lipoproteinosis, whereas the druginduced condition is referred to as phospholipidosis be cause it is part of a more generalized phospholipid distur bance. In both instances, however, the main abnormality is intra-alveolar accumulation of large a m o u n t s of phos pholipid derived from alveolar surfactant, together with small a m o u n t s of surfactant protein and other proteins. The material is strongly periodic acid-Schiff (PAS) posi-tive and ultrastructurally is found to consist mostly of lamellar and tubular arrays of phospholipid and frag mented lamellar bodies derived from alveolar type II cells. Alveoli are lined by type II cells, but inflammatory and fibrotic changes are usually minimal. Evidence to date indicates that production and accumulation of large amounts of surfactant phospholipid in alveoli suppress inflammation. Alveolar lipoproteinosis (phospholipidosis) is an im portant condition in rats and mice, but it is not a significant naturally occurring entity in domestic animals other than the goat, in which it appears in association with chronic interstitial pneumonia such as that caused by the caprine arthritis-encephalitis virus and possibly lungworm infes tation. Pulmonary hyalinosis, which consists of multifocal ac cumulations of macrophages and giant cells containing hyaline or laminated material, is seen in the lungs of dogs. Grossly detectable foci occur mainly subpleurally, espe cially at the narrow ventral margins of the lungs. They are grayish white to tan, nodular or confluent, and firm to gritty. Histologically, the cytoplasm of macrophages and giant cells is greatly distended and disrupted by amor phous or sometimes laminated material. The material is amphophilic, often staining with a pronounced bluish tinge with hematoxylin and eosin. It is strongly PAS positive, and limited ultrastructural observations have shown that it consists of packed segments of cytoplasmic membranes. Plasma cells, lymphocytes, and small amounts of fibrous tissue usually surround individual or clustered giant cells and macrophages. The lesions can be found occasionally as incidental findings in the lungs of old dogs. They have been referred to as pulmonary granulomas with PAS-positive bodies and are reported mostly in brachycephalic breeds, particularly boxers. They are usually found accompanying chronic pulmonary injury such as pneumoconiosis or experimental radiation pneumonitis. The lesions of pulmonary hyalino sis in dogs are somewhat similar to those of pulmonary corpora amylacea of humans, but the two conditions are not clearly defined. Granulomatous or pyogranulomatous pneumonia may occasionally be caused by Actinobacillus, Actinomyces, or Nocardia spp. In these cases there is usually local damage to pulmonary tissue, such as by trauma or aspi rated foreign body, or suspicion of systemic immunodefi ciency. An example of the latter is the occasional finding of systemic nocardiosis, including multifocal pulmonary pyogranulomas, in dogs with distemper or in Arabian foals with combined immunodeficiency. More important granu lomatous pneumonias are tuberculosis and fungal infec tions of the lung (pneumonomycoses), which are described under these specific headings. Another category of granu lomatous pneumonias consists of those caused by inhaled or aspirated insoluble particles. These include the multifo cal granulomas caused by inhaled silicious dusts in horses and foreign-body granulomas enclosing inhaled feed par ticles. Naturally occurring infectious pneumonias of clinical significance usually have complex causes. Interaction of two or more organisms is commonly involved, and often there are predisposing environmental factors. The rela tively nonspecific nature of many pneumonic lesions com pounds the difficulty of attributing them to specific causes. In the following discussion, features of pneumonias caused by, or strongly associated with, individual infec tious agents will be presented first. The variety of agents implicated in causing conditions grouped under epidemio logic terms such as enzootic pneumonia will be summa rized afterward. Generalizations about the complex interactions of viral pathogens, pulmonary cells, and the immune and inflam matory responses are inevitably accompanied by signifi cant exceptions. Nevertheless, most of the important viral pathogens of the lung have an aerogenous portal of entry, replicate in airway and alveolar epithelial cells, and induce a characteristic pattern of pulmonary inflammation in air ways and proximal acinar alveolar tissue (bronchointersti tial pneumonia). If the virus also replicates in macrophages and/or is immunosuppressive or can evade host defense mechanisms, more diffuse interstitial pneumonia may re sult as well as dissemination to other tissues. The virus causes a bronchointerstitial pattern of pneu monia. Grossly there is usually evidence of mild mucopu rulent inflammation of nasal passages and upper airways. Early macroscopic lung lesions are limited to irregular lobular foci of atelectasis or slightly consolidated purplered foci in cranioventral regions (Fig. 6.53A ). In more developed lesions, -4-12 days after experimental infec- tion, there is more confluent consolidation. Therefore, affected regions are less frequent and more atelectatic as they undergo resolution. In the airways, parainfluenza virus replicates in ciliated, nonciliated, and mucous epithelial cells. In alveolar tissue, replication is largely confined to type II alveolar epithelial cells and macrophages. H o w e v e r , in other hosts such as rodents, parainfluenza virus also replicates in type I alveo lar epithelial cells. Histologically, in the more severe viral infections, there is initially an acute bronchitis and a more obvious bronchiolitis, with extension to adjacent alveoli. T h e bronchiolar and alveolar exudate is predominantly neu trophilic, although e d e m a and hemorrhage m a y be pres ent in the alveoli. F r o m ~2 to 4 days after infection, bronchiolar epithelium is variously hyperplastic or vacu olated and necrotic. Acidophilic intracytoplasmic inclu sions can be found at this stage in vacuolated bronchiolar epithelium and to a lesser extent in bronchial epithelium. Intracytoplasmic inclusions are present infrequently in type II alveolar epithelial cells. Occasional binucleate or multinucleate forms of type II cells are present. Multinucleated cells are rarely found in bronchioles. The F-glycoprotein in the envelope of parainfluenza virus has a fusion protein function which mediates viral entry into cells through fusion of the viral envelope and the host cell plasma m e m b r a n e . During viral assembly, viral glycoproteins are inserted into the m e m b r a n e of the infected cell, and this results in cell fusion and the formation of occasional multinucleated cells. The exudate in bronchioles and alveoli contains macro phages and lymphocytes mixed with neutrophils and sero fibrinous material. M a n y alveoli are atelectatic because of bronchiolar obstruction. L y m p h o c y t e s and plasma cells also accumulate around vessels, bronchioles, and within alveolar septa. Lesions are of maximal cellularity -6-12 days after infection and are dominated by hyperplasia of bronchiolar epithelium and alveolar type II epithelial cells. S q u a m o u s metaplasia m a y be present. Intracytoplasmic inclusions are seldom found after 7 days, the time of maximal epithelial proliferative response. Early bronchiolitis fibrosa obliterans can be seen in se verely affected bronchioles at the peak of the pneumonic involvement, but it is more likely when secondary bacte rial infections cause more severe exudative airway and alveolar inflammatory responses. The severity of alveolar damage and the range of lesions produced depend on the extent to which virus reaches the alveolar epithelium and replicates, thus causing necrosis. This in turn is governed by the virulence of the strain of virus, the method of inoculation, and the viral immunity and innate susceptibility of the calf. Also, intercurrent immunosuppression as well as other forms of lung injury induced by pulmonary toxins such as 4-ipomeanol can exacerbate the severity of virus-induced lesions. In general, experimental infections deliver more virus to deep regions of the lung and hence cause more alveolar damage. In natural infection, viral replication seems usu ally to be more limited to airways and hence is character ized more by bronchiolitis than by pneumonia. In severe experimental infections, the amount of alveolar epithelial damage can be pronounced. T h e degree of alveolar exuda tion and subsequent proliferation of alveolar type II epi thelial cells (epithelialization) is correspondingly more dramatic. T h e extent to which syncytial or multinucleated giant cells are seen on the alveolar walls or in the bronchio lar epithelium varies. Although intracytoplasmic inclusion bodies are present as the virus-induced lesions approach their peak, they are rarely encountered in calves that die with respiratory disease, because secondary bacterial damage usually obscures possible earlier viral lesions or causes death after the stage at which inclusion bodies are detectable. One of the most important pathogenetic attributes of bovine parainfluenza type 3 virus is its ability to inhibit pulmonary bactericidal defense mechanisms, most nota bly at the level of alveolar macrophage function. Virus replicates in macrophages and can induce decreased phagocytosis and killing of bacteria. The role of parainfluenza type 3 virus infection in sheep is similar to its role in cattle in that it acts mostly to pave the way for severe Pasteurella pneumonia. T h e experi mental lesions in lambs are essentially the same as those produced in calves. Parainfluenza type 2 virus infection in dogs, which was formerly referred to as parainfluenza SV-5, has been men tioned in its role as one of the causative agents of infectious tracheobronchitis. Lesions are those of a mild tracheo bronchitis and bronchiolitis. T h e acute viral-induced air way lesions are characterized by mild epithelial necrosis with intercurrent mixed cellular inflammatory infiltrates and submucosal edema. T h e virus does not replicate in macrophages and does not induce significant bronchoin terstitial pneumonia in i m m u n o c o m p e t e n t dogs. ii. Respiratory Syncytial Virus Bovine respiratory syncytial virus belongs to the Pneumovirus genus of para myxoviruses. Virulent strains of the virus are some of the synergistic agents involved in bovine respiratory disease but are also capable of causing outbreaks of respiratory disease and occasional deaths independently, most often in animals < 1 year of age. Outbreaks usually occur in fall or early winter, generally within a few weeks of the animals' being housed. Late-weaned calves seem to be most prone to the disease. Prominent clinical signs are coughing and tachypnea, and in the most severely affected animals, there is respiratory distress with open-mouthed breathing and forced, grunting expiration. Gross lesions in animals dying of the naturally occurring disease are irregular lobular or confluent regions of atelec tasis and consolidation in cranioventral portions of the lungs (Fig. 6.53B) . Interstitial e m p h y s e m a is frequently present and is particularly evident in more caudal regions where there sometimes are large bullae within interlobular septa. There is often mucopurulent exudate within bronchi of pneumonic and atelectatic regions. The exudate may be foamy in major bronchi. Histologically, inflammation of trachea, bronchi, bronchioles, and proximal acinar areas, especially in cranioventral areas, is a major c o m p o n e n t of the disease. A special characteristic of the bronchiolar response is the frequent prominence of syncytial giant cells formed by proliferating nonciliated bronchiolar epi thelial cells, some of which may contain acidophilic intra cytoplasmic inclusion bodies. Alveoli are either atelec tatic, because of bronchiolar obstruction, or contain a mixed cellular exudate in their lumina with mononuclear thickening of their septa. When alveoli are directly in volved, alveolar epithelial proliferation with tendency to form large syncytial giant cells is as prominent as in bron chioles, and here also acidophilic intracytoplasmic in clusion bodies are sometimes seen. There is moderate accumulation of lymphocytes and plasma cells in the peri bronchiolar and associated connective tissues. Experimental infections with virulent strains of the vi rus produce a bronchointerstitial pneumonia with peak involvement ~5 to 8 days after infection. Syncytial giant cells of bronchiolar and alveolar epithelium are an out standing feature during this period, and many contain in tracytoplasmic inclusions (Fig. 6 .53C). Both natural and experimental infections can lead to prominent bronchio litis fibrosa obliterans in surviving animals. T h e virus has been shown to replicate in ciliated and nonciliated epithe lial cells in bronchioles (Fig. 6 .53D) and in type I and type II alveolar epithelial cells. Only limited viral replication occurs in macrophages. Bronchoconstriction is a prominent feature of the dis ease, resulting in extensive airway obstruction and termi nal interstitial e m p h y s e m a . Although viral antigen can be readily demonstrated in cranioventral areas of the lung where severe bronchiolitis and pneumonia are present, it is not readily demonstrable in caudodorsal areas where evidence of bronchoconstriction is present. Respiratory syncytial virus-infected cells are capable of activating complement. There is evidence suggesting that mast cell degranulation occurs in airways throughout the lung dur ing infection, possibly as a function of activated comple ment c o m p o n e n t s , and that mast cell mediators such as 46: 554, 1985.) histamine are responsible for the bronchoconstriction away from areas of viral replication. Other evidence indi cates that the level of viral-specific IgE antibody in cattle predicts severity of disease signs during acute infection. Research on h u m a n respiratory syncytial virus provides the greatest insight into hypersensitivity mechanisms that may modulate disease expression. Children making high IgE responses to the virus have the most severe disease. Early vaccine trials demonstrated that alum-containing vaccines that stimulated IgE and poor neutralizing anti body actually potentiated disease symptoms when a spon taneous infection occurred. Secretory immunity following infection is not long-lived, and it is possible under sponta neous infection conditions that initial exposure to the virus in some cattle may actually sensitize them to the virus through genetically controlled IgE responses and that sub sequent exposure to the virus may precipitate exaggerated viral airway disease. There is evidence from studies on acute interstitial pneumonia in feedlot cattle that bovine respiratory syncy tial virus may contribute to the development of the dis ease, but the situation is far from clear. Sheep are also susceptible to respiratory syncytial virus and spontaneous infections in sheep have been detected. The pulmonary lesions induced by the sheep virus are similar to those induced by the bovine virus. A respiratory syncytial virus has been isolated from cats, but its significance is not established. iii. Canine distemper remains one of the most ubiquitous and serious of the diseases of dogs. In spite of the development of effective vaccines, the disease remains endemic in most parts of the world. All members in the Canidae (e.g., dog, dingo, fox, coyote, wolf, jackal), Procyonidae (e.g., raccoon, coati, kinkajou, panda), and Mustelidae (e.g., ferret, mink, badger, weasel, otter) families are thought to be susceptible, but cases have not been proven in some species of these families. Clearly the canine distemper virus is a remarkable patho gen that can cause infection and disease in a wide variety of domestic and wild animals. This variety has been appar ently extended to include seals, porpoises, and dolphins, which have sustained substantial mortalities as the result of canine distemper or a canine distemperlike infection. In seals, two agents appear to be involved-canine distem per virus and phocid distemper virus, possibly a mutant of the classic virus. Investigators have also discovered the distemper virus causing a fatal central nervous system disease in javelinas (collared peccaries), a feral animal of the United States Southwest not previously thought to be susceptible. The ferret is remarkably susceptible to distemper virus and for this reason was used extensively in investigation of the disease. Carre first demonstrated that the causative agent is a filterable virus. This virus is a paramyxovirus, subgroup Morbillivirus, a large RNA virus closely related to measles virus of humans and to rinderpest virus of cattle. Various isolates of the virus cannot be distinguished serologically, but they differ in the type and severity of the disease they produce. Infection by canine distemper virus is pantropic, and the manifestations protean. The disease is described here because respiratory signs and lesions, although variable in severity, are relatively constant in occurrence. Effective antibacterial therapy has greatly reduced the incidence of secondary bronchopneumonia, but it is still frequently seen in neglected cases. Intestinal disease is also common in dogs with distemper. The disease is a summation of the effects of the virus and of secondary infections with other organisms. These secondary infections are particularly important in this dis ease because one of the primary sites of action of the virus is the lymphoid tissue, causing suppression of immune function. Secondary bacterial infections in the alimentary tract are nonspecific, but in the respiratory tract Bordetella bronchiseptica is frequently associated with suppurative bronchopneumonia. Activated toxoplasmosis develops in dogs whose immune systems have been damaged by the distemper virus, and in fact toxoplasmosis as a clinical disease seldom occurs in dogs other than in association with canine distemper or other diseases that cause immu nodeficiency. The virus is shed in all the excretions from infected animals during the systemic phase of the infection, and natural transmission is usually by inhalation. The patho genesis of the infection has been followed in dogs, the distribution of the virus having been monitored by the use of immunofluorescence. After aerosol exposure, the virus appears in macrophages of the bronchial lymph nodes and tonsils during the first 24 hr. The virus proliferates in the bronchial lymph nodes and 2 -5 days after exposure is distributed throughout the lymphatic tissue, including bone m a r r o w , t h y m u s , and spleen. The animals b e c o m e febrile and viremic at this stage, and cells of the buffy coat contain virus. The infection is primarily confined to the lymphoid tissues until 8 -9 days after e x p o s u r e . In some infections, the virus spreads no further, and the disease is mild or inapparent. The control of the infection at this stage is correlated with the development of neutralizing antibody. If protective titers develop within the first 2 w e e k s of infection, spread of virus does not occur, and virus disappears from lymphoid tissues. If protective lev els of antibody are not reached, the infection persists in lymphoid tissues and spreads to the epithelium of the alimentary, respiratory, and urogenital tracts, and the skin and endocrine glands, and may reach the brain. In the central nervous system, the virus appears first in perivas cular and meningeal macrophages, but infection of the choroid plexus epithelium occurs early, and the cerebro spinal fluid contains large amounts of virus. T h e critical timing involved in the rise of neutralizing antibody titer, and its role in influencing the pattern of disease, appears to offer a partial explanation for the variability in the severity of the disease produced by the canine distemper virus. T h e disease is more severe in young animals in which the immune system is less well developed but, even among littermates infected by the same strain of virus, the disease is unpredictable in severity. T h e incubation period of canine distemper, as indicated by the onset of acute fever, is rather constant at -5 days. T h e febrile reaction is typically diphasic with a second peak occurring at -11 d a y s , but this diphasic response is seldom observed clinically. The fever is continuous for the course of the systemic infection, which may last some w e e k s . T h e clinical signs are variable in their severity and in their emphasis on particular systems. A syndrome consisting of catarrhal oculonasal discharge, pharyngitis, and bronchitis is c o m m o n but may be so mild as to be missed. Signs of pulmonary involvement a c c o m p a n y mod erate to severe damage, whether purely viral with e d e m a and interstitial inflammation or mainly bacterial with bron chopneumonia. The alimentary disturbance is usually ex pressed as diarrhea, which b e c o m e s more severe as the disease a d v a n c e s . T h e feces b e c o m e semifluid, slimy, foul, and occasionally streaked with blood. The animals lose weight, and dehydration results. Vesicles and pus tules develop in the skin in some cases. These cutaneous lesions are confined to the epidermis beginning in the deeper layers, and are particularly to be found on the thin skin of the a b d o m e n and inner aspects of the thighs. They are bacterial complications usually produced by staphylo cocci and streptococci. Cutaneous hyperkeratosis and parakeratosis also occur, but these never reach the degree of development that is seen in ferrets and mink except on the footpads (Fig. 6 .54A) and nose. In dogs, there is at most a generalized scurfiness of the skin. Small zones of The gross lesions seen in canine distemper will depend on the phase of the disease w h e n the animal dies or is killed. W h e n death occurs early in the course of the disease and systemic effects are still prominent, as is usual in pups, gross lesions can be expected. In most cases which die or are killed because of the encephalitic effect of the virus, however, there may be little to be seen grossly. Visceral lesions of canine distemper are c o m m o n in the respiratory system, but they may be subtle. Inflammation of the nasopharynx is serous in initial stages and in the course of 3 or m o r e w e e k s b e c o m e s catarrhal and some times purulent. T h e mucosal vessels of the larynx and trachea are congested. T h e bronchi contain a small amount of foamy serous fluid which has c o m e from the e d e m a t o u s lungs, and they may contain a mucopurulent exudate in complicating bacterial pneumonia. T h e lungs are edema tous, and w h e n this is severe, there is also serous effusion in the pleural sacs. The specific lesion is an interstitial pneumonia. T o a variable extent, the lungs may reveal the smooth liverlike appearance associated with extensive serofibrinous filling of alveoli, but the more usual lesions are reddish-tan patches immediately beneath the pleura, and grayish zones of firmer consistency along the sharp margins of the lobes. Deflation is incomplete in such lungs. Lesions are regularly present in the lymphoid organs, but except for the t h y m u s , these changes are difficult to recognize grossly. If the animal dies or is killed during the acute systemic phase of the disease, the lymph nodes may be variable in size. S o m e are large and e d e m a t o u s ; others, small and atrophic. In the large, e d e m a t o u s n o d e s , cortical and medullary distinction may be lost. T h e thymuses of affected animals at this stage are greatly reduced and in some cases are difficult to identify. L a t e r in the course of the disease, lymphoid tissue of lymph nodes and thymuses can regenerate and may be of normal size in animals dying in the chronic neurologic phase of the disease. Many animals dying of canine distemper are severely emaciated and their muscles, wasted. The lobular pattern of the liver is sometimes prominent because of mild fatty change and centrilobular congestion. Large irregular whit ish areas of necrosis and mineralization are often seen in the myocardium of very young suckling p u p s , which are most apt to die during the acute early phase of the disease. T h e histologic changes in canine distemper, w h e n pres ent, are fairly specific; specificity depends on the demon stration of the viral inclusion bodies or, better yet, detec tion of viral antigen by immunofluorescence. The number and distribution of inclusion bodies vary from case to case and with the phase of the disease. Their appearance coincides with, or follows shortly after, the appearance of systemic signs of illness, from -10 to 14 days after infection. By about the fifth or sixth w e e k s , their numbers diminish rapidly in most tissues and disap pear. Of the non-neural tissues, they persist longest in the lung. Inclusion bodies can be found in the central nervous system before changes of encephalomyelitis are present, and they persist in the neural tissue w h e n they have disap peared from all extraneural sites, provided that infection of the brain has occurred. The inclusion bodies are acidophilic and occur in either the nucleus or cytoplasm or both, depending on the tissue. They are usually easier to find and recognize with confi dence in brain and epithelial tissues. In lymph n o d e s , they can be very easily confused with eosinophilic debris unless their specificity can be proven by fluorescent antibody. T h e earliest lesions of canine distemper are those affect ing the lymphoid tissues. T h e s e are rarely seen in clinical cases, as dogs only rarely die during this period, but in experimental series it has been shown that as early as the sixth day after e x p o s u r e there is a depletion of lympho cytes in the cortical zone of the lymph n o d e s . By the ninth day, the lymph nodes are largely depleted of l y m p h o c y t e s , and the cortical zones are reduced to thin rims. Individual lymphocytes undergo necrosis, and the sinusoids and cords are infiltrated by neutrophils. Similar lesions de velop in the spleen, and small foci of necrosis may be scattered throughout the white pulp ( Fig. 6.54B T reduction in the medulla. In some animals which die, the t h y m u s e s show no tendency to regenerate, but regenera tion, if it is to occur, c o m m e n c e s at the same time as it does in the nodes. Severe leukopenia is a characteristic feature of canine distemper. It is due chiefly to a lymphopenia. T h e lympho penia develops at the time the initial necrosis of lymphatic tissue occurs and is most likely the result of viral multipli cation and destruction of the lymphoid tissues. The lym phopenia persists in the acute disease until death or recov ery, but some animals die of encephalitis after the circulating lymphocyte levels have returned to normal. L y m p h o p e n i a coincides with the onset of the leukocyteassociated viremia, but persists long after viral antigen can no longer be demonstrated in the buffy coat. T h e characteristic changes in the lung produced by the virus of canine distemper are those of interstitial p n e u m o nia (Fig. 6.55 ), but the lesion found at autopsy may be complicated by secondary bacterial bronchopneumonia. The change is diffuse in the lungs, although more severe in some areas than in others. Syncytial giant cells formed by alveolar type II epithelial cells are a characteristic feature of the interstitial pneumonia caused by the virus. M a n y contain the acidophilic intracytoplasmic viral inclu sions (Fig. 6.56 ). As the systemic phase is o v e r c o m e in the chronic disease, residual changes tend to persist in patches beneath the pleura and about venules and small bronchioles as areas of thickened alveolar septa with epi- thelialization and accumulation of alveolar macrophages. Specific inclusion bodies can sometimes still be found in the cytoplasm of altered alveolar epithelium and in the bronchial mucosa. A m o n g non-neural tissues, they are most likely to be found in the alveolar epithelium because they persist longest in these cells in terms of the disease process, and these cells are not so subject to postmortem lysis and sloughing as most epithelial cells. Intracytoplasmic inclusion bodies are regularly found in the transitional epithelium of the urinary tract in the acute systemic disease. Intranuclear inclusions are less c o m m o n . In some c a s e s , inclusions are found in the epithe lium of the collecting tubules. T h e epithelial cells are often swollen and hydropic, and in the absence of these degener ative changes, inclusion bodies are unlikely to be found. Mild interstitial epididymitis and orchitis are c o m m o n in canine distemper; inclusion bodies are found in the epididymal epithelium, and the interstitium is mildly infiltrated with mononuclear cells. Inclusion bodies can occasionally be found in the epithelium of the biliary and pancreatic ducts and in the pancreatic exocrine tissue. Inclusions are c o m m o n in the gastric epithelium but u n c o m m o n in the intestine. In the stomach, they are found in superficial epithelium as well as in chief and parietal cells; the latter frequently show acute degenerative changes. Necrosis and cystic degeneration of ameloblastic epi thelium of the developing tooth give rise to the defective enamel seen in animals which have recovered from infec-tion. T h e defects may consist of small focal depressions to large areas lacking enamel. The boundaries of the de fects are discrete. Intraocular lesions occur in most cases of canine dis temper. Ulcerative keratitis may complicate a purulent conjunctivitis, but this is u n c o m m o n . More c o m m o n l y , the anterior segment is not significantly changed except for leukocytic infiltrations in the ciliary body. Distinctive retinal lesions of variable severity and extent are present, and nuclear and cytoplasmic inclusions may be found in the retinal ganglion cells and glia, as well as in glia of the optic nerve. T h e retinal changes may be predominantly exudative in the acute cases, but in those of longer dura tion, they are predominantly degenerative (Fig. 6.57) ; in all cases, there is prominent proliferation of the pigmented epithelium. T h e earliest changes include severe degenera tion of the retinal ganglion cells revealed as dispersion of the Nissl substance and migration of the nucleus to the margin of the cell. The degenerative changes in the gan glion cells are diffuse, but these cells tend to persist until the layered organization of the retina is lost. In acute retinitis, there is congestion and cuffing of the blood ves sels in the optic nerve and ganglion cell layers. Patchy e d e m a often separates the fibers of the optic nerve layer and the reticular layers and produces focal retinal detach ments. Atrophy of the retina may be patchy or complete. In some c a s e s , the atrophy is limited to the layer of rods and c o n e s , the outer limbs of which shorten and disappear concurrent with pyknosis of the nuclei. In other foci or cases, the atrophy results in disorganization of the layers and, w h e n the ganglion cell layer disappears also, the retina in such areas consists of disorganized remnants of the layer of bipolar cells. Swelling and proliferation of the Only a few ganglion cells and r e m n a n t s of outer nuclear layer persist. in the ventral than in the tapetal fundus, and is also com mon in the pars ciliaris retinae. Associated with the reac tive changes in the pigmented epithelium is a migration of pigment into the retina. Pigmentation of the retina is rather c o m m o n in old dogs, but in these it tends to be restricted to the periphery of the retina and is not obviously associ ated with reactive changes in the epithelium; in canine distemper, the pigmentation occurs centrally as well as peripherally, and activity of the epithelium may be suffi cient to cause focal d e t a c h m e n t s of the retina. Changes in the optic nerve are inconstant, but papilledema may be observed in acute c a s e s , and gliosis of the nerve head or demyelinating neuritis in chronic o n e s . Demyelination is the salient feature of the encephalo myelitis of distemper. The lesions are widespread, but correlation with the clinical signs is often not apparent. The lesions have a pattern of development with regional differences in quality and severity. T h e y are most severe and obvious in the cerebellum ( Fig. 6.58A,B) , surrounding the fourth ventricle, and in the optic tracts. Meningitis is always present, but usually mild and consists of accumula tion of mononuclear cells, mainly l y m p h o c y t e s , most obvi ous on the ventral surface of the brain. Inclusion bodies can be demonstrated in meningeal macrophages in both nuclei and cytoplasm. Acute degenerative changes in the neurons occur exten sively in the brain, but are m o d e s t in the cord. Experimen tal studies, both immunofluorescent and ultrastructural, associate this degeneration with viral infection of the neu rons. T h e cells most susceptible to this virus-induced in j u r y are the small pyramidal cells of the motor cortex and Purkinje cells of the cerebellum. More widespread neuronal degeneration occurs in subacute or chronic cases, particularly in the pyriform cortex, A m n i o n ' s horn, and deep structures in the temporal lobes. T h e degenerat ing neurons have eosinophilic granular cytoplasm and are often shrunken. T h e nuclei are pyknotic and may be eccen tric. T h e surrounding neuropil is e d e m a t o u s , and the endo thelial cells of the capillaries are swollen and proliferating. The malacic lesion remains virus associated in these c a s e s , and inclusion bodies can be seen in the n e u r o n s and astrocytes, but the neuronal injury may be indirect and caused by immune m e c h a n i s m s , ischemia, or anoxia. Patchy demyelination is very c o m m o n in dogs that c o m e to autopsy. Early in the course of the cerebral involvement (this may be difficult to j u d g e in clinical material b e c a u s e of the great variation in the onset in neurologic signs), there is vacuolation of the white matter. This vacuolation may be widely spaced or focal, giving the lesion a spongy a p p e a r a n c e . In some foci, there is a reduction only in the intensity of myelin staining, which can be best demon strated by myelin stains. At this stage, there is no perivas cular infiltration and little or n o astrocytic reaction, al though viral inclusion bodies can be frequently seen in their nuclei. There appears to be no special affinity of the demyelinating process for particular tracts, but it is usually more severe in some locations than others. T h e commonly Later stages of demyelination are characterized by reac tive changes of astrocytes, consisting of diffuse prolifera tions of astrocytes and some microglia. Occasionally pro liferating astrocytes form multinucleated syncytial cells. Inclusion bodies can be found in both types of astrocytes. The demyelination b e c o m e s m o r e obvious, but it is usual for the original framework of the tissue to remain and to produce a lacelike appearance. Occasionally, especially in the folia of the cerebellum, there are foci of colliquative necrosis in which nothing remains except a few vessels and cells surrounded by fluid. T h e s e colliquative foci in the cerebellum may involve the granular layer but, as is usual for the lesions of canine distemper, spare the molecular layer. T h e demyelination reaction can progress to this stage with only very minor perivascular cuffing developing. In canine distemper, perivascular cuffing is a late devel o p m e n t and follows the demyelination. At the margins of larger foci in the chronic stage of the demyelination, thick perivascular cuffs of mononuclear cells form. At this stage, the lesions have a distinctly motheaten appearance. The role of the canine distemper virus in old dog enceph alitis remains unclear. Old dog encephalitis (see T h e Ner vous System, Volume 1, Chapter 3) is a disease of mature dogs characterized clinically by progressive motor and mental deterioration and pathologically by encephalitis with widely scattered perivascular infiltrations of lympho cytes and plasma cells and by intranuclear inclusions in the astrocytes and neurons. T h e inclusion bodies have been shown to contain paramyxovirus nucleocapsids and the viral antigen of canine distemper, but most investiga tors have been unable to recover the distemper virus from affected dogs or transmit the disease to either dogs or distemper-susceptible ferrets. The nature of the lesions and the localization are distinct between old dog encepha litis and the demyelinating encephalitis of canine distem per. T h e cerebellum, which is regularly involved in canine distemper encephalitis, is usually spared in old dog en cephalitis, and clinical signs of the two entities are differ ent. If the canine distemper virus can be a cause of old dog encephalitis, the pathogenetic mechanisms must differ from those that operate to produce the conventional disease. Dunkin, G. W . , a n d Laidlaw, P . P . Studies in d o g distemper. J Comp Pathol 39: 2 0 1 -2 2 1 , 1926. Hall, W . W . , I m a g a w a , D . T . , a n d C h o p p i n , P . W . Immunological evidence for t h e synthesis of all canine d i s t e m p e r virus poly peptides in chronic neurological diseases in dogs. Chronic distemper a n d old d o g encephalitis differ from S S P E in m a n . Invasion of a few cells is sufficient to initiate focal lesions and progressive damage to the protective mucus layer. Attachment is the property of viral hemagglutinin. The virus enters the cell by endocytosis, and replication within the cell leads to the release of virions into the airways and to spread of the infection. Virtually every epithelial cell may become infected, and the protective mucociliary blan ket is stopped as the epithelial cells are destroyed. The degenerative changes occur very rapidly but are also halted rapidly by production of new epithelium, which is resistant to infection. The severity of these infections is often governed by the complications of compromised respiratory defenses, as discussed earlier in this chapter. Although the influenza viruses also involve the intestine and are viremic in birds, the viruses usually remain confined to the respiratory epi thelium in animals, although viremia and infection of fe tuses may occur with virulent infections. The influenza viruses of pigs and horses belong to the A type, which is notable for the antigenic changes which can occur spontaneously in the hemagglutin and neuramin idase glycoproteins of the envelope. The changes may be the result of minor mutations which produce slight antigenic differences between viral strains, or they may be the result of gene acquisition producing a completely new type of envelope glycoprotein, and the potential for new pandemics. Several subtypes are identified, based on antigenic differences in the hemagglutin (H) or neuramini dase (N) proteins. i. Swine Influenza Swine influenza is an acute conta gious disease caused by type A viruses. The classic disease is caused by the subtype HJNJ, which contains distinct antigenic variants which may circulate concurrently in pig populations in different parts of the world. Subtype H1N1 is the main agent of swine influenza in North America, is present in the pig population throughout the year, and produces disease of seasonal occurrence. The same sub type circulates widely in other parts of the northern hemi sphere. Subtype H3N2 is prevalent in Europe; on sero logic evidence, -30% of pigs in England have been infected. The swine viruses are zoonotic. There is circumstantial evidence that the classical swine subtype, HJNJ, was ac quired from humans in the 1918 pandemic, and the subtype H 3 N 2 was also acquired from humans after its emergence in 1968 as Hong Kong flu. The traffic of infection can, however, be two-way, with humans acquiring infection by antigenic variants currently circulating in swine. In surveyed pig populations, the serologic evidence of infection is much higher than the clinical evidence, which suggests that additional factors are necessary to convert the initial infections into disease. These factors are not understood, but the stress of climatic change and of man agement procedures is circumstantially important. So too may be concurrent viral infections such as by porcine coronaviruses. Affected pigs have sudden onset of coughing and high fever, which rapidly spread to pigs of all ages. There is stiffness, weakness, and serous oculonasal discharge. The virus itself causes a mild illness lasting no more than a week; more severe illness and deaths are usually because of secondary bacterial pneumonia. Uncomplicated viral infection rarely causes death, and the lesions have been studied mostly in experimental situa tions. Grossly, there is evidence of acute tracheobronchi tis with reddened, swollen mucosa and filling of the air ways by tenacious mucus, particularly in cranioventral regions. Because of the airway obstruction, there is alveo lar atelectasis. This is seen as groups of clearly defined, plum-colored lobules in the cranioventral lung regions. The overall extent of the atelectasis depends on the sever ity of the viral bronchitis and bronchiolitis. In fatal cases, in addition to atelectasis, there is diffuse hyperemia and edema of the lungs, and the interlobular septa are widened by edema fluid. The airways contain bloodstained foam as well as thick mucus, and as a result, there can be terminal air trapping in non-atelectatic regions of the lung. The pleura is normal or covered by a small amount of serous or serofibrinous exudate, and there is excess fluid in the pleural cavity. The pulmonary lymph nodes are enlarged by hyperemia and edema. There is usually a nonspecific, severe congestion of the gastric mucosa along the greater curvature. In the more common instances where pigs die of secondary bacterial pneumonia, usually involving Haemophilus spp., Pasteurella multocida, or both, the lesions are characteristic of an acute bacterial broncho pneumonia. Microscopically, there is patchy, acute inflammation of oculonasal membranes and mucosa of the tracheobron chial tree. The severity of infection is correlated with the extent of involvement of the respiratory tract. In mild cases, viral replication and the lesions it causes are limited to the upper respiratory tract. In severe infection, viral involvement extends to the bronchioles and alveolar pa renchyma. Viral replication begins in epithelial cells by 2 hr after infection, and by 8 hr there is loss of cilia, extrusion of mucus, and vacuolar degeneration of epithelial cells. Within 24 hr, there is epithelial necrosis and sloughing with emigration of leukocytes, chiefly neutrophils, into the airway lumen. The net effect in severe infections is an acute bronchiolitis and bronchitis in which plugs of neutrophilic exudate are responsible for alveolar atelecta sis. Extension of virus infection to alveolar epithelial cells causes alveolar flooding by serofibrinous exudate and neu trophils. The response after the first 24-48 hr becomes increasingly mononuclear. There is extensive infiltration of lymphocytes and smaller numbers of other leukocytes into the walls of airways and into the peribronchiolar and adjacent alveolar interstitium. Macrophages become the predominant cell in alveolar lumina. Epithelial prolifera tion and repair are easily detected histologically by the third to fourth days and lead to hyperplastic cells, which by light microscopy have an undifferentiated appearance. Return to ciliated and secretory cells occurs more slowly. The bronchial and bronchiolar epithelia frequently consist of several layers of stratified cells with the superficial ones degenerating and desquamating into the residual luminal exudate. The lesion likely to be seen in the few animals dying primarily of the pure viral infection is one in which there is severe involvement of the bronchiolar-alveolar regions. The acute inflammatory exudate and associated interstitial accumulation of mononuclear cells give the characteristic bronchointerstitial pattern of pneumonia defined earlier. In pigs dying because of secondary bacterial infection, the exudative bacterial pneumonia obscures the earlier viral lesion. ii. Equine Influenza Equine influenza is caused by ei ther of two subtypes of type A virus (A/equi 1, H 7 N 7 and A/equi 2, H 3 N 8 ). A role for type B virus is unconfirmed. The clinical syndrome caused by the influenza viruses overlaps those caused by equine herpesvirus 4 (rhinopneumonitis), equine arteritis virus (see The Cardiovascular System, Volume 3, Chapter 1), and perhaps equine parain fluenza type 3, rhinovirus, and reovirus. The subtypes of equine influenza virus have remained relatively stable with only antigenic drift in H 3 N 8 . In common with other influenza infections, the disease spreads rapidly among susceptible horses. All ages in a previously unexposed population are susceptible, but the disease is seen most often in young animals brought to gether or mixed with older animals. Main clinical signs are coughing, serous to purulent oculonasal discharge, fever, and weakness. Most horses have a mild illness which resolves within 1-2 weeks, but death can occur either from secondary bacterial bronchopneumonia or from se vere viral infection involving damage to brain, heart, gas trointestinal tract, kidney, and other parenchymal organs, as well as severe ocular and pulmonary lesions. Edema tous swelling of subcutaneous tissues of legs and, less commonly, ventral trunk may also be present. Respiratory lesions are those of hyperemia, edema, ex udation, desquamation, and focal erosions in the upper respiratory tract. In severe cases, there is an acute bron chointerstitial pneumonia accompanied by more wide spread pulmonary edema, as described for swine influ enza, and a tendency for secondary bronchopneumonia caused mostly by streptococci but occasionally by Esche richia coli, Pasteur ella multocida, or various other organ isms normally resident on the nasopharyngeal mucosa. lated to picornaviruses and, originally, feline caliciviruses, which are the important members of the genus causing respiratory disease, were discussed as feline picornavi ruses. Feline calicivirus infection is commonly manifest as an upper respiratory tract disease (see Rhinitis, Section II,D,1 of this chapter). Feline caliciviruses can replicate in a variety of tissues, but their pathogenic effects are usually limited to the oral and respiratory mucosa and to a lesser extent the conjunctiva. Clinical signs are principally fever, oral ulceration, rhinitis, conjunctivitis, and possibly pneumonia. The range and severity of lesions depend on the virulence and tropism of the particular strain of calic ivirus and on the mode of infection. Ulceration of oral epithelium is a common finding in both natural and experi mental infections and reflects the close relationship of feline caliciviruses to vesicular exanthema virus of swine. The ulcers, which occasionally are detected in the earlier transient vesicular stage, are most often present on the dorsal surface or lateral margins of the tongue and on the hard palate and external nares. Serous or mucoid rhinitis and conjunctivitis are less consistent findings but are more common in natural infections, and in experimental infec tions if the virus is administered intranasally rather than by aerosol exposure. Clinical signs of pneumonia may be present in natural infections, but affected cats usually recover within 7-10 days unless bacterial complications ensue. Most information on the pneumonia caused by feline caliciviruses is derived from experiments using heavy ex posure to aerosolized pneumotropic strains. This pro duces an exaggerated picture of lung lesions compared to natural infections. Nevertheless, certain strains of the virus have a strong tropism for alveolar type I epithelial cells. The resulting lesion is an acute to subacute intersti tial pneumonia with little of the bronchiolitis produced by the viral infections described previously. Grossly, the pneumonia involves cranioventral margins of the lungs and possibly irregular foci elsewhere. Early lesions are bright red and become gray-red at the peak of consolida tion (7 to 10 days) and thereafter become gray-tan as resolution occurs. Histologically the lesion is an interstitial pneumonia initiated by virus-induced necrosis of alveolar type I epi thelial cells. The epithelial necrosis is extensive from 12 to 96 hr after infection and is accompanied by exudation of serofibrinous fluid and large numbers of neutrophils. Hyaline membranes may be present. As the viral replica tion, necrosis, and acute inflammation subside, type II epithelial cells proliferate to line denuded alveolar walls, and the inflammatory cells become increasingly mononu clear. Between 7 and 10 days after infection, alveoli are epithelialized by type II cells, lumina contain mostly mac rophages, and alveolar septa are.thickened by accumula tion of lymphocytes, plasma cells, and sometimes fibro blasts. Few residual lesions are present after 30 days other than scarring as the result of necrosis of alveolar walls and hemorrhage. The upper respiratory tract involvement in feline herpesvirus infections compared to the oral and pulmonary distribution of lesions in calicivirus infections is a useful differential feature. Specific diagnosis, how ever, requires demonstration of virus in tissues by immu nofluorescence. Bibliography Langloss, J. M., Hoover, E. A., and Kahn, D. E isolated from most species of animals. They have differing virulence and tissue tropisms, but more often cause respi ratory and enteric disease than other manifestations. The most pronounced feature of the pneumotropic strains is a necrotizing and proliferative bronchiolitis. Severe natu-rally occurring disease usually requires an immunodefi ciency state. hepatitis and is described with diseases of the liver (Chap ter 2, Section X,B,1 of this volume). C a n i n e a d e n o v i r u s 2 is more strictly associated with respiratory disease, but strain differences within both serotypes make their distinc tion not so clear-cut as once thought. T h e contributory role of the virus in causing infectious tracheobronchitis (kennel cough) h a s already been mentioned. Naturally occurring pulmonary disease caused by adenovirus in dogs is mostly found in conjunction with canine distemper or other conditions causing immunologic impairment. T h e salient features are necrotizing bronchiolitis and the pres ence of large, amphophilic, intranuclear inclusions in swollen nuclei of degenerating bronchiolar epithelial cells. Intranuclear inclusions are usually less c o m m o n in alveo lar a n d bronchial epithelial cells and alveolar macro phages. T h e inclusions either fill the nuclei or are sepa rated by a narrow clear zone from t h e thickened nuclear m e m b r a n e (Cowdry type A inclusion). Affected bronchi oles are filled with debris of sloughed epithelium and neu trophils. W h e n viral infection of alveolar cells is extensive, there is an accompanying exudate of serofibrinous mate rial, neutrophils, erythrocytes, a n d macrophages. Alveo lar epithelialization can be prominent after viral replication has peaked (-10 days). Interstitial thickening by mononu clear cells and neutrophils occurs but is not an impressive feature. but mainly causes disease in young Arabian foals with congenital, combined, or selective immunodeficiency dis ease. Pulmonary lesions are a combination of coalesced atelectatic and consolidated lobules in cranioventral re gions; large a m o u n t s of lung m a y be affected. Mucopuru lent exudate is frequently present in the airways. Histolog ically, the main lesion is a severe bronchiolitis, which varies from necrotizing to proliferative, depending o n t h e age of the lesions and t h e proportion of epithelial cells infected with virus. In t h e early stage of severe infection, there is extensive necrosis a n d sloughing of bronchiolar epithelium (Fig. 6.60A ). L a t e r , bronchiolar epithelium is hyperplastic, and swollen superficial epithelial cells con tain amphophilic intranuclear inclusion bodies. Large, in distinct, blue inclusions a r e present in nuclei of dead cells which have been sloughed into t h e lumen ( Fig. 6.60B ). T h e combination of sloughed or hyperplastic epithelium and luminal filling by cell debris a n d neutrophils causes bronchiolar obstruction that is responsible for t h e wide spread alveolar atelectasis. T h e uncomplicated adenoviral lesion is sometimes limited to airways, without direct alve olar involvement. In other instances, there a r e intra nuclear inclusions in alveolar epithelial cells a n d an alveolitis characterized mainly b y accumulations of mac- rophages and a variety of leukocytes. Epithelial lesions and inclusions may also be present in conjunctival and upper respiratory epithelium during the height of the dis ease. They can also occur in epithelium of the renal pelvis, ureters, urinary bladder, urethra, lacrimal and salivary glands, and pancreas. The viral bronchiolitis or broncho pneumonia and the associated immunodeficiency state may combine to lead to secondary bacterial pneumonia or Pneumocystis pneumonia. A variety of epitheliotropic and endotheliotropic bovine and ovine adenoviruses have been isolated from rumi nants. Circumstantial evidence indicates that certain sero types of the bovine virus (particularly type 3) can cause mild respiratory or enteric disease or a combination of both. Bovine adenoviruses are not generally considered important pathogens; however, experimental infection of calves with epitheliotropic strains can cause necrotizing and proliferative bronchiolitis with intranuclear inclusions similar to the lesions occurring in foals. Only rarely are the characteristic lesions found in naturally occurring disease, usually in very young calves that lack colostral antibody or in which environmental stress or intercurrent diseases have impaired immune responses. A similar situation seems to exist in sheep. A noteworthy feature of the le sions caused by at least one strain of adenovirus from sheep is the exaggerated enlargement of both nucleus and cytoplasm of inclusion-bearing bronchiolar and alveolar epithelial cells. The pronounced cytomegaly can cause confusion with the cellular enlargement associated with cytomegalovirus infections. Porcine adenoviruses studied so far appear to have less affinity for pulmonary epithelium than those from the spe cies already mentioned. Limited experimental information indicates that pulmonary lesions are probably more a true interstitial pneumonia with alveolar septa thickened by proliferation of alveolar epithelial cells and accumulation of macrophages, lymphocytes, and plasma cells. Cells within alveolar septa, some possibly capillary endothelial cells, contain bluish intranuclear inclusions. Bronchiolar epithelial necrosis or hyperplasia is not a significant fea ture. Porcine adenoviruses have been associated with field cases of encephalitis or diarrhea but have not been estab lished as an important cause of respiratory disease. The severe acute lesion is hemorrhagic consolidation of cranioventral regions of the lung, which histologically has necrotizing lesions in bronchioles and adjacent alveoli as the principal features. Acidophilic or amphophilic intra nuclear inclusions may be found in bronchiolar and alveo lar epithelial cells early in the infection. Genital System, Volume 3, Chapter 4). It can occasionally be associated with usually nonfatal respiratory infection in older animals, either alone or with other infectious agents. The respiratory lesions are those to be expected from herpesviruses, namely a necrotizing rhinotracheitis and possibly bronchopneumonia. Acidophilic intranuclear inclusions can sometimes be found in epithelial cells in early lesions, more commonly in nasal and turbinate mucosa. is an im portant respiratory tract pathogen and, in contrast to equine herpesvirus 1, causes predominantly pulmonary lesions. The respiratory disease occurs independent of abortions caused by equine herpesvirus 1, and it now appears that different equine herpesviruses are specifically associated with each syndrome. For the role of equine herpesviruses 1 in causing genital lesions and abortion, see The Female Genital System (Volume 3, Chapter 4). The clinical respiratory disease is seen mostly in wean ling foals during the fall. It is characterized by slight fever, serous or catarrhal rhinitis, and conjunctivitis. Rarely, there is diarrhea and edema of the extremities. Recovery occurs in ~ 1 week but may be delayed when secondary bacterial infections supervene and cause mucopurulent or suppurative rhinitis and pharyngitis, or possibly pneumo nia. The uncomplicated viral infection is not fatal even when severe, as it can be in young horses crowded in stockyards or stables. When fatalities occur, they are usu ally due to secondary suppurative bacterial bronchopneu-monia. Intranuclear inclusions are extremely rare in post natal respiratory infections. has b e e n isolated from normal a n d diseased respiratory tracts (in cluding lymphofollicular pharyngitis a n d pneumonia), but its pathogenic importance is questionable. . Pulmonary lesions a r e usually those of severe acute to subacute pulmonary con gestion a n d e d e m a secondary to t h e myocardial damage. A true viral interstitial pneumonia is generally limited to very young pups ( < 2 weeks of age) in which there is generalized parvovirus infection. In such cases, basophilic intranuclear inclusions can b e found in the vascular endo thelium of many organs, including t h e lung. In t h e lung, viral infection of capillary endothelium, and perhaps alve olar epithelium, causes necrosis a n d accumulation of mixed inflammatory cells, mostly lymphocytes and mono cytes. Alveolar e d e m a is partly the result of local alveolar septal inflammation and partly cardiac failure. The pulmonary disease caused by t h e m a e d i -v i s n a vi rus occurs widely throughout E u r o p e , N o r t h America, Africa, a n d Asia and, until t h e development a n d u s e of serologic tests for detecting infected animals, w a s being spread further by importation of affected sheep. In addi tion to the terms ovine progressive pneumonia and maedi, the condition is k n o w n as G r a a f f -R e i n e t disease in t h e Republic of South Africa, zwoegerziekte in t h e Nether lands, a n d la bouhite in F r a n c e . The virus is spread by close contact among sheep a n d in milk from e w e to lamb. In utero infection can also occur. Infection of sheep is c o m m o n in regions where the disease is endemic, b u t many go t o slaughter without developing clinical signs. Because of t h e slow rate of progression of pulmonary lesions, clinical signs a r e u n c o m m o n until sheep reach 2 years of age. Evidence of disease is most frequent among sheep 5 -1 0 years of age. T h e early signs are loss of weight a n d increased respiratory rate on exer tion. Once signs begin, death usually occurs within -6-8 months because of continuing deterioration in condition and increasing respiratory difficulty. The specific lesions of ovine progressive pneumonia occur in the lungs and their associated lymph nodes. Grossly, the lungs of severely affected sheep do not col lapse fully when the thorax is opened, and sometimes the impressions of the ribs are retained. In cases uncompli cated by bronchopneumonia or abscessation, the lungs are mottled gray to grayish tan, and the pleura is smooth and glistening (Fig. 6.61 ). Lungs are much heavier than usual, often two or more times the normal weight. Close examination of the lung reveals that, although the lesions are widespread, there is relative sparing of the cranioven tral regions in the absence of secondary b r o n c h o p n e u m o nia. Least involved regions have an irregular grayish speckling against a light tan background. Greater involve ment results in a reticular pattern, and in most severely affected regions there is homogeneous grayish consolida tion. The lungs have a soft rubbery consistency or are moderately firm depending on the degree of confluence of the lesions. T h e cut surface is moist, but without oozing of free fluid. When complicated by bronchopneumonia, there are the typical cranioventral consolidations with pusfilled airways. There can also be coexistent lungworm lesions. A consistent gross finding in ovine progressive pneumonia is enlargement of bronchial and mediastinal lymph n o d e s , with soft grayish-white, homogeneous thick ening of cortical regions on cut section. Histologically, the most characteristic feature of ovine progressive pneumonia is the extensive lymphofollicular proliferations which occur predominantly in the perivas cular, peribronchial, and peribronchiolar sheaths in asso ciation with the pulmonary lymphatics. The most consis tent association is with pulmonary veins. M a n y of the lymphoid follicles contain germinal centers (Fig. 6.62A ). These prominent lymphofollicular features have led to the designation, lymphoid interstitial pneumonia. The next most striking feature is hyperplasia of smooth muscle, which is most evident in the walls of terminal bronchioles and alveolar ducts, but also extends into the walls of neighboring alveoli (Fig. 6.62B ). Alveolar septa are thick ened by infiltrations of lymphocytes and macrophages, especially at the periphery of the lymphoid nodules. The a m o u n t of interstitial fibrosis is usually slight but tends to be exaggerated by collapse of small clusters of alveoli and apposition of their walls (microatelectasis). Hyperplasia of alveolar type II epithelial cells is not usually a prominent feature of ovine progressive pneumonia, in striking con trast to ovine pulmonary adenomatosis (see N e o p l a s m s of the L u n g , Section VI, J of this chapter). Partial or complete lining of alveoli by cuboidal type II cells does occur, but usually only in alveoli adjacent to the large interstitial lymphoid follicles or occasionally lining large cystlike spaces. Bronchiolar epithelial hyperplasia is also not a prominent feature of uncomplicated ovine progressive pneumonia, although collapsed airways have pleated epi-thelium which can be mistaken for hyperplasia. The alveo lar exudate in the uncomplicated disease is usually sparse and consists mainly of alveolar macrophages and small amounts of debris. Multinucleated macrophages are a vari able feature. Suppurative lesions oriented on bronchioles indicate a secondary bacterial bronchopneumonia. Bron chial and mediastinal lymph nodes have a chronic hyper plastic lymphadenitis in which the main feature is pro nounced follicular hyperplasia. Pathogenesis of the disease involves infection of cells of the monocyte-macrophage lineage, possibly also a few T lymphocytes, with subsequent positive feedback estab lished by macrophage-derived cytokines and the re sponding lymphoid cells releasing their cytokines in turn. There presumably is also low-grade involvement of an assortment of additional inflammatory mediators. In in fected flocks, there is usually serologic evidence of infec tion of many animals and the maedi-visna virus can be isolated from both normal and diseased lungs. The diagno sis of ovine progressive pneumonia depends mainly on the presence of the characteristic lymphofollicular interstitial pneumonia. Progressive pneumonia is a fairly common manifesta tion of disease in sheep long infected by the maedi-visna virus. Mastitis appears to be a more common manifesta tion if deliberately sought by postmortem examination. Chronic proliferative arthritis is less common than pneu monia and meningoencephalitis (visna) is the least fre quent manifestation. Caprine arthritis-encephalitis (CAE) is a disease com plex in goats caused by a lentivirus antigenically closely related to the maedi-visna virus but separable on the basis of the large differences in nucleic acid sequences. The caprine virus has been studied mainly in reference to its ability to cause encephalitis and arthritis, as the name indicates [see The Nervous System (Volume 1, Chapter 3), and Bones and Joints (Volume 1, Chapter 1) ]. An alternative term for the disease is viral leukoencephalomyelitis-arthritis. There are brief descriptions of a chronic interstitial pneumonia produced by the virus, but there has not been a detailed study of the pulmonary lesions. The virus also causes mastitis, so the range of organ involvement of the maedi-visna virus and CAE virus are the same. Naturally occurring chronic pneumonia in older goats often has two prominent features lacking in ovine progressive pneumonia. One is extensive alveolar filling mainly by dense, acidophilic, proteinaceous (lipoproteinaceous) material. The other is widespread lining of alveolar septa by alveolar type II epithelial cells. The pathogenesis of these components and their relationship to infection with the caprine arthritis-encephalitis virus remain to be determined. Bibliography spiratory coronavirus emerged in Europe and Britain in 1986. The rapidity of spread suggested respiratory trans mission, and this route is successful for experimental transmission. The natural infection has not been responsi ble for clinical disease; it is detected by seroconversion against the classical transmissible gastroenteritis coro navirus of pigs of which it is probably a derivative. The respiratory agent replicates in the epithelial lining of air ways and in alveolar macrophages but is without signifi cant tropism for intestinal mucosa. Experimental infection can cause severe illness and death from bronchopneu monia. Porcine epidemic abortion and respiratory syndrome is a syndrome awaiting etiologic and pathologic clarification. The syndrome emerged in 1987 and has increased in impor tance as a cause of respiratory disease and pregnancy wastage in Canada, United States of America, Europe, and Britain. A virus designated as Lelystad agent and of undetermined taxonomic position is responsible for much of the European syndrome, whereas in North America the picture is somewhat clouded by other and mixed infections by such agents as Haemophilus paras uis, Streptococcus suis, Pneumocystis, swine influenza virus, encephalomyocarditis virus, and inclusion-body rhinitis virus. The disease is expressed as pneumonia or as pregnancy wastage. The route of infection is respiratory, but pulmo nary signs may be minimal in older pigs. The peak age for the respiratory disease is 4-10 weeks, in the range of 2-16 weeks. The lesions fit the description of bronchointerstitial pneumonia, which progresses in anteroventral lobes to suppurative bronchopneumonia and in the dorsal lobes to interstitial pneumonia with prominent epithelialization. Grossly, there is confluent consolidation of anterior lobes and ventral parts of the diaphragmatic lobes, together with lobular consolidation in dorsal areas. Often there is con fluent consolidation of all lobes of both lungs. In sows, infection is characterized by inappetence and fever, usually with brief but varying periods of blue discol oration of the ears, abdomen, and vulva. Infection in the pregnant sow during the first half of pregnancy (21-60 days of gestation) is followed by a return to estrus associ ated with embryonic death, absorption, or abortion, and in the last half of gestation by mummification, abortion, stillbirth, and the birth of live piglets, 50% of which may be nonviable. Piglets born alive are frequently weak, inappetent, and a high proportion die of respiratory disease. In contrast, feeder pigs are only transiently affected. a. PASTEURELLOSIS The pasteurellae are strict parasites of animals, their usual habitat being the mucous mem branes of the nasopharyngeal and oral regions. The type species is Pasteurella multocida. The other species of major importance for respiratory disease in domestic ani mals is P. haemolytica. A third, P. pneumotropic a, can frequently be isolated from the pharynx of cats and may contaminate bite wounds made by cats. The collective term pasteurellosis will be used in this section for infections by either P. multocida or P. haemo lytica. Pasteurellosis may be manifested as a peracute or acute septicemia, or be slightly less acute and cause signs according to the organ in which the infection is localized. Thus, in the various species, pasteurellosis can take a variety of forms. It may be a primary infection, a contami nant of cutaneous or mucosal injuries, or a secondary infection, especially following viral disease of the respira tory tract. Pasteurella multocida can be isolated from pathologic conditions in cattle, sheep, buffaloes, deer, pigs, rabbits, and other animals, and from a variety of birds, in which it causes fowl cholera. In the past, the different strains have been named for the species of host in which they are found, but it is current practice to regard these as types of the one species, P. multocida. Mammalian isolates of P. multocida are typed by biological characteristics (biotype) and serologically (serotype). The important strains are assigned on the basis of capsular antigens to one of five serotypes: A, B, D, E, and F. Further characterization can be made on the basis of the 11 somatic antigens. Types B and E are the cause of epidemic pasteurellosis, the classic hemorrhagic septicemia of cattle, sheep, goats, deer, and buffaloes. Type B is widespread in tropical Asia and Africa and in southern Europe. Type E occurs mainly in central Africa. Type A is ubiquitous and responsible for sporadic infections in many species; strains of this serotype are the ones usually isolated from pneumonia of cattle and fowl cholera and are sometimes found in pneumonia of swine. Type D is ubiquitous but has been found particularly in association with atrophic rhinitis and pneumonia in swine. It is also occasionally isolated from pneumonia in sheep. Strains of P. haemolytica are also classified by biotype and serotype. The organism is weakly hemolytic, and as a rule is nonpathogenic for rodents. The two main biotypes are A (arabinose fermenters) and T (trehalose fermenters). There are 16 currently recognized serotypes based on analysis of capsular antigens, 12 in type A and 4 in type T. Type Al is the usual cause of severe pneumonic pasteu rellosis (shipping fever) of cattle. Type A strains are asso ciated with pneumonia in sheep and septicemia in lambs before weaning. Type T strains cause septicemia in lambs past weaning age. Pasteurella multocida and P. haemolytica are both members of the bacterial flora of normal nasopharyngeal and oral mucous membranes, with the former usually pre dominating. Outbreaks of disease caused by the organisms occur when local and systemic defense mechanisms are impaired and virulent strains of pasteurellae undergo massive proliferation prior to invading the nasopharyn geal mucosa or being inhaled in large numbers into the lung. Predisposing factors, such as the stress induced by transportation, crowding, climatic changes and poor management, or the damaging effects of respiratory viral infections, were mentioned previously (see Broncho pneumonia, Section VI,F,1 of this chapter). Effects of stress are mediated partly by adrenocorticosteroid re lease. i. Cattle The major pasteurelloses of cattle are hemor rhagic septicemia and pneumonic pasteurellosis. Two other forms of pasteurellosis, meningitis in calves and mastitis in cows, occasionally are important in local situations. Meningeal pasteurellosis of calves is caused by P. multoc ida, and it is usually a disease of housed calves of 2-4 months of age. The reaction is fibrinopurulent and is some times accompanied by polyarthritis of the same type. Bo vine mastitis is caused by either P. multocida or P. haemo lytica. Sporadic, peracute, fatal mammary infections occur, caused by P. haemolytica; these infections are characterized by severe hemorrhagic inflammation of the parenchyma and a fibrinous and necrotizing inflammation of the ducts, quite similar to the peracute inflammation produced by coliform organisms. The pathway of infection is via the duct system. Pasteur ella multocida can be re sponsible for outbreaks of mastitis in a herd. If the mastitis is acute, it may be progressive and result in fibrosis and atrophy. The route of infection is assumed to be through the ducts, and the source of infection, in some cases at least, is assumed to be the suckling calf. is sometimes responsible for outbreaks of abortion in cattle in which there are no premonitory signs. The classic form of bovine pasteurellosis is hemorrhagic septicemia caused by P. multocida types B or E. This disease was originally recognized in western Europe in the nineteenth century as a severe epidemic in deer; it later spread to cattle, wild and domestic pigs, and horses. It has been observed as an epidemic disease of cattle, sheep, and horses in the Argentine, in bison in the western United States, and it is the disease known as El Guedda of Syrian camels and barbone of Italian buffaloes. Hemor rhagic septicemia is now limited largely to tropical lands from Egypt to the Philippine Islands and in these regions is primarily a disease of buffaloes. The most detailed descriptions are of the disease as it occurs in Asia, where outbreaks occur particularly during the rainy season. In intervening periods, the organism is apparently maintained in the nasopharyngeal regions of carrier cattle or buffaloes. The start of an outbreak de pends on some stress disturbing the balance in a carrier animal. This results in extensive proliferation and dissemi nation of the organisms to susceptible contact animals. Approximately 10% of animals survive subclinical in fections and become immune, but once the infection is established clinically, the mortality is almost 100%, even though the bacteria may be killed by chemotherapy. This, together with the immense proliferation of organisms in the clinical disease, indicates that toxins, particularly en dotoxins, are important in causing death. Hemorrhagic septicemia is almost by definition a per acute disease with death often so early that few signs are observed. When observed clinically, there is high fever and rapid prostration, with profuse salivation. The saliva and feces contain large numbers of pasteurellae. The post mortem picture is characterized by petechial hemorrhages on the serous membranes and in the various organs, espe cially the lungs and muscles. Severe endotoxemia may cause an acute, fibrinohemorrhagic interstitial pneumonia. The lymph nodes are swollen and hemorrhagic, and there may be bloodstained fluid in the serous cavities. Acute gastroenteritis, which can be hemorrhagic, is often pres ent. The spleen is not greatly enlarged, which is a point of differentiation from anthrax. An edematous form of hemorrhagic septicemia may also be peracute. Edema of the throat is a regular part of hemorrhagic septicemia, and in some cases it can be unusually pronounced. It is characterized by extensive swelling of the subcutaneous tissues, especially of the throat, but it may affect the whole head, the tongue, or some other part of the body, such as the brisket or a limb. The swellings are produced by a copious, clotted, strawcolored exudate. The additional lesions in this form of pasteurellosis are those of hemorrhagic septicemia, al though death may be caused by asphyxiation. Pneumonic pasteurellosis refers to forms of pneumonia in which the predominant pulmonary damage is caused by pasteurellae. The most important form is the severe acute fibrinous or fibrinonecrotic pneumonia caused usually by P. haemolytica type Al. The pneumonia has a bronchopneumonic pattern or, in its most fulminating form, a lobar pattern. The frequent occurrence of this form of the dis ease in the period soon after transportation (shipping) and crowding of beef cattle led to the widespread use of the term shipping fever. This term emphasizes the major cir cumstances under which pneumonic pasteurellosis oc curs, but cannot be used with precision as a synonym. Acute fibrinous broncho-or lobar pneumonia can also occur in very young calves, in older calves as an infection superimposed on enzootic pneumonia, and sporadically in cattle of any age. The fibrinous pneumonia is principally the result of rapid and massive proliferation of organisms. Although this is mostly associated with pathogenic strains of P. haemolytica in animals whose pulmonary defense has been compromised by various environmental stresses, and often a predisposing viral infection, it can also be caused by P. multocida. Occasionally Haemophilus somnus causes an indistinguishable lesion. Of the various vi ruses that have been incriminated as predisposing to the severe pasteurella pneumonia, parainfluenza 3 virus, BHV-1, and bovine respiratory syncytial virus are impli cated most often. The general features of fibrinous lobar pneumonia and bronchopneumonia have been described under those headings. In addition to the extensive reddish-black to grayish-brown cranioventral regions of consolidation with prominent gelatinous thickening of interlobular septa and fibrinous pleuritis, areas of coagulation necrosis are a char acteristic feature. At their most prominent, they appear as irregular but sharply demarcated regions with thick white boundaries and sunken, deep red, central zones. Histologically, the necrotic regions are frequently seen to supervene as coagulation necrosis in previously pneu monic tissue. They usually contain very large numbers of bacteria, particularly at the periphery adjacent to the compacted debris of inflammatory cells that form the white boundary zones seen grossly. T h e cause of the necrosis is not fully determined. Although it has been attributed to thrombosis (infarction), the occurrence of thrombosed vessels is not consistent enough to be a satisfactory expla nation, nor would it account for the necrosis sometimes cutting across interlobular septa into neighboring lobules (Fig. 6.63) . In view of the massive numbers of bacteria present, it is m u c h more likely that the necrosis is caused by the necrotizing effect of the large a m o u n t s of bacterial endotoxins and leukotoxins released locally and by the associated capillary thrombosis. Another characteristic histologic feature is the presence of clustered inflamma tory cells with elongated or streaming nuclei (Fig. 6.41C) . These are commonly referred to as oat cells. They seem to be an effect of bacterial toxins on leukocytes accumulating within inflamed alveoli. The extent to which they are de rived from blood monocytes or neutrophils is not firmly established. T h e less fulminating, fibrinous, or fibrinopurulent bron chopneumonias ( Fig. 6 .64) tend to be more often caused by P. multocida than by P. haemolytica. The nature of the pneumonia caused by pasteurellae depends on the rate and extent of bacterial proliferation and the amount of toxins released, which in turn depend on the virulence of the strain of organism and the degree to which the defenses of the host are impaired. Although in general P. haemolyt ica more often causes acute fibrinous lobar or broncho pneumonias, and P. multocida causes less acute fibrino purulent b r o n c h o p n e u m o n i a s , this generalization does not hold true in all circumstances, and intermediate lesions (Fig. 6 .65) may be found among cases in the same out break. Studies of the pathogenesis of the pneumonia caused by P. haemolytica have examined the relative roles of the endotoxins and leukotoxins produced by the bacteria and the various cells and corresponding cytokines and media tor cascades which amplify and are eventually responsible for most of the tissue damage. As far as toxic products of P. haemolytica are concerned, the relative importance of endotoxin and leukotoxin is not firmly established, but evidence to date supports the conclusion that, though both are involved, the endotoxin is more important. With re gard to the cellular and humoral c o m p o n e n t s involved, alveolar and intravascular macrophages appear to be ini tially involved, followed by neutrophil and platelet aggre gation in alveolar capillaries. F r o m there on, the mediators of inflammation and tissue damage would be those com mon to other forms of acute lung injury, particularly eicosanoids, T N F a , lysosomal proteases and reactive oxygen species. Macrophage-derived T N F a is probably an im portant initial c o m p o n e n t of the cytokine cascade because endotoxin is a potent stimulus for its production and re lease. T u m o r necrosis factor-a enhances neutrophil adher ence to capillary endothelium, stimulates neutrophil activ ity, and has a procoagulant effect, although it is not alone in these respects. T h e bovine pulmonary response to P. haemolytica is noteworthy for the predominance of fibri nous exudate. Alveolar macrophages from affected lungs have greatly increased procoagulant activity and greatly decreased profibrinolytic activity, and this, together with presence of antiplasmin and inhibitor of plasminogen acti vator in the acute alveolar exudate, could account for the large quantities of fibrin deposited within alveoli. There are several syndromes in sheep associ ated with P. haemolytica or P. multocida. Mastitis in ewes caused by Pasteurella spp. is discussed with The Female Genital System (Volume 3, Chapter 4). The principal forms of pasteurellosis in sheep are septicemia caused by P. haemolytica and sporadic or enzootic pneumonia, associated more often with P. haemolytica than with P. multocida. Septicemia caused by P. haemolytica, biotype T, occurs mainly in weaned lambs during the fall m o n t h s , but it can occur in other age groups and at other times of the year. D e a t h s , which seldom exceed 5 % of the sheep at risk, usually follow within a few days of changes in pasture, feed, or other management practices. The clinical syndrome is not specific. Signs of illness are vague and the usual course is short, with sudden death reminiscent of clostridial enterotoxemia. At necropsy, pe techial and ecchymotic hemorrhages are usually present but sometimes are difficult to detect. They occur in subcu taneous tissues, particularly of the neck and thorax, in T h e lungs have diffuse, severe congestion and e d e m a with abundant white or bloodstained foam in the airways. Discrete hemorrhagic foci (infarcts) can some times be seen scattered throughout the lungs. The liver is usually congested, and in some cases, there are many yellowish necrotic foci disseminated through the paren c h y m a . These are usually of miliary size but can be as large as 1 cm in diameter and surrounded by a narrow red border. Occasionally there is inflammation of joints, pericardium, meninges, and choroid plexus, but the devel opment of these lesions requires that the course be a little longer than usual. These additional lesions are observed more frequently in the experimental disease, which is less fulminating than the natural one. Microscopic examination of tissues reveals widespread bacterial embolism. The pale hepatic foci consist of colo nies of bacteria with a surrounding ischemic zone. There m a y be thrombosis of the adjacent tributaries of the portal vein and small amounts of parenchymal necrosis, but gen- Pneumonic pasteurellosis in sheep is usually caused by P. haemolytica, biotype A. T h e same biotype can also cause septicemia in the absence of pneumonia in lambs < 2 months of age. T h e generalizations regarding circum stances giving rise to pneumonic pasteurellosis in cattle hold true for sheep. Most outbreaks occur in lambs during late spring and early summer. Sudden climatic changes, gathering, and handling are the most commonly recog nized predisposing situations. Viral infection, particularly by parainfluenza-3 virus, is also believed to play a role. Other viruses implicated occasionally are respiratory syn cytial virus and adenovirus. The lesions tend to be those of acute hemorrhagic or fibrinonecrotic lobar or broncho pneumonia and serofibrinous pleuritis in acute cases ( b r o n c h o p n e u m o n i a with abscessation. Pleuritis frequently accompanies the pneumonia, and sometimes pericarditis also o c c u r s . Septicemic pasteurellosis due to P. multocida is occasionally observed in neonatal pigs, and meningitis can also be present in the s a m e age group. Pasteurella haemolytica rarely affects swine but has been recovered from aborted fetuses. Septicemic disease without localization or distinctive lesions is seen in adult pigs, especially those that are specific pathogen free. T h e disease in these animals is peracute, and P. multocida can be recovered from all organs in large n u m b e r s . There is a report from India of a hemorrhagic septicemia type of pasteurellosis in pigs from which was isolated P. multocida type B . Severe, acute, fibrinous p n e u m o n i a s analogous to the more fulminating Pasteurella pneumonias in cattle and sheep are sometimes caused by P. multocida in pigs. As in cattle and sheep, stressing factors are usually involved. T h e s e are usually poor m a n a g e m e n t and perhaps intercur rent infection by viruses such as swine influenza or hog cholera (swine fever). The acute fibrinous or fibrinonecrotic p n e u m o n i a is sim ilar in many respects to the lesion in cattle. T h e extensive gelatinous thickening of interlobular and subpleural tis sues and the severe serofibrinous pleuritis lead to the term pleuropneumonia being used on occasion. In this connec tion, although epidemiologic patterns indicate that most severe pneumonias of the pleuropneumonia variety are caused by Actinobacillus In addition to the severe thoracic lesions in pneumonic pasteurellosis, there is often acute pharyngitis and in flammatory e d e m a of the throat and yellow jaundicelike discoloration of the carcass of u n k n o w n cause. Severe pharyngitis can be necrotizing and ulcerative. A fibrino hemorrhagic polyarthritis may be present, and there is intense congestion of the gastric and intestinal mucosa. Complete recovery from p n e u m o n i c pasteurellosis seldom occurs in pigs. Animals which survive the acute disease tend to develop chronic lesions which are usually fatal in due course. In these, most obvious findings are polyarthri tis, adhesive pericarditis, and pleuritis, and extensive areas of fibrotic lung, which contain n u m e r o u s abscesses or fibrous capsules enclosing sequestrae or caseous detri tus. As is usual in the fibrinous pneumonias caused by Pasteurella s p p . , the bacterium can often be cultured from the blood and other organs as well as the lung. T h e septice mic or bacteremic nature of the infection is revealed also by the recovery of the bacterium from aborted fetuses from pregnant sows which survive the acute disease. The etiologic role of P. multocida in atrophic rhinitis of swine is discussed with that disease. iv. Other Species P. multocida has been reported in fatal infections in horses, and the latter were included Biberstein, E . L . , a n d Gills, M . G. T h e relation of antigenic types to t h e A a n d T types of Pasteurella haemolytica. J Comp Pathol 72: 316-320, 1962. Biberstein, E . L . , a n d K e n n e d y , P . C. Septicemic pasteurellosis in lambs. Am J Vet Res 20: 9 4 -1 0 1 , 1959. Biberstein, E . L . , a n d This disease has increased dramatically in major swine-raising areas of the world during recent years. The characteristic lesion is a severe fibrinonecrotic and hemorrhagic pneumonia with accom panying fibrinous pleuritis, hence the designation pleuro pneumonia. Actinobacillus pleuropneumoniae is highly pathogenic and often appears capable of invading and rapidly proliferating within the lung in the absence of obvi ous predisposing factors. All aspects of pathogenesis of field outbreaks of the disease, however, are not under stood. There are twelve known antigenic varieties of A. pleuro pneumonia based on capsular antigens, and protective immunization is serotype specific. There appear to be geographic differences in the distribution of serotypes and also differences in virulence between and within sero types. The dynamics of the disease in infected herds are influenced by passive immunity in the young, which will persist for 8-12 weeks after peaking at ~4 weeks. Active infections in chronically infected herds, and seroconver sion, begin in the period in which passive immunity is declining. Peak mortality occurs in the period from 10 to 16 weeks of age. Factors in the bacterial virulence are not clear. The organism adheres poorly to tracheobronchial mucosa but adheres well to pulmonary tissue, which it must reach in droplet nuclei in inhaled air. The ability to adhere appears not to be related to serotype. The organism produces a hemolysin and a potent heat-labile cytotoxin with activity against endothelial cells and pulmonary alveolar macro phages. The local pathogenesis of the lesion will depend on complex interactions involving an activated coagulation system, direct cytotoxicity, early chemotaxis of neutro phils, and release by them of injurious hydrolases and free radicals, and impairment of macrophage clearing. Contagious pleuropneumonia can affect pigs of any age but is more common from ~6 weeks to 6 months of age. The severe form of the disease occurs mostly in later stages of fattening and can cause a mortality in the 20-80% range. Peracute, acute, and subacute to chronic forms are recognized, the latter representing residual lesions of the acute disease. Deaths in the peracute and acute forms occur suddenly or after a short period of depression, fever, and possibly hemorrhage from nose and mouth. The main gross lesions are bloody nasal discharge, bloodstained foam in trachea and bronchi, and large regions of hemor rhagic or fibrinonecrotic pneumonia accompanied by fi brinous pleuritis. Since the tissue damage is caused by massive bacterial proliferation and release of toxins, the essential features are similar to those already described for fulminating pneumonic pasteurellosis in cattle, but vas culitis is an additional important feature. There is less tendency for the pneumonic foci caused by A. pleuropneu moniae to be limited to the cranioventral lung regions, however, presumably because of the greater virulence of the organism and the influence of vasculitis. Irregular, well-circumscribed regions of hemorrhagic consolidation or necrosis are commonly found in more dorsocaudal re gions, especially surrounding major bronchi near the hilus of the lung (Fig. 6.67B ). The foci of consolidation are also particularly prone to undergo sequestration, with the result that in subacute cases, there may be large foci of caseous or cavitating yellow-gray or tan necrotic debris surrounded by fibroblastic zones. Many of these can subsequently become abscesses through secondary con tamination by Actinomyces pyogenes, P. multocida, B. bronchiseptica, H e m o r r h a g i c consolidation a n d necrosis in dorsal and hilar regions with fibrinous pleuritis (Courtesy of B . W . F e n w i c k . ) tococci, o r others. T h e end result c a n b e a severely scarred, abscessed lung which is tightly bound to the tho racic wall by fibrous adhesions. Extrapulmonary vascular lesions sometimes occur in acutely affected pigs, particularly in the kidneys. Hyaline thrombosis and fibrinoid necrosis of glomerular capillar ies, afferent arterioles, a n d interlobular arteries indicate the probable effect of severe endotoxemia. Other Haemophilus s p p . c a n cause lung lesions. Haemophilus parasuis has been referred to as a synergistic infection with swine influenza. It causes a nonspecific suppurative bronchopneumonia. F o r its involvement in polyserositis a n d arthritis of swine, see Bones a n d Joints (Volume 1, Chapter 1). Haemophilus somnus is discussed with Diseases of the N e r v o u s System (Volume 1, Chapter 3). It occasionally produces a lesion indistinguishable from the fibrinous lobar pneumonia of pneumonic pasteurello sis. More c o m m o n descriptions of pneumonia associated with H. somnus in calves are of a subacute to chronic, fibrinopurulent, or purulent bronchopneumonia in which bronchiolar epithelial necrosis and bronchiolitis fibrosa obliterans are frequent features. Although H. somnus h a s been shown t o b e capable of causing some degree of bron chiolitis fibrosa obliterans experimentally, t h e obvious presence of this lesion in naturally occurring pneumonias should arouse t h e strong suspicion of a previous viral infection, such as by bovine respiratory syncytial virus. Vasculitis c a n also be found in pneumonia caused by H. somnus, but it is mostly a feature accompanying acute septicemic episodes or in acute experimental lesions re sulting from endobronchial inoculation of the organism. c. BORDETELLOSIS Bordetella bronchiseptica is an obli gate parasite of t h e upper respiratory tract of rodents, dogs, and pigs, and can occasionally b e found in various other species. In dogs, it is involved in the causation of kennel cough a n d chronic bronchitis, as discussed pre viously. It is also frequently associated with the develop ment of suppurative bronchopneumonia in dogs with inter stitial pneumonia caused by t h e distemper virus. Bordetella bronchiseptica can also cause secondary bron chopneumonia in association with other diseases leading to reduced pulmonary defenses. In swine, the role of B. bronchiseptica in the production of atrophic rhinitis has been dealt with under that heading. As a pulmonary pathogen, B. bronchiseptica is most im portant as the occasional cause of septicemia or severe bronchopneumonia in suckling pigs usually < 3 weeks of age. Mortality can b e high in these outbreaks. T h e bron chopneumonia is predominantly suppurative, affecting in dividual lobules o r small groups of lobules in a scattered rather than confluent pattern, although mainly present in apical a n d cardiac lobes. Typically, it is associated with acute bronchitis and rapid onset of fibrosis, which is most evident in peribronchiolar sites. Fibrosis m a y extend to other interstitial regions when the amount of inflammation and exudation is severe. Bordetella bronchiseptica m a y also be a cause of suppurative bronchopneumonia in older pigs, mostly as a complication of mycoplasmal pneumonia in fattening animals. bronchiseptica has also been recorded as an occasional cause of suppurative bronchopneumonia in cats and foals. Bordetella parapertussis has been implicated as one of the bacterial agents involved in the production of enzootic pneumonia in sheep, but its importance relative to other agents is not established. Tuberculosis is an ancient disease and is still wide spread in some parts of the world. In many areas, how ever, the incidence of classic tuberculosis in humans and animals has been reduced to the point where mycobacte rial disease is more often caused by atypical (nonmammalian) acid-fast bacilli. Infection and disease caused by these atypical mycobacteria are probably more widely recognized because they are no longer overshadowed by the classic disease and have been revealed for more detailed investigation. Changing environments and a sus ceptible population no longer provided with the crossprotection afforded by infection with the classic myco bacteria probably also play some role. The emergence of a wide range of mycobacteria as agents capable of causing disease has resulted in both diagnostic and taxonomic confusion. This is compounded by the large number of saprophytic mycobacteria now recognized and the lack of clear-cut separation between saprophytic and potentially pathogenic species. Assessment of the etiologic role of a mycobacterium isolated or identified in a particular case therefore needs to be made on the basis of specific evi dence available for that case rather than on the basis of generalizations. Mycobacteria are widely distributed in nature. Many are saprophytes, and some of these are opportunistic pathogens. Others, as far as is known, are strictly para sitic. Some of the pathogenic types cannot be cultivated in vitro, and those that can be cultivated generally grow slowly. For these reasons, taxonomic classification has been difficult. Currently, a variety of cultural and biologi cal characteristics including serotyping, lipoprotein analy ses, and phage typing are used in numerical classification schemes. More than 100 properties of new isolates can be subjected to computer analysis. A high degree of matching (>80% of characteristics) is used to group organisms to gether as the same species. Mycobacterial classification is still incomplete, however, so in the meantime, the follow ing categorization puts the organisms into useful perspec tive. The listing is incomplete, and not all are of known veterinary significance. as the M. avium-intracellulare complex. To avoid confusion surrounding the term tuberculosis, con vention limits it to diseases caused by M. tuberculosis or M. bovis. Other conditions are referred to as mycobacter iosis, qualified with the specific agent where known (e.g., avian mycobacteriosis when caused by M. avium). Atypi cal mycobacteriosis is sometimes used as a general term to cover all the diseases other than those caused by M. tuberculosis and M. bovis. In most veterinary literature, however, disease caused by M. avium is still included as one of the classic forms of tuberculosis, and this usage will be continued in this chapter. Mycobacteria which can have an independent sapro phytic existence in nature are widespread in soil and wa ter, on vegetation, and in mucous membranes of the oro pharynx. There are a large number of species whose taxonomic status is not fully established. When these or ganisms cause disease, it is usually in immunologically compromised hosts, and the manifestations are either cer vical lymphadenitis, pulmonary lesions similar to tubercu losis, or cutaneous lesions associated with local penetra tion of organisms through wounds or abrasions of the skin. An example is M. marinum, which is abundant in pools in regions with temperate climates and causes tuberculous disease in fish and cutaneous ulcers in humans. This organ ism is grouped with the photochromogens (Runyon's group I) together with M. kansasii. The latter produces cervical lymphadenitis and pulmonary disease in humans, and has been isolated from cow's milk and from cattle in the United States and the Republic of South Africa. Scotochromogens produce pigment without photoactivation (Runyon's group II) and include M. scrofulaceum, which is closely related to the M. avium-intracellulare complex. These organisms have been isolated from dis ease in cattle and tuberculous-type lesions in dogs. An-other member of the group, M. aquae, has been isolated from nodular lesions on the teats of cows. Nonphotochromogens (Runyon's group III) have organisms in the M. avium-intracellulare complex as the most important members. Organisms belonging to this complex have been isolated from tuberculin-sensitive cattle and pigs, and their pathogenicity has been assessed experimentally in calves and pigs. Some strains are virtually nonpathogenic, and others produce generalized disease. Mycobacteria of group IV are rapid growers at room temperature, usually nonpigmented, and include many saprophytes. Within this group, M. smegmatis is one of the organisms isolated from tuberclelike lesions in lymph nodes of swine, and it has also been associated with devel opment of bovine mastitis following its injection into the udder in oily infusions of penicillin. Another member, M. fortuitum, was initially isolated from lesions in bovine lymph nodes and is an occasional cause of mastitis in cattle. Members of this group, particularly M. fortuitum, M. chelonei, and M. phlei are the usual causes of cutane ous mycobacteriosis in cats and dogs. Further discussion of cutaneous lesions caused by mycobacteria, including those associated with M. lepraemurium, will be found in bacterial diseases of the skin (Volume 1, Chapter 5). Other important distinct species of mycobacteria are M. leprae of human leprosy, M. lepraemurium (rat lep rosy), and M. paratuberculosis (johnei). The last named causes Johne's disease in ruminants (see The Alimentary System, Chapter 1 of this volume). It will be evident that the pathogenic mycobacteria pres ent a wide range of specializations, from saprophytes to the extremes of parasitism represented by M. leprae and from a wide host range to infectivity for only specific hosts. As parasites, they are principally intracellular. They are mostly within macrophages in an association which does not necessarily cause their death or the death of the host cell. The lesions produced tend to be similar and of granulomatous type characterized by collections of mac rophages, epithelioid cells, and giant cells. Additional components of inflammation and necrosis depend on the degree of cell-mediated response of the host against living bacilli with the corresponding production of cytokines and other inflammatory mediators. The phenomena of chronicity and latency are common to the mycobacterial infec tions. Both are related to the resistance of the organisms to phagocytic killing, to the slow growth of the organisms, and to the complex interactions between the organisms and the cellular immune system of the host. The three main species of tubercle bacilli, M. tuberculo sis, M. bovis, and M. avium, occur most frequently in their respective hosts, but cross-infections do occur, and various other species of animals are affected. Under natu ral conditions, M. bovis causes disease chiefly in cattle, humans, swine, and occasionally in horses, dogs, cats, and sheep; M. avium causes disease chiefly in birds and occasionally is found in cattle, swine, horses, sheep, and captive monkeys; M. tuberculosis is chiefly responsible for tuberculosis in humans, and occasionally infects pigs, captive monkeys, dogs, cats, cattle, and psittacine birds. The expression of tuberculosis in the various hosts usually differs somewhat according to the type of bacillus in volved, as well as to other factors. Although the human and bovine bacilli can produce disease in a wide range of species under conditions of special exposure, they are each naturally maintained in only one species, the human bacillus in humans and the bovine in cattle. Thus, in the absence of infection from cattle, the bovine type disap pears from the human and porcine populations. The situa tion with the M. avium-intracellulare complex is not so clear because of saprophyte members. In addition to the hosts just mentioned, others of almost unlimited variety can be infected experimentally with one or more species of the tubercle bacilli. The differential pathogenicity of the organisms for guinea pigs, rabbits, and fowls was the original basis of the biological classifi cation of organisms as to type in diagnostic laboratories. Fowls are highly susceptible to the avian types, but highly resistant to the mammalian types. The avian type will, with the usual test doses, produce progressive infection in rabbits, but only localized lesions in guinea pigs. For the differentiation of mammalian strains, the rabbit is usually used. In rabbits, the bovine bacillus, in the standard dose for the test, produces progressive infection which is fatal in 3 months; the human type does not kill rabbits although isolated tubercles can be found in various organs. The guinea pig is highly susceptible to both mammalian types and therefore useful for isolating the organisms. The mycobacteria are nonmotile, non-spore-forming pleomorphic coccobacilli. They are Gram-positive but al most unstainable by the simpler bacterial stains because of their high content of lipids. They are routinely stained with hot carbol dyes, usually carbolfuchsin, and then resist decoloration by inorganic acids. This property of acidfastness, or acid-alcohol fastness, of the stained bacilli depends on the amount and spatial arrangement of mycolic acids and their esters in the bacterial wall. Sometimes, in cultures or in old lesions, the organisms have a beaded or granulated appearance. This beading is partly caused by the presence of lipid droplets within the bacteria and is an indication of an unfavorable environment for organisms in the postexponential growth phase. Staining of the bacilli can be facilitated by incorporating a surface-active wetting agent, such as Tween 80, in the dyes. They are also demon strable by fluorescence microscopy when stained by a fluorescent dye such as auramine. Much attention has been given to the chemical composi tion of the mycobacteria, particularly the cell walls, in the interests of clarifying the pathogenesis of the lesions, perfecting diagnostic techniques, and developing vac cines. The chemical composition of the cell wall is domi nated by complex lipids, which include glycolipids, peptidoglycolipids, lipopoly saccharides, lipoproteins, and waxes. The mycolic acids, on which acid-fastness de pends, are among them. The precise role of the various lipids in contributing to the virulence and immunogenicity of the organisms is still unclear. The waxes, which are themselves composed of various proportions of lipids, glycolipids, and peptidoglycolipids depending on the spe cies of mycobacterium, are important in the initial foreignbody type of macrophage response. Waxes, together with peptidoglycan (muramyl dipeptide) and various glycolip ids, are responsible for most of the adjuvant activity of mycobacteria. Attraction of antigen-processing cells (macrophages) and presentation of antigen in appropriate surface configuration are major attributes of adjuvant ac tivity. Increased glycolipid content of mycobacterial cell walls is associated with increased virulence. A close paral lel is with the amount of cord factor (trehalose dimycolate). This correlates with the fact that in general the more acid-fast strains are more virulent. Other glycolipids (mycosides) appear to form a barrier against lysosomal diges tion and partly explain the ability of the organisms to survive after phagocytosis by macrophages. Intracellular survival is also facilitated by the bacteria preventing fusion of phagosomes and lysosomes, possibly by secretion of cyclic adenosine monophosphate (AMP). The differing effectiveness of such mechanisms determines the relative ability of various mycobacteria to resist intracellular deg radation. Tuberculoproteins are the other major category of immunoreactive substances in mycobacteria. They provide most of the antigenic determinants, but in order for an animal to produce an immunologic response to these deter minants, the adjuvant activity of the lipids and polysaccha rides in the mycobacterial cell wall is needed. Purified protein derivatives from mycobacteria are capable of elic iting the delayed-type hypersensitivity once the animal is sensitized, however, and this is the basis of tuberculin testing. Both tuberculoproteins and the adjuvant lipids are present in infection, and the result is the development of both humoral and cell-mediated immune responses. The humoral antibodies can be demonstrated by serologic techniques but do not participate in pathogenesis of the characteristic lesions or in the production of immunity. Cell-mediated responses are responsible for both aspects of the disease. Cell-mediated immunity and delayed-type hypersensi tivity are expressions of immune responses mediated by lymphocytes, mostly T cells. Both manifestations usually develop simultaneously. They do not have identical mech anisms, however, because sometimes one is present with out the other, and there is no quantitative relationship between them when both are present. The dissociation between the two types of responses appears likely to be explained on the basis of involvement by different subpopulations of T cells and corresponding sets of cytokines. Cell-mediated immunity is effected by the enhanced ability of activated macrophages to phagocytose and kill bacilli. Macrophages are activated by cytokines secreted by specifically sensitized T lymphocytes, which respond to processed antigens released by previously infected mac rophages. Most activated macrophages are derived from blood monocytes. Immunity to tuberculosis therefore is principally determined by the ability of macrophages to inhibit the growth of intracellular bacilli. Both innate (ge netic) and acquired resistance are involved. Macrophages, for unexplained reasons, can also respond differently in organs such as the liver and kidney in the same animal. Since the balance between the virulence of the myobacteria and the ability of macrophages to kill them is often a precarious one, any compromise of the host's immune system is prone to precipitate or exacerbate the disease. This is revealed by the frequent clinical association of tuberculosis with immunosuppression caused by diseases, drugs, hormones, or malnutrition. Delayed-type hypersensitivity is also mediated by cy tokines released mainly from sensitized T cells in response to antigenic materials from the tubercle bacilli. The cyto kines cause further accumulation of macrophages and lym phocytes. Release of cytotoxic factors and hydrolytic en zymes from macrophages is principally responsible for the caseation necrosis characteristic of many tuberculous lesions. Functionally heterogeneous populations of lympho cytes and macrophages are present in tuberculous lesions. Relative numbers of the various subpopulations of these cells partly determine whether activation of macrophages and inhibition of bacterial growth (cell-mediated immu nity) or a severe delayed-type hypersensitivity response is the dominant feature. The importance of hypersensitivity in the pathogenesis of lesions of tuberculosis was first demonstrated by Koch in what is now known as the Koch phenomenon. If a normal guinea pig is inoculated subcutaneously with a culture of tubercle bacilli, generalization of the infection causes death in 2-3 months. At the site of inoculation, a hard nodule or tubercle develops in 10-14 days. This nod ule soon breaks down to form an ulcer, which persists until the animal dies. If, however, the inoculation is made into a tuberculous guinea pig, the events are quite differ ent. An acute response characterized by exudation and necrosis develops at the site of inoculation. The necrotic tissue soon sloughs, the lesion heals permanently and quickly, and the infection is not disseminated from it, even to the regional lymph node. The injected organisms which provoke the hypersensitivity reaction in the skin are fairly rapidly destroyed, but those in the primary lesions of the disease are not destroyed, and their persistence and prolif eration may eventually kill the animal. Whether the hyper sensitivity reaction is beneficial or harmful to the host depends on the circumstances. In common with most com plex inflammatory conditions, there is a balance between inhibitory and amplifying factors. On the one hand, hyper sensitivity to relatively small numbers of bacilli causes accelerated tubercle formation which enhances the killing of the organisms, and helps prevent reinfection or dissemi nation from the initial site of infection. On the other hand, the hypersensitivity response to large amounts of myco bacterial antigen causes extensive cell necrosis and tissue destruction, which is seriously detrimental. Liquefaction, which is brought about by hydrolytic enzymes of macro phages and possibly neutrophils, is the most harmful re-sponse. T h e bacilli multiply extracellularly in the liquefied material and are available in large numbers for dissemina tion through cavities, vessels, and airways. In s u m m a r y , the final determinants of the nature and intensity of lesions are the mass of bacterial antigen presented to specifically reactive lymphocytes and the modifying influences of the structure of the tissue involved. T h e lesions of tuberculosis are the prototype of granulo matous inflammation. The tuberculous granuloma (tuber cle) is mainly cellular, and its development is frequently designated productive or proliferative in contrast to the more exudative type of lesion it occasionally causes. W h e n tubercle bacilli are initially implanted in tissue, they behave as relatively bland lipid-rich foreign particles would be expected to do and incite a foreign-body macro phage response. Bacilli are phagocytosed by macro phages, and if the resistance of the macrophages is ade quate, the bacilli are eventually killed. If the balance tips the other w a y , however, the bacilli proliferate and are released from killed macrophages together with antigenic materials which sensitize attracted T lymphocytes. By the tenth day or so after e x p o s u r e , by which time hypersensi tivity is developing, many bacilli are present, and the tempo of events begins to quicken. Cytokines secreted by the sensitized T lymphocytes cause the attraction, prolif eration, and activation of macrophages which are derived mostly from blood m o n o c y t e s . In the infected foci, macro phages assume a distinctive appearance which causes them to be designated as epithelioid cells because of a vague histologic similarity to sheets of large epithelial cells. T h e epithelioid cells have large vesicular nuclei, and extensive pale cytoplasm with ill-defined borders. The epithelioid cells ultrastructurally are characterized by abundant organelles and extensive interdigitations of their plasma m e m b r a n e s . They contain ingested bacilli within their cytoplasm, and the structural changes indicate a heightened bactericidal activity. Mixed in with the epithe lioid cells is a variable number of giant cells of the Langhans type (Fig. 6.68A ). These are large cells with several eccentric nuclei and are formed by the fusion of macro phages. This admixture of epithelioid and giant cells forms the center of young tubercles. At the periphery is a narrow zone of lymphocyte, plasma cells, and unaltered mono cytes. As the lesion progresses, the classic tubercle devel ops peripheral fibroplasia and central necrosis (Fig. 6 .68B). These t w o features are not present in all tubercular infections; there are both species and individual varia tions. Encapsulating fibroplasia is more conspicuous in those individuals which have considerable powers of resis tance, and it may, as tuberculous granulation tissue, over grow and dominate the lesions. T h e development of cen tral necrosis gives to the tubercle its high degree of histologic specificity. The necrosis is a product of cellmediated hypersensitivity and is of caseous character. The necrotic material is most commonly inspissated into a yellowish cheesy m a s s , but may liquefy or calcify. Calci fication is a characteristic development in some species of animals, but seldom observed in others. The exudative type of lesion in tuberculosis usually develops acutely. The exudate is relatively voluminous and consists of fibrin and neutrophils as well as the usual mononuclear cells. Eventually, the exudate clots, and it too caseates. A combination of factors is usually regarded as responsible for the exudative lesions. Chief among them are rapid bacterial proliferation, presence of abundant re active lymphocytes, and a site of localization in easily distensible or space-lining tissues. There are various portals of entry available to the tuber cle bacilli. Infection can occur congenitally by way of the umbilical veins, or postnatally through alimentary, respiratory, genital, or cutaneous routes. G r o w t h of the original tubercle takes place by centrifugal expansion and by the development of satellite tubercles formed by spread of bacilli from the initial focus. T h e new tubercles may coalesce to produce large lesions. In a susceptible unsensitized animal, the bacilli spread rapidly, either free or in macrophages, along the lymphatics (Fig. 6.69) to the re gional lymph n o d e s , where further tubercles develop. The combination of lesions in the initial focus and in the re gional lymph node is k n o w n as the primary complex of R a n k e . It is always present with first infection in animals, but both c o m p o n e n t s may not be detectable because when infection occurs across a mucous m e m b r a n e , such as of the pharynx or intestine, the initial lesion in the m e m b r a n e may not be visible w h e n the nodal lesions are present. The decision as to which lesions in a case of generalized tuberculosis constitute the primary complex is often im possible to m a k e . The relative age of the lesions is an indication, as is their localization, because the site must be intimately related to one of the portals of entry. As lesions develop in the regional lymph node, the infection passes successively from one node to another, and can eventually reach the blood, for potential wide spread dissemination. Extensive hematogenous dissemi nation, however, is most frequently the result of break down of a blood vessel by an expanding caseating tubercle or cavitating lesion. The n u m b e r of bacilli then released into the blood can be very large, and w h e n these are removed by phagocytes in the various organs, a large number of small tubercles develop. T h e course of the disease after massive generalization is short, and the dis ease is then referred to as miliary tuberculosis because of the large number of tubercles the size of millet seeds. H e m a t o g e n o u s dissemination is, however, not always massive; the course then is much longer, and the meta static foci are large and few or solitary. Some organs such as muscle, thyroid, and pancreas seldom develop lesions of hematogenous origin. Spread can occur via natural passages. C o m m o n exam ples are spread from the kidney along the ureter to the bladder, from one bronchus to another by coughing and aspiration, or from the lungs to the intestine when infected sputum is swallowed. Rapid spread is possible in cavities such as the meningeal space and serous cavities of the trunk. Involvement of a serous m e m b r a n e is usually by direct extension from an underlying lymph node or viscus. W h e n the bacilli are freed on the serous surfaces, they are readily distributed by m o v e m e n t s such as respiration and peristalsis. i. Cattle Bovine tuberculosis has been, and in some areas remains, one of the most important diseases of cat tle. In areas where the incidence is high, the disease is caused almost exclusively by M. bovis. W h e n bovine tu berculosis is brought under control by eradication pro grams, however, the patterns of infection change, and the proportion of infections caused by the M. avium-intracel lulare complex increases. Infections with M. avium usu ally have a benign self-limiting course. Often no lesions are detectable. If lesions develop, they are usually found in the mesenteric and retropharyngeal lymph nodes and are seldom > 2 c m in diameter. T h e y are usually caseous and encapsulated and may be either calcified or liquefied. There is commonly no spread from these sites, but some times initial lesions in intestinal m u c o s a are detected as focal thickenings. W h e n extension of the avian-type infec tion occurs in cattle, the serous surfaces are most often involved. Occasionally, lesions may be found in the udder, lungs, liver, kidney, and spleen. T h e uterus is the most frequently involved organ in pregnant c o w s , and abortion or congenital disseminated tuberculosis in n e w b o r n calves can result. Large n u m b e r s of epithelioid cells are a regular feature of the histologic response, and pleomorphic acidfast bacilli are abundant. The human bacilli, at most, cause small nonprogressive lesions in the lymph nodes of the pharynx, thorax, and mesentery. T h e usual routes of infection by M. bovis are respiratory and alimentary. T h e unusual routes, which will be consid ered first, are cutaneous, congenital, and genital. Infection via t h e skin is rather rare. It requires that other primary cutaneous lesions be contaminated with the tubercle bacil lus. T h e infection is limited t o the initial site or may spread to the local lymph node. In congenital tuberculosis, the infection spreads via the umbilical vessels to the fetus. This route of infection is of some importance where the disease is c o m m o n in cattle and where as many as 0 . 5 % of newborn calves have been found t o have tuberculosis. This route is of little significance in other species because only in cows is tuberculous endometritis c o m m o n . W h e n the primary complex is present in congenital infection of calves, it is in the liver and portal lymph nodes. But, as elsewhere, the complex m a y be apparently incomplete, and the lesions are found only in the nodes. In a fetus or calf of a few days of age, lesions in the portal node are assumed t o b e evidence of congenital infection; this is not necessarily the case in older calves because the portal node is also the regional node of the d u o d e n u m . Congenital tuberculosis in calves progresses quite rapidly, and the animals usually die in a few weeks or months. By that time, the disease has generalized, and lesions can be found especially in the lungs and regional lymph nodes, and in the spleen. Tuberculous lesions rarely occur in the spleen of adult cattle and when present, irrespective of the age of the animal, they are regarded as indicative of congenital infection. F o r congenital tuberculosis to occur, infection must be present in the uterus. Small tubercles can be found in the endometrium. Typical placental lesions are a slimy exudate separating the placenta from the endometrium and caseonecrotic foci in the cotyledons. Extensive areas of tuberculosis in the uterus result in repeated abortions. G e n i t a l infection occurs in cattle but is not c o m m o n ; its development requires that the sexual organs of either the female (usually uterus) or male (usually epididymis) are tuberculous. M a m m a r y infusions used in the treatment of mastitis and contaminated with tubercle bacilli are respon sible for occasional, but epidemiologically important, cases of tuberculosis of m a m m a r y gland. Most bovine tuberculosis is acquired by inhalation or ingestion. Management factors and age at which the dis ease is contracted are major determinants of which route is the more probable. The location of the primary complex in the alimentary or respiratory tract can be helpful, but the evidence is sometimes not clear. T h e incidence of respiratory versus alimentary infection in postnatal calves is difficult t o determine precisely, especially in very young calves, because it depends o n whether involvement of the portal nodes, in the absence of intestinal or hepatic lesions, is taken t o indicate alimentary or congenital infection. Primary complexes in the intestine are c o m m o n in calves, particularly those which have been allowed t o suck tuber culous udders or which have been given tuberculous milk to drink. Pulmonary complexes are also c o m m o n in calves more than a few w e e k s of age. Pulmonary infections may well b e more important than alimentary infections under crowded conditions. Tuberculosis of the anterior cervical nodes occurs with both aerogenous and alimentary routes of infection and is not, therefore, an indication of the route of infection. Most cattle obtain their infections when they are older than 6 m o n t h s . In these adult infections, the majority of lesions are in the retropharyngeal, mediastinal, and bron chial lymph n o d e s . W h e n the lesions are limited to the retropharyngeal n o d e s , infection could be by either oral or nasal routes. Lesions are seldom found in the lungs with a frequency equal to their occurrence in t h e thoracic lymph nodes. This is probably because primary lesions in the pulmonary p a r e n c h y m a c a n b e very small and difficult to detect. In the very few series in which the examination has been thorough, the p r e p o n d e r a n c e of primary com plexes in the lung h a s been revealed. Intestinal infections do occur, and lesions in the mesenteric lymph nodes are c o m m o n , but a significant proportion of these, perhaps most, are secondary infections which are established when sputum is swallowed. In adult cattle, therefore, primary infection is usually in the lungs, and is caused by inhalation of infected droplet nuclei. T h e primary lesions m a y be single or multiple and may occur in any lobe, but they occur predominantly in a subpleural location in the dorsocaudal portions of the cau dal lobes. There are almost always lesions in the regional lymph n o d e s , but they m a y be absent in some cases of chronic tuberculous pneumonia. T h e t u b e r c u l o u s p u l m o n a r y p r o c e s s usually starts at the bronchiolar-alveolar junction and extends into the alveoli, so that it is initially sublobular or lobular. T h e histologic structure is typically tuberculous. There may be more than one focus within a lobule, giving a cloverleaf appearance, and more than o n e lobule can be involved (Fig. 6 .70). The initial lesions and their secondaries in the lymph nodes can heal completely, persist without progression, or progress. It is generally believed, on good but not certain grounds, that bovine tuberculosis most often progresses, with acquired cellular resistance slowing the progress con siderably but not halting it. T h e appearance of the pulmonary lesions varies with their age and rate of progress. T h e earliest lesions are not encapsulated, but are small and surrounded by condensed alveolar tissue. E v e n in these early lesions, the yellowish caseation and the calcification which are so characteristic of bovine tubercles can be seen. Caseated lesions can be encapsulated and heavily calcified. The capsules are not necessarily evidence of successful containment because many such nodules communicate with an airway and allow local dissemination. Multiple initial foci can coalesce to form large regions of caseating b r o n c h o p n e u m o n i a (Fig. 6 .70), which in due course are usually encapsulated and calcified. Cavitations may form in any of these lesions, but they are never large because of the limitations imposed by the interlobular septa. Dissemination of the infection within the lung can be by way of an intrapulmonary tuberculous lymphangitis but is mainly through the airways. T h e bronchogenic ex tension may be by direct contiguity, or it may be by aspira tion of exudates, but in either case, what is initially a lobular type of lesion c o m e s to involve much or all of a bronchopulmonary segment, or even most of a lobe. The reaction is the same as that in the primary lesion, although often more severely caseating. Depending on the rapidity and extent of spread, the lesions form a pattern of irregular caseous b r o n c h o p n e u m o n i a or more confluent caseous lobar pneumonia. In association with chronic progressive pulmonary tu berculosis, it is c o m m o n to find ulcers in the trachea and bronchi. These can arise by implantation of bacilli coughed up in the sputum or by progression of tuberculous lym phangitis. They begin as typical tubercles in the m u c o u s m e m b r a n e , especially near the bifurcation of the trachea, and are followed shortly by ulceration. Similar ulcers de velop on the larynx by implantation of bacilli. A feature of tuberculosis in cattle is the tendency to spread to the serous m e m b r a n e s (Fig. 6.71 ). This can take place by direct expansion of the original lesion, by lymphogenous extension from the lungs, by direct hema togenous dissemination, or by local expansion from a he matogenous focus in an adjacent organ. Once the tubercu lous process breaches the serosa, the bacilli are distributed by respiratory m o v e m e n t s and may be widely implanted. Pleural tuberculosis may be largely nodular, diffusely case o u s , or of intermediate type. The affected areas of pleura, both visceral and parietal, are thickened by fibrous granu lation tissue, and as a rule the tuberculous process does not invade the underlying tissue. T h e characteristic lesions are nodular and tend to occur in clusters. They may be sessile or pedunculated and frequently coalesce to form cauliflowerlike masses. In the early stages, they consist of reddish tags of granulation tissue containing typical tubercles and may be soft. Later, heavy calcification is usual and is largely responsible for the term pearl disease. C a s e o u s tuberculous pleuritis consists of large plaques of caseous exudate beneath which the pleura is uniformly thickened. Fibrin may be deposited on and between the plaques. Generalization of the infection (dissemination to other organs) can occur early in the course of the disease (post primary generalization) or late in the course of the disease (late generalization). In late generalization, it is assumed that the immunity the animal has acquired has broken d o w n , thereby permitting wide spread. Generalization may be sudden and massive, w h e n large n u m b e r s of the bacilli enter the blood stream (miliary tuberculosis), or it may be more protracted with fewer bacilli entering the circulation. The latter, w h e t h e r early or late, is the more usual, and the lesions are larger and often of different ages. In the respiratory pattern being described, the bacilli can enter the bloodstream in the lungs w h e n the caseating process erodes a vessel, usually a small vein, or they may pass through the lymphatics and lymph nodes to the vena cava. In either event, the h e m a t o g e n o u s metastases occur more frequently in the lung than elsewhere. H e m a t o g e nous metastases can also occur in most of the major organs and in lymph n o d e s , skeleton, and serous m e m b r a n e s , including the peritoneum, pericardium, and meninges. Or gans such as salivary glands, p a n c r e a s , spleen, brain, m y o cardium, and muscles are rarely affected by hematogenous metastases in postnatal infections. Miliary lesions in the lungs are associated with a fulmi-nating course of the disease. The lesions are typical, small, grayish tubercles which are translucent at first but soon become caseous and centrally calcified. Hematogenous tubercles are diffusely scattered in both lungs although there is a tendency for them to be more numerous in the cranial portions. In slow or protracted generalization, which is the more usual type, the metastatic tubercles tend to be few in number, large, caseated, and calcified, and are often surrounded by a heavy capsule. Tuberculosis of the peritoneum is less common than that of the pleura. It can arise in a number of ways. Perito nitis surrounding the liver is common in the congenital infection and is regarded as being of local and lymphatic spread. Peritonitis may also be hematogenous in the con genital disease as well as in postprimary and late general ization. Ulcerative intestinal tuberculosis which extends to the serosa is an important route of peritoneal infection in postnatal life. In adults, the intestinal lesions are usually secondary to respiratory lesions. Spread to the peritoneum from the uterus via the uterine tubes no doubt occurs, but the reverse is probably more common. The peritoneal lesions are similar to those of the pleura but are usually not so clearly nodular or pearly. They tend to be softer and more diffuse and to consist of extensive granulation tissue in which the tubercles are embedded (Fig. 6.71 ). Hepatic lesions are hematogenous in origin. Infection arrives either through umbilical veins, as in congenital infections, through arteries as part of hematogenous dis semination, or through portal veins when lesions are pres ent in the intestine. The hepatic foci may be miliary but, as elsewhere, it is more usual for the coarse nodular type of lesion to be present, sometimes only in one lobe. The portal lymph nodes are affected. The coarse nodular types of lesions occur in varying numbers and can be quite small or as large as 10 cm in diameter. They tend to be rounded and often project hemispherically above the surface. When sectioned, the nodules are seen to be enclosed by a heavy capsule, and the contents are bright yellow and caseous; the exudate may be inspissated and calcified or sometimes liquefied. The renal lesions resemble in structure and type those of the liver. Miliary lesions are limited to the cortex, the initial development of the tubercles occurring in the inter stitial tissue. The coarse nodular lesions may be multiple, but often they are limited to one or two adjacent lobules of the kidney. The caseating tubercles can be very large and may erode into the pelvis to cause a descending infec tion of the urinary tract. Frequently, the renal lymph nodes are concurrently involved. Tuberculosis of the skeleton is usually hematogenous and occurs mainly in young animals. Its distribution is governed by the usual factors in hematogenous osteomy elitis. The lesions are most frequent in the vertebrae, ribs, and flat bones of the pelvis-all bones that are spongy and highly vascular. The epiphyseal-metaphyseal regions of long bones are also predilection sites. The osteomyelitis is in the form of miliary tubercles or large granulomas. Caseation is extensive in the granulomas, and there is a tendency to liquefaction resulting in the formation of tuberculous abscesses. The liquefied lesions especially tend to be progressive. They erode and fistulate through the cortex and erode the articular cartilages to produce tuberculous arthritis. Regenerative osteophyte formation is not prominent in tuberculosis as it is, for example, in actinomycosis. The predominantly erosive type of process is referred to as caries. Through the cortical fistulae, the infection spreads to the adjacent connective tissues and muscle. This is the usual pathogenesis of tuberculous myo sitis. Tuberculosis in the central nervous system begins mainly as a meningitis and is more common in the cerebral than in the spinal meninges. Involvement of the spinal meninges may be direct from a vertebral osteomyelitis or hematogenous. Involvement of the cranial meninges is hematogenous, the initial lesions occurring usually in the basilar meninges and extending from there in the arach noid spaces between the hemispheres and cerebellum, to the choroid plexuses and, to a limited extent, into the Virchow-Robin spaces and the brain itself. The meningeal lesions are similar to those of the serous membranes but are generally more exudative and necrotizing. Miliary or conglomerate tubercles are an uncommon development. Tuberculous lesions, either small nodules or craterous ulcers, are occasionally found in the epithelium of the upper alimentary tract and abomasum. Whether primary or as endogenous secondaries, however, lesions in the alimentary lining membranes are uncommon. In contrast, the regional nodes, particularly of the retropharynx (Fig. 6 .72) and mesentery, are often severely involved. In young calves, round or oval ulcers of small size may be found, especially in the ileum. These probably begin as small tubercles in the Peyer patches or solitary lymphoid nod ules. Tubercles and ulcers can be found in the small intes tine and cecum in adults, in which they frequently repre sent reinfection from the lungs. The ulcers vary in size and are either rounded or elongate in the axis of the intes tine. The margins of the ulcers are distinct, firm, and raised. The bases are firm and usually covered with dry caseous exudate on granulation tissue speckled with tiny hemorrhages. Granulomas are sometimes visible in the draining lymphatics. Horses apparently possess a high innate resistance to tubercle bacilli, because the disease is rare in them. Most infections involve M. bovis, but both M. avium and M. tuberculosis can produce localized or gener alized disease. Many of the bovine strains recovered from horses are of lowered virulence when tested in laboratory animals. The route of infection is almost exclusively alimentary. The primary complex is often incomplete, with large le sions in the retropharyngeal or mesenteric nodes but with out an obvious primary focus in the related mucosa. In some cases, primary ulcers are present in the intestine. Bacilli of the M. avium-intracellulare complex sometimes produce a proliferative enteritis closely resembling Johne's disease of cattle. Lesions may be limited to the alimentary tract, but in fatal cases there is generalization with either miliary tubercles or scattered coarse nodular lesions. Secondary lesions have been described in the lungs, liver, spleen, serous m e m b r a n e s , m a m m a r y gland, and skin. They are unusual in the last two sites. Tubercu lous changes in cervical vertebrae are repeatedly cited as being c o m m o n in the disease in the horse, but this has not been thoroughly explored. If lesions occur in the central nervous system or genitalia, they are rare. T h e lesions of tuberculosis in the horse often differ from those in cattle. W h e r e a s extensive caseation and calcification are typical of bovine tubercles, the equine tubercles more commonly have a uniform, gray, smooth (lardaceous) appearance grossly resembling a sarcoma. Caseation does occur sometimes in the center of a lesion, but it is of minor degree, and calcification is rarely observ able by the naked eye. Histologically, the early lesion is a tubercle which consists of macrophages, epithelioid cells, and few or many giant cells without a peripheral zone of lymphocytes. As the lesion progresses, it develops more and more proliferative fibrous tissue in which ill-defined tubercles are scattered. It is sometimes very difficult to find bacilli in these lesions, but the occasional tubercle which liquefies contains very large n u m b e r s . Pulmonary tuberculosis in horses is usually hematogenous and may be miliary or coarsely nodular. Usually there are miliary foci which appear like glassy d e w d r o p s but are very firm. The coarse, nodular lesions, which grossly resemble sar c o m a s , are fewer and larger. Progression is by expansion of the lesion. Intrabronchial spread, which is so important in cattle, is of no significance in horses. T h e bronchial lymph nodes are invariably involved w h e n the lung is; their appearance is that of a firm sarcoma, and corticome dullary distinction is lost. W h e n the primary lesions are found in the intestine, they take the form of tuberculous ulcers, which are more c o m m o n in the large than in the small intestine. Tubercles in the liver and spleen are usually nodular rather than miliary. They can be extremely large and the organs corre spondingly so; the spleen is m o r e frequently affected than the liver. The lesions are of the usual lardaceous type. The serosal lesions, which are relatively c o m m o n , are nodular and sometimes are accompanied by m u c h effusion into the cavity. Sheep and goats do not appear to have any special resistance to tubercle bacilli, except possibly the h u m a n t y p e , but tuberculosis in them is rare. iv. Swine Pigs are susceptible to all three major spe cies of mycobacteria. T h e incidence of a particular species in any population of pigs depends largely on the species to which they are exposed and is, therefore, a reflection of the incidence of tuberculosis in associated cattle, poul try, or h u m a n s . Mycobacterium bovis is more capable of producing generalized disease than is the M. aviumintracellulare complex. Mycobacterium tuberculosis rarely spreads past the nodes local to the point of entry. Tuberculosis is seldom observed in pigs except at meat inspection and, b e c a u s e these animals are usually young, a local lymphadenitis is the extent of the disease usually observed. Tuberculous infections of w o u n d s , castration w o u n d s especially, occur in swine, and occasionally the primary infection is respiratory. As a general rule, h o w e v e r , the route of infection is alimentary (Fig. 6 .73). T h e primary complex in swine is seldom complete by gross inspection, but tubercles can usually be found microscopically in the m u c o s a of the p h a r y n x or small intestine w h e n gross le sions are present in the retropharyngeal, portal, or mesen teric n o d e s . Ulceration of a primary focus in a m u c o u s m e m b r a n e is rare. There are certain differences b e t w e e n the lesions pro duced by the bovine and avian types of bacilli. T h e bovine bacilli produce caseocalcareous tubercles similar to those which occur in cattle, and the lesions are often surrounded by a fibrous capsule. In the liver, there is a t e n d e n c y for the caseous centers to liquefy. T h e avian bacilli produce lesions which are proliferative in nature and consist of tuberculous granulation tissue resembling the lardaceous or sarcomatous lesions described in equine tuberculosis. Caseation is not a feature of these lesions, although it may occur as minute foci, especially in the hepatic tubercles. There is little tendency for these caseous foci either to calcify or to liquefy, or for the lesions to be encapsulated. Affected lymph nodes are only slightly enlarged, and on cut surface they have a lardaceous appearance. The histo logic appearance is of diffuse accumulations of macro phages, epithelioid cells, and L a n g h a n s ' giant cells accom panied by extensive fibroplasia. T h e bacilli are numerous in these lesions, and they may also be recovered from nodes which appear grossly to be normal. Pulmonary tuberculosis in swine is hematogenous and is usually of the miliary pattern. In some infections with the bovine bacillus, there is extensive consolidation of the cranial lobes resembling grossly the caseous broncho pneumonia of cattle, but histologically seen to be a con fluence of n u m e r o u s hematogenous tubercles. In this form of the pulmonary disease, there may be a tuberculous tracheitis. Miliary lesions in the lungs produced by the avian bacilli resemble d e w d r o p s , and there appears to be a characteristic tendency for these to spread along the subpleural and septal lymphatics which are beaded by small tubercles. T h e hepatic lesions produced by the bovine bacilli take the form of miliary or, more usually, coarse nodules. T h o s e produced in the liver by the avian bacilli ( Fig. 6.74 ) are quite different. The early lesions are scattered and miliary and are not discrete but blend peripherally with the portal stroma. The later lesions are merely an extension of this and, although softer, closely resemble the lesions of parasitic hepatitis produced by Ascaris suum and Ste phanurus dentatus. Hepatic tuberculosis of avian type also cannot be distinguished grossly from the infiltrates of myeloid or lymphoid leukemia. Tuberculous granulation tissue spreads along the portal triads, surrounding and obliterating lobules, and at the periphery unites with the expansions of adjacent lesions. Typical tubercles do not occur. Splenic lesions regularly occur in the generalized dis ease (Fig. 6 .75). They project hemispherically above the surface, and their a p p e a r a n c e , as previously indicated, depends on the type of bacilli present. Tuberculosis of the serous m e m b r a n e s is seldom observed in swine. Skeletal lesions, often confined to individual bones of the axial skeleton, are c o m m o n . Tuberculous meningitis, primarily basilar in location, is relatively frequent in generalized infections by the bovine bacilli. The meningeal lesions in swine are more nodular than those in cattle, in which there tends to be diffuse exudation. Tubercles may also be found in the genital organs, skin, and eye. v Cats appear to be more susceptible The lesions of tuberculosis in carnivores differ from those in other species. Typical tubercles are not so com mon, and when they occur, caseation necrosis is not a prominent gross feature. More often there is a nonspecific granulation tissue in which macrophages are scattered at random and giant cells are rare ( Fig. 6 .76). T h e discrete tuberculous granulomas that do occur are c o m p o s e d prin cipally of epithelioid cells surrounded by narrow zones of fibrous tissue in which there are scattered small collections of lymphocytes and plasma cells. Necrosis is often present in the centers of larger granulomas. Giant cells are rare or absent. T h e presence of central necrosis and fairly small numbers of acid-fast bacilli in lesions of cats helps to distinguish lesions of tuberculosis from those of feline leprosy. The frequently sarcomatous gross appearance of the lesions can easily lead to misdiagnosis. This is particularly the case in cats. T h e pattern of pale h o m o g e n e o u s tissue causing enlargement and effacement of lymph nodes and present as diffuse or nodular lesions in the intestine and possibly other viscera can readily be mistaken grossly for lymphoma. The primary foci in the lungs of dogs develop in most cases in the dorsal part of the caudal lobes. They appear Fig. 6 .76 Nonspecific a p p e a r a n c e of p u l m o n a r y granuloma in disseminated (miliary) tuberculosis. Dog. as firm, pale, bulging nodules -1-3 cm in size. The cut surface can be uniform, but frequently there is central liquefaction and a tendency to fistulate onto the pleura to produce serofibrinous or serohemorrhagic pleuritis. Meta static nodules in the lung are usually few in n u m b e r with an appearance similar to that of the primary foci. The bronchial lymph nodes are regularly involved. They are sometimes only moderately enlarged with softened ne crotic areas on cut surfaces, but they may be very large and centrally liquefied. Dissemination within the lungs occurs quite rapidly and is predominantly intrabronchial with the production of a tuberculous bronchitis and bron chiolitis rather than a b r o n c h o p n e u m o n i a . T h e granulation tissue involves and destroys segments of the bronchial walls, and cavitation occurs by liquefaction and evacua tion of exudate. Pleuritis is particularly c o m m o n in tuberculosis of dogs, and ascites is also likely to be present w h e n the abdominal viscera are affected. T h e serosal lesions are not at all like those in cattle. Instead, there is diffuse or finely nodular pleural thickening by nonspecific granulation tissue. A large a m o u n t of serofibrinous exudate accumulates in the pleural cavity; this is often bloodstained. T h e pleural le sions may be unilateral or bilateral. Peritoneal tuberculosis accompanies lesions in the mesenteric nodes and liver and is accompanied by ascites. Large or small nodules of granulation tissue or a diffuse thickening occur on the visceral layers especially, and the o m e n t u m is often con- 6 . verted to a partially necrotic ropy mass in which there are very large numbers of bacilli. Tuberculous processes are seldom found in other organs, although involvement of the meninges, uveal tract of the eye, genitalia, bones, and skin have all been reported. Hypertrophic osteopathy is a possible sequel to pulmonary tuberculosis (see Bones and Joints, Volume 1, Chapter 1). Rhodococcus equi is an important cause of pneumonia in foals. It can also cause intestinal and occasionally more widespread lesions. Bacteria of the Corynebacterium, My-cobacterium, Nocardia, and closely related genera share the property of having cell walls containing complex lipids. The pathogenic features of R. equi infection therefore resemble those of mycobacteria. It is a facultative intracel lular parasite of macrophages and causes a predominantly pyogranulomatous response characterized by abundant caseation necrosis. Rhodococcus equi is an inhabitant of both soil and the intestinal tract of mammals and birds. Whether it is a true soil saprophyte is still uncertain. Buildup of organisms in soil and dust occurs principally in association with the presence of carrier horses. This emphasizes the importance of its commensal status in the horse. Pneumonia caused by R. equi generally causes clinical signs in foals 1-6 months of age, but the subacute to chronic nature of the lesion indicates that infection occurs well before clinical signs in most cases, and lesions can sometimes be found in foals dying for other reasons. Signs of the disease are fever, cough, nasal discharge, and in creased respiratory rate. Because lesions are usually well advanced by the time the pneumonia is clinically apparent, mortality is commonly in the 40-80% range. Characteristic gross lesions are multiple firm nodules of various sizes separated by congested and partly atelectatic lung. A typical feature is the very large size of many of the foci. There is sometimes evidence of their origin by coalescence of clustered small nodules. There is a ten dency for more rapidly progressive lesions to be distrib uted widely throughout the lungs, and occasionally an acute clinical form in foals is associated with miliary pyo granulomatous foci. Lesions of slower, more insidious onset occupy cranioventral regions of the lungs, usually bilaterally, and therefore have the distribution pattern of a bronchopneumonia (Fig. 6 .77A). The nodular lesions are often referred to as abscesses if circumscribed or as areas of suppurative bronchopneumonia if irregular and less well defined. They are, in fact, usually regions of caseation necrosis with either a slimy, homogeneous tex ture or a moist crumbly consistency with fluid-filled fis sures. In most instances, there is no distinct fibrous tissue capsule surrounding the necrotic tissue ( Fig. 6 .77B). Histologically, the lesions produced by R. equi are pre dominantly pyogranulomatous. Alveoli are filled with masses of macrophages containing many organisms ( Fig. 6 .77D). Giant cells containing organisms are common; neutrophils are less numerous. Lymphocytes and plasma cells are present in moderate numbers, mostly in alveolar septa and other interstitial zones. Necrosis of bacterialaden macrophages and other cells involves local alveolar septa. Necrosis spreads gradually to affect large amounts of pulmonary parenchyma and produce the caseonecrotic foci seen macroscopically. The bronchial lymph nodes are swollen and edematous. Sometimes they contain soft caseonecrotic foci. Histologi cally there is a pyogranulomatous lymphadenitis with simi lar components to the pneumonia. Pleuritis is uncommon, even when pulmonary involvement is extensive. After the lungs, the next most frequent sites of lesions caused by R. equi in foals are the intestinal tract and mesenteric lymph nodes. Intestinal involvement may oc cur in upward of 50% percent of foals with pulmonary lesions, but intestinal lesions by themselves are uncom mon. The intestinal lesion is an ulcerative enterocolitis ( Fig. 6 .77C), which mainly involves the cecum and colon. The mucosa has numerous, irregular but well-defined ul cers with fibrinonecrotic surfaces, red bases, and raised borders. Ulcers are based on lymphoid tissue, Peyer's patches in the ileum, and solitary nodules of the large intestine. Mesenteric lymph nodes are swollen and edema tous. Those of the large intestine frequently contain ca seonecrotic foci. Histologically, the main intestinal lesions are pyogranulomatous inflammation of lymphoid tissue and fibrinonecrotic ulceration of the overlying epithelium. Inflammatory cellular components are the same as those in the pulmonary lesions. More widespread dissemination of infection in foals can occasionally give rise to suppurative arthritis, dermal abscesses, hepatic or splenic abscesses, vertebral ab scesses, and hypopyon. Rhodococcus equi may also be a cause of ulcerative lymphangitis. The pathogenesis of R. equi infection in foals is incom pletely understood. The abundance of the organism in dusty environments where foals contract pneumonia, to gether with the predominant bronchopneumonic pattern of the disease, indicate that aerosol infection is the com mon route of pulmonary involvement. Aerosol exposure will produce the disease experimentally in foals to 2 weeks of age; later they become resistant, which suggests that susceptible animals may have delayed maturity of phago cytic cells. It also appears that the alimentary route of infection is the usual one for the intestinal form of the disease. Culture of the organism from parenchymal organs and occasional development of widespread lesions indi cate that hematogenous dissemination also occurs. Infec tion of foals in utero, during birth, or through neonatal umbilical contamination are probably unimportant routes. equi has also been associated with metri tis and abortion in mares, metritis in cows, pneumonia in calves, and tuberclelike lesions in lymph nodes of pigs and cattle. Its etiologic role in some of these instances is still questionable. A large variety of Gram-positive a n d Gram-negative bacteria c a n cause pneumonia, either singly o r in mixed infections. They mostly cause a suppurative b r o n c h o p n e u m o n i a in lungs damaged by a preceding disease process such as a viral or mycoplasmal infection, o r w h e n pulmonary defenses a r e impaired for reasons outlined previously. There is consid erable overlap among t h e bacteria found in t h e different species of animals, but t h e sets of organisms most com monly involved, a n d their relative importance, vary ac cording to the species of animals affected. There is also some variation according to geographic location. Since the pneumonic lesions a r e relatively nonspecific, identifi cation of causative agents must be by bacteriologic m e a n s , but, because bacteria can b e opportunistic invaders of pneumonic tissue, isolation of an organism does not neces sarily indicate a causal role. T h e presence of large numbers of a bacterial species in pure culture, o r as the predominant agent, provides presumptive evidence of its importance in causing t h e pneumonic process. Difficulty in fulfilling K o c h ' s postulates often leaves a measure of uncertainty even after considerable study. This was formerly t h e case for pneumonic pasteurellosis a n d still holds true for some of the mycoplasmal infections, as will b e discussed later. Pyogenic organisms, especially streptococci, staphylo cocci, Actinomyces pyogenes, Pseudomonas aeruginosa, and Klebsiella pneumoniae, a r e usually associated with suppurative b r o n c h o p n e u m o n i a s , which m a y progress to abscessation. Either more virulent organisms o r more se verely compromised host defenses c a n lead to fibrinone crotic o r hemorrhagic pneumonias, such as the pneumonia caused by Salmonella choleraesuis in swine. This pneu monia c a n have t h e same appearance as pneumonic pas teurellosis in swine. In contrast, Salmonella typhisuis characteristically causes a chronic suppurative broncho pneumonia in which grossly there a r e large confluent re gions of swollen, creamy-tan consolidation. On cut sec tion, these appear smooth and h o m o g e n e o u s except where there a r e granular or friable foci of necrosis. In addition t o the b r o n c h o p n e u m o n i a s , various bacteria cause interstitial pneumonia as part of a pyemia o r septice mia. T h e s e are usually in very young animals and are most commonly caused by streptococci, Escherichia coli a n d , in foals a n d pigs, by Actinobacillus s p p . Actinobacillus (Shigella) equuli in foals is typically associated with multifocal purulonecrotic foci, often recognizably involv ing small vessels. Fulminating systemic bacterial infec tions causing septicemias m a y b e accompanied by little evidence of direct pulmonary involvement, o r there m a y be a severe, diffuse, acute interstitial p n e u m o n i a with intravascular leukocyte sequestration, foci of alveolar wall necrosis, a n d widespread fibrinohemorrhagic exudation into alveoli. T h e acute interstitial p n e u m o n i a is particu larly likely to b e associated with t h e endotoxemias a n d septicemias caused by Gram-negative organisms such as Salmonella s p p . (Fig. 6 .78) a n d E. coli. Finally, it is convenient t o mention here that bacteria resembling Pasteurella s p p . have been isolated from multifocal suppurative t o pyogranulomatous interstitial pneumonia in several cats, a dog, and a tiger cub represent ing regions as far apart as California, Australia, and North ern Ireland. T h e bacteria are of uncertain taxonomic status and a r e currently referred to as eugonic fermenter-4 ( E F -4). T h e s e organisms a r e present in t h e oral a n d nasopha ryngeal flora of dogs a n d cats, a n d have been isolated from infected bite w o u n d s in h u m a n s a n d animals. T h e pulmonary lesions a r e n u m e r o u s , firm, cream-colored, o r light tan nodules t o 1 c m in diameter scattered throughout the pulmonary p a r e n c h y m a . Histologically, they a r e foci of massive accumulations of neutrophils, m o n o c y t e s , a n d macrophages which efface alveolar architecture a n d con tain n u m e r o u s bacterial colonies interspersed among them. Necrosis of inflammatory cells a n d alveolar walls occurs in foci of intense inflammation. T h e distribution of the lesions indicates a probable hematogenous origin, but the site of bacterial invasion of the bloodstream has not been identified to provide supporting evidence for this speculation. Baskerville, A., and Dow, C Mycoplasmas are the smallest, free-living prokaryotes. They are placed in a separate class from other bacteria, mainly on the basis of their lacking the genetic capability to synthesize a cell wall (class Mollicutes, soft skinned). Lack of a cell wall results in extreme pleomorphism of the organisms. The type species of Mycoplasma is Myco plasma mycoides subsp. mycoides. This organism was isolated from contagious bovine pleuropneumonia and therefore gave rise to the former designation of mycoplas mas as pleuropneumonialike organisms (PPLO). It is difficult to prove a definite pathogenic role in the production of pneumonia for many infectious organisms. This is especially true for the mycoplasmas. They are ubiquitous inhabitants of moist mucosal surfaces, particu larly of the respiratory tract, and are common opportunis tic inhabitants of pneumonic lung. Proving the etiologic role of mycoplasmas isolated from pneumonic lung is com plicated by several factors. Species of mycoplasmas vary in pathogenicity, and there is a tendency for the more virulent strains to be the most difficult to culture. This can divert attention to relatively nonpathogenic species. When a mycoplasma suspected of having a causal role is cul tured, Koch's postulates are hard to fulfil because enhanc ing factors are usually involved in development of the naturally occurring disease. Simultaneous evaluation of the role of the mycoplasma and the nature and importance of enhancing factors, whether they are additional damag ing agents or act by reducing pulmonary defenses in other ways, causes difficulty in designing experimental proto cols that can convincingly demonstrate the mycoplasma's pathogenic importance. The degree of uncertainty regard ing the significance of a species or strain of Mycoplasma is inversely proportional to its pathogenicity. Since estab lishment of a highly virulent species, Mycoplasma my coides subsp. mycoides, as the causal agent of contagious bovine pleuropneumonia was difficult, it is easy to under stand why considerable uncertainty still exists concerning the importance of many much less virulent species. A further source of uncertainty is the lack of understanding of the mechanisms by which mycoplasmas cause injury to tissues. The relative importance of a direct effect on cilia, effects on ciliated and other cells of proteolytic enzymes and membrane-associated toxins, macrophage-neutrophil interactions, and various immune-mediated responses are under investigation. The set of pathogenetic mechanisms appears to vary from one species of mycoplasma to an other. There are two types of pneumonia associated with mycoplasmal in fection in cattle. One is contagious bovine pleuropneumo nia. The other is mycoplasmal bronchitis, bronchiolitis, and pneumonia of calves, an important component of en zootic pneumonia. i. Contagious bovine pleuropneumonia is caused by Mycoplasma my coides subsp. mycoides (small-colony type). The smallcolony designation is currently used to distinguish the organism causing bovine pleuropneumonia and Myco plasma mycoides subsp. mycoides (large-colony type), which is a cause of disease in goats. Contagious bovine pleuropneumonia is characterized by a fibrinonecrotic pneumonia ( Fig. 6 .79A,B) with abundant serofibrinous pleuritis. Presence of necrotic material sequestered by fibrous capsules is a usual finding in subacute or chronic cases ( Fig. 6.79C,D) . The pattern of pneumonia is usually that of a lobar or bronchopneumonia (see Anatomic Pat terns of Pneumonia, Section VI,F of this chapter). The lungs of cattle dying in the more acute stages of the disease typically have a marbled appearance in which relatively normal lobules are intermixed with lobules showing red or gray consolidation or necrosis. The marbled effect is heightened by the distension of interlobular septa and interstitium surrounding vessels and airways by broad bands of fibrinous exudate. It is also enhanced by the dense yellow-gray zones of packed inflammatory cells sur rounding the necrotic areas. The fibrinonecrotic pneumo nia and accompanying pleuritis of contagious bovine pleu ropneumonia have features similar to those of the fibrinonecrotic pneumonia of acute pneumonic pasteurel losis. The marbled effect is more pronounced in conta gious bovine pleuropneumonia, however, and the lesions are more prone to involve the caudal lobes. There is also a much greater frequency of development of sequestra in the mycoplasmal disease. It appears that the disease originated in central Europe and remained endemic there until spread by the movement of cattle during the Napoleonic wars, and later by the growth in international commerce. Toward the end of the nineteenth century, it had become almost worldwide in distribution. It was eradicated from North America and much of Europe before the turn of the century and more recently appears to have been eradicated from Australia. It now occurs mostly in parts of Asia, central Africa, Spain, and Portugal. Enormous losses were reported from this disease in the nineteenth century, and in endemic areas the mortality rate among indigenous breeds of cattle is reported still to be more than 40%; in improved Euro pean breeds, the mortality in an unrestricted outbreak is not expected to exceed 10% of the animals. Species such as the buffalo, reindeer, and yak are susceptible to the disease, but are seldom affected. Sheep and goats do not appear to contract the natural disease caused by M. my coides subsp. mycoides (small-colony type) and do not appear to develop the pulmonary disease after experimen tal infection, but they do develop a severe local reaction and septicemia if the organism is inoculated. The transmission of infection requires close contact between infected and susceptible animals. It seems proba ble that the disease is transmitted by the inhalation of infected droplets exhaled by affected animals because the most reliable means of reproducing the disease experimen tally is by endobronchial or aerosol exposure of suscepti ble cattle with suspensions of infected lung or organisms obtained from early subcultures. Factors other than the administration of the organism are evidently involved in determining whether cattle develop the disease, but ex actly what these are is not known. Variations in innate susceptibility, interaction with other microorganisms or preexisting pneumonic lesions, and the state of pulmonary defenses have all been suggested as being important. It appears necessary for the organisms to reach the alveolar parenchyma, but the subsequent chain of pathogenetic events is still uncertain. It has been suggested that the acute vasculitis, fibrinous exudation, thrombosis, and ne crosis are due in part to an Arthus-type or mixed hypersen sitivity in animals with circulating antibodies capable of reacting with surface antigens on the mycoplasmas. What ever the pathogenesis of the vasculitis, the thrombosis it can cause is to a large extent responsible for the infarction and sequestra formation. The disease which can be produced in a percentage of animals following the aerosolization or endobronchial instillation of cultured organisms is similar to the natural disease, but the lesions are frequently small and multifocal and are not as likely to cause confluent consolidation of large regions of lung such as occurs in field outbreaks. Use of a suspension of infected lung is a more reliable method of reproducing the disease. Transmission experiments have confirmed that in an exposed population, 10-30% of the animals are refractory to infection. This resistance is native and not acquired by prior exposure to the organism. The natural incubation period is quite variable, but usually it is longer than 1 month. The clinical signs are those associated with fever and severe damage to lung and pleura, with a course of 2-8 weeks ending in death or slow recovery. Peracute cases which die in less than 1 week do occur. On the other hand, there are mild cases and some which are subclinical. Mortality can range from 10 to 70% in outbreaks. Slaughter of affected herds of cattle on occa sion reveals frequency of pulmonary lesions approaching 90%, even though clinical signs may be obvious in only 30% of the animals at the time killing starts. There is no particular age distribution. Evidence of extrapulmonary localization may be observed in young calves as a polyar thritis, and in pregnant cows as abortion. As many as a third of cases that recover from the acute disease harbor residual infection in pulmonary sequestra. The organisms may remain viable in a sequestrum for several years. Cat tle with sequestra that break down and discharge liquefied or caseous debris containing viable mycoplasmas into the airways are frequently the source of new outbreaks of the disease. Mycoplasmal bronchitis and bronchiolitis or bronchointerstitial pneumonia is an important component of enzootic pneumonia of calves, which involves syner gistic action of several infectious agents. Enzootic pneu monia will be discussed subsequently, but the pulmonary lesions attributable to mycoplasmas will be considered here. More than a dozen species of mycoplasmas can be isolated from bovine lungs, and mixed infections are frequent. The difficulties in proving pathogenetic signifi cance for most of the mycoplasmas recovered from pneu monic lung were referred to earlier. Evidence supports the view that among the various mycoplasmas isolated from pneumonic calf lungs, M. bovis is at least moderately pathogenic. Others, such as M. dis par, Ureaplasma spp., and possibly M. bovirhinis, are generally accepted as being capable of producing slight subclinical bronchiolitis or pneumonia. A fifth species, M. bovigenitalium, is experi mentally pathogenic for lung but is rarely isolated from the respiratory tract. Experimentally, intratracheal inoculation of large doses of M. bovis culture causes suppurative bronchiolitis with peribronchiolar lymphoid hyperplasia. A majority of calves also have a bronchopneumonia characterized by small foci of coagulation necrosis surrounded by a zone of macrophages and plasma cells. The necrotic foci are associated with large n u m b e r s of M. bovis as revealed by immunoperoxidase labeling. Mycoplasma bovis is there fore more invasive and destructive than other mycoplas mas isolated from pneumonia in calves, and this is sup ported by the ability of the organism to cause mastitis and arthritis. Evidence that M. bovis is an important c o m p o nent in the complex etiology of enzootic pneumonia in calves will be referred to under that heading. With the possible exception of M . bovis, mycoplasmas colonize the upper respiratory tract of calves soon after birth and extend to various depths of airways. They attach to the ciliated epithelial cells and, w h e n present in large n u m b e r s , can be seen by electron microscopy to be packed two to three layers deep on and b e t w e e n the microvilli and base of the cilia. Their characteristic effect is to cause a chronic catarrhal bronchitis and bronchiolitis which, over the course of several m o n t h s , leads to the development of prominent lymphofollicular sheaths around the airways. T h e term cuffing p n e u m o n i a is sometimes applied to lungs in which this is the predominant finding ( Fig. 6 .80). T h e uncomplicated mycoplasmal lesion is usually in conspicuous. Grossly there are patchy, purple-red atelec tatic foci in cranioventral regions of the lungs (Fig. 6 .81 A). More confluent, meaty consolidation is an indication of probable involvement by additional organisms. Micro scopically, the lesion for the first several weeks after infec tion is a catarrhal bronchitis and bronchiolitis. Accumula tions of neutrophils and mucus are present in the lumina Widespread lymphofollicular accumulations containing germinal centers develop slowly and are not usually pres ent in calves < 3 months of age. T h e follicular or ensheathing collars of lymphocytes extend into the lamina propria, often obliterate the bronchiolar smooth muscle, and cause narrowing of the bronchiolar lumina. This is the hallmark of cuffing p n e u m o n i a (Fig. 6.80) . T h e r e is associated epi thelial hyperplasia, including goblet cells, in bronchi and large bronchioles, and hypertrophy of bronchial submuco sal glands. Alveolar regions are principally atelectatic be cause of bronchiolar occlusion by lymphofollicular accu mulations and intraluminal e x u d a t e , but there may be an alveolitis as described for the earlier stages. T h e epithe lium covering large lymphofollicular nodules in the submu cosa of bronchi tends to a s s u m e the flattened a p p e a r a n c e characteristic of lymphoepithelium. Because the uncomplicated mycoplasmal lesion is rarely, if ever, lethal, it is usually detected as a cuffing type of p n e u m o n i a in slaughtered veal calves or in calves dying for other reasons. It can also be a c o m p o n e n t of other pneumonias of calves (see enzootic p n e u m o n i a of calves, in Section V I , H , 7 of this Chapter). Other than the designation of cuffing p n e u m o n i a , various morphologic descriptors have been used. T h e most appropriate one for the airway lesion is chronic catarrhal bronchitis and bronchiolitis with lymphofollicular cuffing. W h e n the in flammation extends to peribronchiolar alveoli, the general term bronchointerstitial p n e u m o n i a is applicable. Al though the lesion is a chronic o n e , examination of the lungs of cattle older than 9 -1 2 m o n t h s indicates that it does gradually regress in most instances. species a r e responsible for pneumonia, mastitis, polyar thritis, keratoconjunctivitis, o r a combination of these. Septicemic forms can also occur, mostly in young kids. Manifestations of mycoplasmosis vary according to preva lence of the various species and strains of mycoplasmas, the husbandry practices, and the presence of environmen tal influences or intercurrent diseases which act as predis posing factors. Contagious caprine pleuropneumonia is t h e most im portant form of respiratory mycoplasmosis in goats. T h e disease occurs mainly in Africa, t h e Middle East, a n d western Asia. T h e prominent lesions are a severe fibrinous or fibrinonecrotic pneumonia and a profuse serofibrinous pleuritis. Fibrinous pericarditis is also c o m m o n . Three species of Mycoplasma have been associated with severe outbreaks of caprine pleuropneumonia: M. mycoides subsp. mycoides (large-colony type), a n unclassified or ganism referred t o as Mycoplasma species F 3 8 , and M . mycoides subsp. capri. It is n o w generally accepted that Mycoplasma sp. F38, which w a s first isolated in K e n y a , was the cause of the classic and highly contagious caprine pleuropneumonia reported from South Africa at the end of the nineteenth century. T h e main points of resemblance are a high degree of contagiousness for goats but not sheep or cattle, a fibrinous pleuropneumonia lacking conspicu ous serofibrinous widening of interlobular septa, and ab sence of local inflammation when the organism is inocu lated subcutaneously. Mycoplasma mycoides subsp. mycoides (large-colony type) a n d t o a lesser extent M. mycoides subsp. capri appear t o cause a form of caprine pleuropneumonia resembling the disease in cattle, in that there is often extensive widening of interlobular septa and peribronchial interstitium by serofibrinous exudate. They also seem t o b e less readily transmitted from goat t o goat by contact. Sequestra a r e present in chronic stages of disease caused b y all three mycoplasmas b u t are not so conspicuous a feature as in contagious bovine pleuropneu monia. Mycoplasma mycoides subsp. mycoides (large-colony type) is found in widespread areas of the world where explosive outbreaks of caprine contagious pleuropneumo nia d o n o t occur. Syndromes caused b y this organism vary and collectively they constitute the most important worldwide mycoplasmal diseases in goats. In North America and F r a n c e , the organism causes severe disease with high mortality in kids. T h e predominant lesion is fibrinopurulent polyarthritis, b u t fibrinous pleuritis a n d pericarditis, acute interstitial pneumonia, and meningitis frequently a c c o m p a n y t h e severe mycoplasmemia. In older goats, less fulminating cases of mastitis, pneumonia, or arthritis a r e more usual. Peritonitis a n d abortion a r e occasional complications. Various other mycoplasmas have been isolated from the lung. Mycoplasma capricolum is principally a cause of fibrinopurulent polyarthritis in kids. A n acute diffuse interstitial pneumonia, such as occurs in other septice mias, occurs in the septicemia associated with acute poly arthritis in young kids. Mastitis can occur in milking fe males. Other mycoplasmas, particularly M. ovipneumoniae and M. bovis, have been isolated from pneumonic lungs of goats. Their significance is uncertain. It is probable that they play a role similar t o that of M. dispar in calves and M. ovipneumoniae in sheep b y causing a mild, subacute to chronic catarrhal bronchiolitis or bronchointerstitial pneumonia and perhaps acting synergistically with other infectious agents to produce an enzootic type of pneu monia. c. RESPIRATORY MYCOPLASMOSIS OF SHEEP The species most frequently isolated from lungs of sheep is M. ovipneumoniae. Most of the evidence indicates that it is one of the etiologic factors that combine to cause enzootic pneumonia of sheep, usually in association with P. haemo lytica. Experimental studies using M. ovipneumoniae alone have been inconsistent and often difficult to inter pret. There is sufficient evidence, however, to show that at least some strains of the organism can cause mild, subclinical lesions in a proportion of infected sheep. Le sions are principally chronic catarrhal bronchitis and bron chiolitis with development of lymphofollicular collars around the airways. The affected alveoli are mostly atelec tatic because of bronchiolar obstruction, although a mild chronic alveolitis may be present. The role of M. ovipneu moniae therefore appears to be analogous to that of M. dispar in calves. mycoides subspecies of caprine origin ex perimentally cause fibrinous pneumonia and pleuritis in sheep. They are isolated only on rare occasions from natu rally occurring outbreaks of pneumonia in sheep, and even in these instances, their etiologic importance is open to question because of the presence of P. haemolytica. spp. can also be isolated occasionally from enzootic pneumonia. Their relative importance in causing the disease is still under investigation. Enzootic mycoplasmal pneumonia of swine is a chronic, usually nonfatal disease of young pigs. It is widespread throughout the world and in its most severe form can affect from 70 to 100% of pigs in a herd. Clinical expressions of the uncomplicated disease are coughing, unthriftiness, poor weight gain, and reduced food-conversion ratio. Be cause there is usually low mortality associated with myco plasmal pneumonia, the lesions are generally seen in slaughtered animals or those dying from other diseases. When deaths do occur because of pneumonia, it is due mainly to superimposed bacterial infections. Pasteurella multocida is the most common secondary invader, but Actinomyces pyogenes, Haemophilus spp., streptococci, staphylococci, Klebsiella spp., and Bordetella bronchi septica can be involved singly or in combination. The characteristic gross feature of mycoplasmal pneu monia is confluent consolidation of cranioventral regions of the lungs (Fig. 6.82) . When the amount of consolidation is small, it tends to affect portions of the right middle and right cranial lobes and the caudal portion of the left cranial lobe, but frequently there is bilateral involvement of more than 50% of cranial and middle lobes, together with the accessory lobe and cranioventral portions of caudal lobes. The consolidated lung ranges from dark red through gray ish pink to more homogeneous gray according to the age of the lesion. This change occurs over the several-month course of disease. Even though there is often extensive confluent consolidation, careful examination reveals a reg ular pattern of small grayish nodules against a red back ground. This denotes the bronchiolar orientation of the inflammation. The cut surface of consolidated lung is moist and meaty, and mucopus is present in the airways. Minor mycoplasmal lesions are less characteristic and have a mosaic pattern of intermixed consolidated, atelectatic, hyperinflated, and more normal lobules. Occasional atel ectatic lobules represent the minimal gross lesion. Some times, pale nodules indicating the presence of peribronchi olar lymphoid tissue can be detected in the centers of atelectatic lobules. Lesions of severe exudative broncho pneumonia or lobar pneumonia, especially with necrosis or abscessation, indicate secondary bacterial infection. can cause fibrinous or serofibrinous pleuritis and inflammation of other serous surfaces. When pleuritis is present, however, it is more probably associated with M. hyorhinis or infections com plicated by P. multocida or Haemophilus spp. Pulmonary lymph nodes are enlarged by nonspecific hyperplastic lymphadenitis to a degree which corresponds to the extent and activity of pulmonary consolidation. On cut surface, they are moist, usually bulging, and sometimes hyperemic. Histologically, mycoplasmal pneumonia in swine has the morphologic pattern of a catarrhal bronchointerstitial pneumonia ( Fig. 6 .83A), with development of prominent peribronchial, peribronchiolar, and perivascular accumu lations of lymphoid tissue in the chronic stages. Thus there is a resemblance to the lesions caused by mycoplasmas associated with enzootic pneumonias in calves and lambs. The mycoplasmas of swine appear to be much more capa ble of eliciting chronic inflammation of the alveolar paren chyma without the assistance of other organisms, how ever, even though they mainly colonize the surface of ciliated cells in the airways as do the mycoplasmas of calves and lambs. In the fully developed mycoplasmal pneumonia, there is extensive lymphoid hyperplasia around airways and their associated vessels. In severe cases, the lymphoid nodules or sheaths efface the muscularis mucosae and cause narrowing of the lumina of airways. Germinal cen ters may be present. The epithelium over prominent nod- ules is often degenerated or ulcerated. Elsewhere, there is epithelial hyperplasia, particularly in bronchioles. Cilia are absent from many surface regions. There is hyperpla sia of goblet cells in the bronchi and larger bronchioles, and the bronchial submucosal glands are increased in size and number. The increased activity of mucus-secreting cells is responsible for the presence of large amounts of mucus or mucopus. The alveolitis component of the bron chointerstitial pneumonia consists of wide thickening of the septa of alveoli adjacent to bronchioles and accumula tion of exudate in their lumina. The alveolar septa are thickened by accumulations of various-sized lymphocytes and small numbers of plasma cells. The intra-alveolar exu date consists predominantly of macrophages ( Fig. 6.83B ), but variable numbers of plasma cells, lymphocytes, and neutrophils are present. There is hyperplasia of type II alveolar epithelial cells of inflamed alveoli in established lesions. This can be difficult to detect histologically when alveolar architecture is obscured by absence of detectable demarcation between thickened alveolar septa and atelec tatic or exudate-filled lumina. Experimental studies of the pathogenesis of mycoplas mal pneumonia indicate that typical gross lesions do not occur until 2-4 weeks after infection. The rate of develop ment of lesions is dependent on factors relating to the dose and strain of Mycoplasma, method of administration, and susceptibility of the pigs exposed. Inoculation of suspen sions of lung containing mycoplasmas is a more reliable way of reproducing the disease, as is also the case with experimental production of respiratory mycoplasmosis in cattle, sheep, and goats. Young pigs naturally exposed to infectious aerosols soon after birth can develop lesions by the time they are 3-5 weeks of age. Initial lesions caused by the Mycoplasma, that is within a week after infection, are a neutrophilic bronchitis and bronchiolitis, and a mixed neutrophil and macrophage accumulation in adjacent alveoli. The numbers of neutrophils diminish, and the lymphoid cells increase over the subsequent several weeks to reach the fully developed stage of consolidation de scribed earlier. There is conflicting evidence concerning persistence of the pneumonia after it has reached its peak some 5-6 weeks after infection. Estimations range from essentially complete resolution of uncomplicated myco plasmal pneumonia within 2 months to no appreciable reduction in its extent even after 3 months. In view of the large number of variables in experimental and especially in field situations, the wide range in persistence is to be expected. Although several mycoplasmas have been isolated from the respira tory tract of horses, particularly Mycoplasma equirhinis and M. felis, there have been no studies to determine whether any of them is capable of causing a subclinical bronchiolitis or bronchointerstitial pneumonia. Myco plasma felis is believed to be a cause of pleuritis in the horse. Of the various mycoplasmas isolated from canine pneumonia, M. cynos experimentally is capable of causing a mild bron chointerstitial pneumonia similar to that produced by my coplasmas in other species and is implicated in the patho genesis of some cases of kennel cough. is also pathogenic, but to a lesser extent. The clinical significance of these mycoplasmas is doubtful, however, because they are usually isolated from severe exudative lesions in which pathogenic bacteria are also present, often in dogs with distemper. Mycoplasma felis is an opportunistic pathogen of the conjunctiva in cats. Neither it nor the other mycoplasmas isolated from the respiratory tract of cats are recognized as significant respiratory tract pathogens. iae can be detected by immunofluorescence, is occasion ally encountered in naturally occurring pneumonia in ru minants ( Fig. 6 .84). The chlamydiae are mostly destroyed during the acute phase of inflammation, which then sub sides, and resolution can be complete within 3 -4 weeks after experimental infection. In assessing the importance of chlamydial infections in ruminants, it is important to note that they are usually capable of inducing only a transient inflammation. This is in contrast to m y c o p l a s m a s , which tend to persist on cili ated epithelium and cause chronic lesions. T h e part chla mydiae play in contributing to the cause of chronic enzo otic pneumonia is therefore probably a relatively minor one. Several rickettsial and ehrlichial diseases can cause in terstitial p n e u m o n i a as one of the manifestations of their systemic involvement. This is particularly true for organ isms affecting vascular endothelium. T h e important organ ism of this type in animals is Cowdria ruminantium which causes heartwater in cattle, sheep, and goats (see T h e Cardiovascular System, Volume 3, Chapter 1). A mild interstitial p n e u m o n i a can be present in salmon poisoning of dogs caused by Neorickettsia helminthoeca (see T h e Alimentary System, C h a p t e r 1, this volume). a. ASPERGILLOSIS Fungi of the genus Aspergillus are ubiquitous, and exposure to the spores is an everyday matter. N o n e t h e l e s s , established infections which pro duce disease are u n c o m m o n in m a m m a l s , although of great importance in birds. Aspergillus fumigatus is responsible for most infections in m a m m a l s , birds, and h u m a n s . Other species, including A. flavus, A. niger, and A. nidulans, occasionally act as pathogens. Aspergillosis in animals is most often a respiratory in fection initiated by inhaled spores. Moldy litter and feeds, especially hay and grain which have been d a m p and heated during storage, support an e n o r m o u s growth of fungi, among which A. fumigatus can predominate. In view of the high rate of exposure that takes place a m o n g housed animals, it is perhaps surprising that m o r e progressive infections are not detected. Very little is k n o w n concern ing the pathogenesis of aspergillosis. It is generally as sumed that a local or generalized immunodeficiency state or a b r e a k d o w n of local barriers must exist for the organ ism to gain a foothold. Questions concerning the suscepti bility of hosts, the n u m b e r of spores necessary to initiate infection, toxigenicity of the organisms, and the role of immunity and hypersensitivity still h a v e to be answered. Aspergillosis can be a respiratory or placental disease in animals. Infections of either the u p p e r or lower respiratory tract are sporadic in all species, but thus far infection of the pregnant uterus and fetus has been found mainly in cattle. T h e latter, which is described with diseases of the pregnant uterus (Volume 3, C h a p t e r 4), is the more eco nomically important of the t w o . Aspergillosis of the respiratory tract appears often to be a complication of some other debilitating disease, but there are cases in which no clear predisposition can be found. The infection may develop as an implantation on the m u c o u s m e m b r a n e of the nasal cavity, sinuses, gut tural p o u c h e s , and tracheobronchial airways, or it may be in the form of a nodular bronchopneumonia. Secondary intestinal infections have been observed in cattle. W h e n the fungi grow on a m u c o u s m e m b r a n e , they may be visible to the naked e y e , first as a whitish growth and later as a powdery feltlike growth with a typical blue-green color produced by the conidia. These superficial colonies may develop after death, and the presence of colonies of the fungus on a m u c o s a is not significant unless there is tissue reaction. The usual reaction is caseating necrosis sur rounded by a zone of hemorrhagic inflammation. Break down of these lesions in the walls of bronchi can result in bronchiectatic cavities. The pulmonary lesions typically occur as one or many discrete gray-white nodules -1 -1 0 m m in diameter, with a narrow hyperemic rim. They may be obscured, espe cially in young animals, by severe pulmonary congestion. The nodules develop around fungal colonies which prolif erate in the terminal bronchioles ( Fig. 6 .85B) and adjacent alveoli. The fungal colony consists of long branching, sep tate hyphae (Fig. 6 .85A) and is surrounded by a zone of neutrophils, macrophages, and debris. The focus e x p a n d s and compresses adjacent alveoli. The affected bronchioles contain plugs of purulent exudate. As is c o m m o n in inva sive fungal lesions of this t y p e , occasional blood vessels are invaded, inflamed, and thrombosed. The nodules may b e c o m e cavitated if they evacuate into airways. Chronic lesions are granulomatous. Macrophages and epithelioid cells predominate in the nodules and extensively infiltrate the septal tissues, and encapsulating fibroplasia is evident. Giant cells are not a significant part of the lesion, although they may be present later w h e n the focus is being obliter ated by fibrosis. Perhaps as an indication of host resis tance, the form of the colonies changes in chronic infec tion. Instead of stretching out freely as long hyphae in all directions, as they do in early and progressive infections, the colonies b e c o m e c o m p o s e d of shorter radiating hyphae which branch freely near their outer e n d s -t h e so-called actinomycotic forms of the fungus. Sometimes asteroid bodies can be found in the nodules and consist of small tangled remnants of the colony surrounded by radiating acidophilic clubs quite similar to those of the granules of actinomycosis ( Fig. 6 .85C). Dissemination of the infection from the pulmonary lesions can occur. Of the m a n y or gans, including the meninges, in which metastases de velop, the kidney seems to be the most prone. b. MORTIERELLOSIS Acute fatal mycotic pneumonia may be associated with placental infection by Mortierella wolfii, the most important cause of mycotic abortion of cattle in N e w Zealand. An acute fibrinonecrotic pneumonia can occur in infected cows at or within a few days of abortion or parturition. There is apparently extensive hematoge nous dissemination of fungal elements when the placenta separates. This is followed by widespread vegetation of hyphae in pulmonary capillaries and larger vessels with resulting inflammation, thrombosis, and necrosis. L e s s severe pulmonary involvement leads to chronic, focal, granulomatous lesions. Other fungi within the class P h y c o m y c e t e s , such as Mucor and Rhizopus spp., are occasional opportunistic invaders of lung and are usually associated with nodular caseonecrotic or granulomatous lesions. c. BLASTOMYCOSIS Blastomycosis is a disseminated or localized mycotic infection caused by Blastomyces dermatitidis. It is a disease chiefly of h u m a n s and dogs in N o r t h America, Africa, E u r o p e , and Asia. It occasionally occurs in cats, horses, and other species. The disease is sometimes referred to as N o r t h American blastomycosis to distinguish it from South American blastomycosis (Blastomyces brasiliensis) and E u r o p e a n blastomycosis (Cryptococcus neoformans). The lesions are typically granulomatous or pyogranulomatous. Blastomyces dermatitidis is a dimorphic fungus; in cul tures at room temperature it produces a mycelial growth, whereas in tissues or culture at 37°C, it is yeastlike, 8 -20 jum in diameter with a thick double-contoured wall, and reproduces by budding. T h e epidemiology of blastomyco sis is obscure. The infection appears not to be contagious from animal to animal or animal to h u m a n s . The available evidence suggests that the source of infection is from growth on vegetation. In N o r t h America, most cases of the disease occur in the Mississippi-Ohio river basins and the central Atlantic states of the United States, and near the northern border of Ontario and Manitoba in Canada. The disease in dogs is found predominantly in young males of large b r e e d s . T h e lung is the most frequent site of primary involvement, but primary cutaneous infections are also found. Systemic dissemination often occurs and is particularly likely to cause clinical signs associated with lesions in lymph n o d e s , eyes, skin, subcutaneous tissue, bones and joints, and the urogenital tract. The pulmonary form of the disease is insidious in onset and has a chronic course which may last many m o n t h s . T h e usual syndrome is one of a chronic debilitating disease with coughing, exercise intolerance, and terminal respiratory distress. The other clinical signs depend on the pattern of dissemi nation. T h e pulmonary lesions of fatal blastomycosis are multiple gray-white nodules of various sizes distributed throughout all lobes (Fig. 6.86 ). Superficial nodules pro duce elevations of the pleura, but it is exceptional for there to be pleuritis. W h e n this does occur, it is because of fistulation from a mycotic abscess. Most pulmonary nod ules are of firm granulomatous tissue, but some undergo central abscessation or caseation and then may fistulate into a bronchus or onto the pleura. Calcification is minimal or absent. Microscopically, the high frequency with which small lesions affect bronchioles and adjacent alveoli can be taken as evidence of aerogenous infection, although intrabronchial spread of organisms confuses the picture. The regional lymph nodes are consistently involved and contain granulomas, a b s c e s s e s , or caseous foci. It is usual for the pulmonary nodules to be m o r e or less of equivalent age, but it is sometimes possible to locate a larger, older caseous lesion in the lung and one in the corresponding lymph n o d e , which together are probably comparable to the primary complex of tuberculosis. Disseminated lesions take the same form as those in the lungs and have been observed in peripheral lymph n o d e s , eyes, skin, subcutaneous tissues, b o n e s , and joints. Testes, prostate, brain, heart, liver, spleen, kidneys, intestines, and other organs are less commonly affected. T h e lesions are either typical granulomas with abundant epithelioid and giant cells or pyogranulomatous foci with central accumula tion and necrosis of neutrophils and m a c r o p h a g e s . T h e yeastlike fungi are plentiful and readily detected in the le sions, either free or in the cytoplasm of m a c r o p h a g e s and giant cells. Identification of the organism and its character istically broad-based, single-budding forms is aided by use of P A S or m e t h e n a m i n e -s i l v e r stains. The cutaneous lesions begin as papules, which soon develop into small abscesses with a surrounding inflam matory reaction. The lesions e x p a n d , with new small ab scesses forming in the expanding margin of the papules while the central areas undergo some cicatrization. Micro scopically, the abscesses and granulomas found within the skin and subcutis are of structure similar to that of the pulmonary lesions. Pulmonary, c u t a n e o u s , or systemic blastomycosis oc casionally occurs in cats, particularly in the Siamese breed. It has also been found rarely in horses and other species. d. CRYPTOCOCCOSIS Cryptococcosis ( E u r o p e a n blasto mycosis) is a subacute or chronic mycosis caused by The organism is monomorphic, yeastlike, reproduces by single buds, and is ~4-8 /im in diameter, not including the large amount of capsu lar material. The disease has worldwide distribution. It may be a localized or disseminated disease, but it has a predilection for the respiratory system, particularly the nasal region, and for the central nervous system. All spe cies of animals appear to be affected occasionally. Cats are affected more than other species. There are several species in the genus, but only C. neoformans is a pathogen. It is distinguished from the nonpathogens by producing disease in experimental mice. The yeast is surrounded by a wide capsule, which is com posed of mucopolysaccharides and, although cultivation of the organism is necessary for proper identification, a confident diagnosis can be made on pathologic material by identification of the capsule. The capsular material is sometimes copious enough to give the lesions a grossly mucinous texture, and it stains well with mucicarmine, the PAS reaction, or alcian blue. The capsule is wider in hydrated than in dehydrated sections. The organisms in wet mounts are not easily distinguished from erythrocytes or lymphocytes, but they are clearly evident by negative staining of the wide capsular zones with India ink or nigrosin. The source of infection is generally believed to be soil, especially when enriched with pigeon or other bird drop pings. Disease is sporadic and, as is usually true for the deep mycoses, the infection is not contagious. Cryptococci are natural saprophytes and only accidentally act as pathogens in animals with impaired local or systemic immunity. Debility, malnutrition, prolonged use of corti costeroids, and feline immunodeficiency virus infection are some of the conditions suspected of predisposing cats to cryptococcosis. Infection is acquired in most instances by inhalation of contaminated dust. The respiratory tract is the usual site of primary infection, with the nasal cavity more often affected than the lungs. The lungs are often stated to be the usual site for systemic dissemination of cryptococcal organisms, but the nasal region is probably the more important because its involvement leads much more frequently to hematogenous dissemination to central nervous system, eyes, lymph nodes, skin, and other or gans than does pulmonary involvement (Fig. 6.87 ). There is also the possibility of local spread to the meninges and brain from nasal lesions. Local inoculation of the organism does not appear to be of general significance, although it has resulted in outbreaks of cryptococcal mastitis in cows (see The Female Genital System, Volume 3, Chapter 4). The cutaneous lesions, which are observed occasionally, may be primary or metastases following hematogenous dissemination from respiratory infection. The infection has a predilection for the central nervous system (Fig. 6 .87A). Lesions can occur there without being grossly apparent in any other organ, but it is usual in the dissemin ated infection to find gross or microscopic lesions in some combination of the respiratory tract and other organs. Intraocular metastases may occur (Fig. 6.87B ). The cutaneous lesions of cryptococcosis take the form of firm, small nodules ( Fig. 6.87C) , which tend to ulcerate, discharge a small amount of serous exudate, and may then heal. In cats, the skin of the head is most commonly affected, but sometimes the lesions are distributed widely over the body. Nasal involvement was described earlier with granulomatous rhinitis. In the parenchymatous or gans, the lesions are discrete, whitish, gelatinous foci, and may not be more than a few millimeters in diameter. Lesions in the meninges, brain, and cord also have a gelatinous character when they are visible, but often there are no significant gross changes. There may be some gelati nous areas in arachnoid spaces, especially around the larger vessels and in the cisterns, but the opacity of bacte rial meningitis is seldom observed. The parenchymal le sions are chiefly in the peripheral gray matter and probably develop by extension of the lesions along the Vir chow-Robin spaces (Fig. 6.87A ). The usual cryptococcal lesions are characterized histo logically as having a soap-bubble appearance because of the unstained capsules of massed organisms. A profound cellular reaction is not typical, in contrast to other mycotic infections, and usually consists of a few macrophages, lymphocytes, and plasma cells (Fig. 6.87D ). Vacuolated and degenerating macrophages may occasionally domi nate the picture. Sometimes, particularly in lungs, the lesions become more typically granulomatous with numer ous epithelioid and some giant cells. The lack of inflamma tion in regions such as the nasal cavity is probably because the capsular polysaccharide inhibits macrophages and an tigen-antibody interactions. Caseation may occur in le sions in lymph nodes, but otherwise necrosis is not part of the reaction to these organisms. When examined in sections stained by hematoxylin and eosin, the fungi appear as typical yeasts surrounded by a clear halo produced by unstained capsular substance. The capsular substance immediately around the organism is of ten condensed into an acidophilic rim. The free-lying organ isms may calcify and stain intensely with hematoxylin. e. COCCIDIOIDOMYCOSIS This disease, which is caused by Coccidioides immitis, is important in humans but also occurs in animals in areas in which the infection is endemic. Most cases of coccidioidomycosis occur in the endemic area of the United States, which includes the arid parts of California, Arizona, and Texas. The disease is also endemic in portions of South and Central America. In arid regions, there is an association between the feces of desert rodents and high concentrations of the fungus. It is not clear to what extent numbers of organisms are increased by spherules excreted in the feces of the rodents as compared to the fecal matter enhancing vegetative growth of the organism in the soil. Vegetation of the fungus occurs in soil after rains, and subsequently, large numbers of infective arthroconidia (spores) are disseminated widely in wind-blown dust after the soil dries. It is estimated that most animals which live in endemic areas eventually become infected, but relatively few become clinically diseased. T h e fungus is dimorphic. In tissues, the distinctive form is a spherule (sporangium) which measures -10-70 /im in diameter and has a thick, double-contoured wall ( Fig. 6 .88A). It is called a sporangium because reproduction in tissues is by endosporulation; the endospores are globose, 2 -5 fim in diameter, and are released into the tissues in large numbers when a spherule ruptures. Mycelia are rare in animal tissues. On most artificial media, however, growth is mycelial. Reproduction in mycelial growth is by arthroconidia, which are produced in very large numbers along the hyphae. These arthroconidia are highly infective and easily detached from the mycelial growth. Coccidioidomycosis is a primary respiratory infection ( Fig. 6.88B ). Local traumatic inoculation can occur and result in a fluctuating a b s c e s s , but dissemination from such a focus is unusual. T h e high susceptibility of the lungs to the establishment of infection can be demonstrated experi mentally by intranasal insufflation of spores. The great majority of respiratory infections are benign and nonpro gressive. This form in humans is known as San Joaquin Valley fever. A small percentage of the infections dissemi nate from the lung and the generalized disease is k n o w n as coccidioidal granuloma, with secondary lesions any where in the body. Among domestic animals, the dissem inated disease has been observed mostly in dogs, and occasionally in horses, sheep, and cats. In these species, the lesions may be limited to the lungs and associated lymph n o d e s . In cattle and swine, lesions have so far been observed only in the lungs and their lymph nodes. The disease is c o m m o n in cattle in endemic areas. As many as 20% of slaughtered cattle from feedlots in Arizona have lesions of the disease, but lesions are observed only in slaughtered animals. There is either a complete pulmonary complex or an incomplete complex with lesions only in the bronchial and mediastinal lymph nodes. Dissemination is c o m m o n only in dogs, and in this spe cies, there is reported to be a predisposition for boxers and D o b e r m a n pinschers. The clinical signs frequently lack specificity and depend on the sites of active lesions. Persistent fever with one or more of respiratory abnormali ties, shifting lameness, and the development of cutaneous nodules suggests the diagnosis in chronically ill dogs in endemic areas. The lameness is ephemeral w h e n first seen, and radiographic evidence of the underlying osteomyelitis ( Fig. 6.89A,B) is obvious only late in the course of disease. Usually the progressive debility leads to cachexia and eventual death, although recoveries d o occur. T h e lesions of coccidioidomycosis are granulomas or pyogranulomas ( Fig. 6.88A,B) . T h e granulomas are gray ish white and usually nodular. There may be central case ation necrosis or liquefaction, but calcification is unusual. A c o m m o n finding, particularly in the dog, is that large granulomatous nodules are c o m p o s e d of collections of discretely unitized small granulomas separated by fibrous tissue (Fig. 6.88A ). T h e cellular reaction on the part of the host depends on the phase of the organism against which it is directed. Spores, w h e t h e r endospores or the initial arthroconidia, provoke an acute exudative reaction in which neutrophils predominate. The larger spherules are usually surrounded by a wide zone of epithelioid cells mixed with a few giant cells, lymphocytes, and neutro phils. Because the organisms in any large focus are often in different phases of growth, there can be variations in the proportions of suppurative and granulomatous re sponses. In contained infections, however, the granuloma tous response predominates, and it may then be difficult to find organisms. In such c a s e s , they are most likely to be found in the cytoplasm of giant cells as large spherules which are either evacuated and crenated or contain endo spores. Often in cattle, and occasionally in other species, the spherules b e c o m e surrounded by a corona of acido philic clubs similar to those which form around colonies of Actinomyces bovis and some other microorganisms. This is an indication of high host resistance. administration of corticosteroids. Pneumocystis pneumo nia has been recorded occasionally in the young dog, foal, goat, and pig as well as in laboratory animals. In horses, it appears mainly in Arabian foals with known or suspect congenital immunodeficiency, sometimes as a complica tion of adenovirus or other infectious pneumonia. Most of the reported canine cases have been in miniature dachs hunds ranging from about 8 to 24 months in age, raising the possibility of a heritable immunodeficiency in this breed. Clinical signs are gradually increasing exercise intolerance, respiratory difficulties, and progressive loss of weight. Gross lesions associated with Pneumocystis pneumonia are diffuse or patchy, red to yellow-brown regions of rub bery firmness or consolidation. The appearance may be modified by coexisting viral or bacterial pneumonia. His tologically, P. carinii causes a diffuse interstitial pneumo nia in which the characteristic feature is prominent filling of alveoli by a foamy, pale acidophilic material ( Fig. 6 .90A). The amount of interstitial inflammation varies from minimal to moderate accumulation of lymphocytes, plasma cells, and macrophages. There are various degrees of hyperplasia of alveolar type II epithelial cells (epithelialization) and accumulation of macrophages within alveo lar lumina. Fibrosis accompanies intense cellular inflam mation within alveolar septa. carinii stains poorly with hematoxylin and eosin and is therefore easily overlooked. Its presence should be suspected when alveoli contain abundant, foamy, pale eosinophilic material, especially in the ab sence of significant inflammatory hallmarks. This is partic ularly important in young animals, in which there may be congenital, drug-induced, or disease-induced immunode ficiency. The foamy acidophilic material consists mainly of trophozoite and cyst forms of the organism. These may be seen as indistinct outlines of erythrocyte-sized struc tures, possibly with the presence of pale basophilic dots. The organism is best demonstrated histologically by methenamine-silver staining. This reveals the argyrophilic capsules of the cysts and trophozoites as round, dis torted, or crescentic structures from 3 to 8 pm in width ( Fig. 6 .90B). The PAS stain is not so satisfactory for demonstration of the organism. Current evidence indicates that P. carinii is mainly kept in check by alveolar macrophages in normal animals, but that this process fails in immunodeficient states. Progres sive colonization of alveolar type I epithelial cells by P. carinii causes their necrosis and replacement by type II cells, with eventual filling of alveoli by the organisms and acellular material rich in alveolar surfactant lipid. Enzootic pneumonia refers to pneumonia that is preva lent in groups of young animals maintained in close con tact. It is mainly of importance in calves, lambs, and young pigs. Since it is an epidemiologic term, it allows consider able latitude in the morphologic and etiologic types of pneumonia it embraces. Both acute exudative broncho pneumonias and more chronic bronchointerstitial pneu monias have been included under the general designation of enzootic pneumonia, but the emphasis has differed ac cording to the species of animal concerned, as will be evident from the following discussion. Enzootic pneumonia of calves is a disease complex in intensively managed calves which is caused by the syner gistic action of two or more of a wide variety of viruses, mycoplasmas and bacteria. The morphologic appearance of the pneumonia varies according to the mix of agents and the age of lesions encountered. The disease mainly affects calves <6 months of age and is of most importance as a cause of unthriftiness. Mortality is low unless there is a coincidence of highly pathogenic agents and predispos ing factors associated with poor husbandry and possibly intercurrent disease. Evidence to date indicates that the acute pneumonia is usually initiated by viral infection. More than one species of virus may be involved in an outbreak or even in a single calf. The relative importance of the 10 or so candidate viruses varies geographically to some extent. In general, respiratory syncytial and parainfluenza 3 viruses are con sidered to be most important. Infectious bovine rhinotra cheitis virus, adenovirus, and the bovine virus diarrhea virus are the next most commonly mentioned. The lesions caused by those and the other viral respiratory pathogens were described earlier in this chapter. Although calves can die because of acute, uncomplicated viral lesions, most fatal cases have a superimposed acute bacterial bron chopneumonia or lobar pneumonia. These have the acute fibrinonecrotic to suppurative exudation characteristic of severe bacterial infection, particularly by Pasteurella haemolytica and Pasteurella multocida. More than 20 dif-ferent species of bacteria have been isolated at various times, however, often in mixed infection. Next to Pasteur ella spp., the most common are Streptobacillus acti noides, Actinomyces pyogenes, and Escherichia coli. Chlamydiae may also be involved occasionally. Since most fatal pneumonias are predominantly the result of bacterial activity, clearly establishing the initial role of viral infection can be difficult and requires attempts to isolate viruses by culture, to demonstrate their presence by immunofluorescence and electron microscopy, and to obtain serologic evidence of an active infection in the affected groups. Histologic search for inclusion bodies is usually unrewarding in fatal field cases, but pays dividends often enough to make the attempt necessary. Mycoplasmas, especially M. bovis, M. dispar, and Ureaplasma spp., are implicated in contributing to the acute form of enzootic pneumonia, together with viruses and bacteria. Mycoplasma bovis has been established as an important pathogen in its own right. It is more invasive than other mycoplasmas isolated from enzootic pneumo nia in calves and experimentally has been shown to cause an acute suppurative bronchopneumonia in which foci of coagulation necrosis are often present. These can to some extent be differentiated from the necrotic foci caused by Pasteurella spp., in that necrosis is a less dramatic feature of the M. bovis-induced lesion, fibrin deposition is not a significant feature, the necrotic zones do not cross inter lobular septa, neutrophils are not a prominent component, and there is not the secondary alteration of leukocytes to form the fusiform oat cells. Immunoperoxidase labeling methods for detection of antigen in necrotic foci are an important diagnostic aid. Isolation of M. bovis has also been correlated with outbreaks of more severe enzootic pneumonia in some calf populations, although still as part of mixed infections. Foci of necrosis similar to those pro duced by experimental M. bovis infection are present in some of the naturally occurring cases. Mycoplasmas are also important in causing the chronic form of enzootic pneumonia. This is the grayish-pink, meaty consolidation of cranioventral regions of the lung found in slaughtered veal calves or calves dying from other diseases. Histologically it is a chronic bronchointerstitial pneumonia with both exudative and proliferative compo nents (see Mycoplasmal Bronchiolitis and Pneumonia of Calves, Section VI,H,3,a,ii of this chapter). This type of lesion appears to represent persistent infection by both the mycoplasmas and bacteria of species similar to those found in more acute lesions. The usual course of chronic enzootic pneumonia is that of a low-grade inflammatory lesion which resolves in several months to a year. The term cuffing pneumonia has been used for chronic enzootic pneumonia in which a dramatic feature is sheathing of small airways by lymphofollicular proliferations. Acute exudative bacterial pneumonia can supervene at any time and cause severe clinical disease or death if the calf's pulmonary defenses are impaired or there is additional infection by virulent pathogens. An alternative sequel is chronic suppurative bronchopneumonia with bronchiecta sis, abscessation, and scarring. Enzootic pneumonia of lambs has many similarities to enzootic pneumonia of calves. The acute form is manifest as pneumonic pasteurellosis, and has been described un der that heading. The chronic, enzootic, bronchointersti tial pneumonia (Fig. 6 .91) has features similar to those of enzootic mycoplasmal pneumonia of swine mentioned previously. Because the term enzootic pneumonia was used initially only for acute pneumonic pasteurellosis in sheep, various descriptive terms have been used for the chronic form. The most frequent ones are proliferative interstitial, proliferative exudative, atypical, and chronic nonprogressive. To avoid confusion, however, the chronic bronchointerstitial pneumonia of lambs should also be referred to as an enzootic pneumonia, just as it is in calves and pigs. The causes of chronic enzootic pneumonia in lambs are not completely established. The disease can be regularly produced by intratracheal inoculation of a suspension of pneumonic lung. Attempts to produce the disease using various combinations of cultured microorganisms isolated from pneumonic lung have indicated that intratracheal or endobronchial inoculation of mixed strains of Myco plasma ovipneumoniae and Pasteurella haemolytica is the most successful. Bordetella parapertussis is capable of producing a mild, acute bronchopneumonia, and the or ganism can be isolated frequently from cases of chronic enzootic pneumonia. It therefore seems that most cases of chronic enzootic pneumonia in lambs probably involve the synergistic action of M. ovipneumoniae, P. haemoly tica, and B. parapertussis. One of these agents alone or in combination with other infectious agents may occasion ally be responsible. The active pneumonic consolidation persists for -3-12 weeks after infection and largely re solves within a few months unless acute bacterial exacer bations occur. Since the disease is not usually fatal, the characteristic cranioventral consolidations (Fig. 6 .91 A) are mostly seen in slaughtered lambs or those dying of other diseases. Enzootic pneumonia of swine is generally held to be synonymous with enzootic mycoplasmal pneumonia (see Respiratory Mycoplasmosis of Swine, Section VI,H,3,d of this chapter). The general features and wide range of causes of inter stitial pneumonia were discussed in the section on Intersti tial Pneumonia (Section VI,F,3 of this chapter). The condi tion in cattle is deserving of further mention, however, because of its frequency and the confusion concerning its causes. Acute interstitial pneumonia is the result of acute dif fuse damage to alveolar septa. Characteristic features in cattle are pulmonary hyperemia, alveolar edema, and hya line membrane formation, hyperplasia of alveolar type II epithelial cells, and interstitial emphysema and edema. Other components may be present, such as larvae and eosinophils when migrating helminth larvae are the cause, but in general the lesion is nonspecific. Extensive intersti tial emphysema and edema are usually found only in cows dying after a bout of severe, labored respiration. When this is prolonged, the interstitial emphysema can dissect through the mediastinum and reach subcutaneous regions of the back. Since the structure of the bovine lung predis poses it to the development of interstitial emphysema when there is severe pulmonary insufficiency and labored respiration for any cause, the diagnosis of acute interstitial pneumonia cannot be made solely on the basis of air in the pulmonary interstitium. Various terms have been used for acute interstitial pneumonia in cattle, the most common one being atypical interstitial pneumonia, in recognition of the acute exuda tive nature of the process. Other terms have been used in certain geographic regions and have emphasized epidemi ologic or morphologic features, the latter usually misleadingly. Examples are fog fever and acute bovine pulmo nary emphysema and edema for pasture-associated acute interstitial pneumonia in Britain and the United States, respectively. The pasture-associated condition usually occurs in adult, beef-type cattle soon after a change from sparse summer range or pasture to relatively lush pastures con taining regrowth following removal of a crop for hay or silage. Cows dying of the disease have gross lesions domi nated by interstitial emphysema and edema. Major air ways contain abundant white foam. The pulmonary paren chyma is purplish to brownish red, depending on the acuteness of the disease, and affected lobules have a ho mogeneous, moist cut section and a soft rubbery texture ( Fig. 6.42A,B) . Irregular lobular or sublobular distribution of the lesions occurs to some extent. There is a tendency for most diffuse involvement to be found in dorsocaudal regions of the lungs. Histologically, the main features are as outlined previously, but hyperplasia of alveolar type II epithelial cells is not a pronounced feature until 4-6 days after the onset of the alveolar damage ( Fig. 6 .42C,D), and at this stage the term subacute can be used. Cows that survive the acute episode usually have residual interstitial fibrosis and some persistence of alveolar type II epithelial cells (Fig. 6 .44). The pasture-associated form of acute interstitial pneumonia is probably related to increased amounts of L-tryptophan in the ingested feed; the quantity of Ltryptophan can be sufficient to provide toxic levels of 3methylindole under the special conditions of rumen fer mentation occurring at the time of change in pasture. Acute interstitial pneumonia can also be caused by the pneumotoxic activity of (1) 4-ipomeanol and related furanoterpenoids from sweet potatoes spoiled by the mold Fusarium solani; (2) perilla ketone from purple mint (Perilla frutescens); and (3) an unidentified toxin from stinkwood (Zieria arbor escens). The condition has also been reported following ingestion of garden beans contaminated with the mold Fusarium semitectum. Apart from chemical toxins, a similar lesion can be caused by massive invasion of the lungs by larvae of Dictyocaulus viviparus or, less com monly, Ascaris suum (see Parasitic Diseases of the Lungs, Section VI,I of this chapter). Acute interstitial pneumonia also occurs occasionally in housed or feed-lot cattle. There is frequently an associ ated, more chronic, cranioventral bronchopneumonia. The factor or factors involved in the pathogenesis of the acute interstitial pneumonia occurring under these circum stances are not understood, however. The association of severe infection with bovine respiratory syncytial virus and acute interstitial emphysema, particularly in newly weaned calves in the fall, has given rise to the suggestion that the respiratory syncytial virus alone can cause an acute interstitial pneumonia under certain circumstances. This is not proven, and it is probable that a degree of acute alveolar damage and development of extensive interstitial emphysema can be final common events in cattle with various forms of severe primary pulmonary damage. Chronic interstitial pneumonia in cattle occurs chiefly as a manifestation of hypersensitivity pneumonitis. This condition is also referred to as bovine farmer's lung or extrinsic allergic alveolitis and is caused by inhalation of dust from moldy hay which contains spores of Micropolyspora faeni and other thermophilic actinomycetes. The disease develops primarily in the winter in housed dairy animals. Death does not usually result from lesions oc curring early in the disease. If lungs are available for examination, careful search reveals multiple, small, gray, subpleural foci and many pulmonary lobules with slightly pale, hyperinflated peripheral zones. Characteristic histo logic lesions are a lymphocytic and plasmacytic bronchitis and bronchiolitis, often with severe obliterative bronchio litis, the presence of scattered granulomas composed of epithelioid and giant cells, and thickening of alveolar septa by infiltration of lymphocytes, plasma cells, and macro phages. Eosinophils, globule leukocytes, and increased mast cells are usually present. Cattle are more likely to die as the result of severe, chronic disease. Additional features of severe interstitial fibrosis, accumulation of al veolar macrophages, and hyperplasia of alveolar type II epithelial cells are present in such cases. There can also be metaplasia of type II cells to ciliated or mucus-secreting cells. Vascular compromise can lead to pulmonary hyper tension and cor pulmonale in a small proportion of cases. In these advanced cases, epithelioid granulomas are incon spicuous or absent. The lungs grossly are pale and heavy. Most severely affected lobules are yellow-white and fi brous or may show evidence of distortion and enlargement of airspaces by the scarring (honeycombing). Asteroids caused by Aspergillus spp. may also be present in these lungs because the conditions leading to heavy exposure to dusts containing M. faeni are also those in which large numbers of spores of Aspergillus spp. are present. A chronic interstitial pneumonia (diffuse fibrosing alve olitis) similar to that occurring in dairy cattle with ad vanced hypersensitivity pneumonitis is sometimes seen in pastured beef cattle. Its cause remains undetermined. The lungs are at the crossroads of parasitic migrations, and the many parasites which pass through them cause various degrees of damage according to the nature and intensity of the host-parasite interaction. Usually, the lesions produced by transient parasites are of slight sig nificance and are resolvable. There are exceptions, how ever. Severe and possibly fatal pulmonary lesions may develop if the migrating parasites are large in number or large in size, or especially when the host has a hypersensi tivity reaction to them. Hypersensitivity occurs because of previous exposure of a natural host or because of infec tion of an unnatural host. Ascaris suum, because of its tremendous biotic potential, may migrate in huge numbers and sometimes kill pigs, which are its natural hosts. It can also cause death of cattle, which are its frequent unnatural host. The lesion is an acute, diffuse, eosinophilic, intersti tial pneumonia associated with the presence of large num bers of larvae. The trematodes Fasciola gigantica and F. hepatica invade the lungs accidentally from the liver. Since they are large parasites which wander extensively, a small number of them in the lungs can produce extensive cavitations. In other instances, lesions caused by parasites may be of some importance for differential diagnosis even though not of much clinical significance. In this category are the worm nodules, such as those caused by migrating Par ascaris equorum larvae in horses. Although distinctive when young by virtue of the mass of eosinophils present, when scarified and calcified they need to be differentiated from residual lesions of small abscesses or infectious gran ulomas such as occur in glanders. The transient parasites with principal habitats in other organs are discussed elsewhere. Here we are mainly con cerned with lungworms whose final habitat is the airways or, less commonly, the parenchyma of the lungs. The Dictyocaulus genus contains the most important lungworms. There are three species: Dictyocaulus filaria is parasitic in sheep, goats, and other small ruminants, D. viviparus is parasitic in cattle, and D. arnfieldi is parasitic in the horse and its relatives. The three species are similar morphologically and in the details of their life cycles; D. filaria will serve as the type for discussion. Dictyocaulus filaria, the large lung worm of sheep and goats, is a slender, whitish worm 3-10 cm long. The adults live mainly in the small bronchi. The life cycle is direct. The eggs are embryonated when laid, and some of them hatch in the lungs. The eggs and larvae are expelled from the lung by coughing; most are subsequently swallowed. The eggs which have not hatched in the air passages hatch in the alimentary canal, and first-stage larvae are passed in the feces. Further development occurs on the ground and requires moisture and moderate to low temperatures. This explains why verminous pneumonia is predominantly a disease of cool, moist climates. The larvae can develop at temperatures as low as 5°C, and their viability is pro longed at these temperatures. The combination of long survival at low temperatures and long patent periods in the host endows these worms with the ability to persist in northern, cold latitudes. The larvae undergo two molts on pasture in ~1 week. The third stage is infective, and infestation can occur only if the third-stage larvae are ingested by the final host. The infective larvae penetrate the wall of the intestine and migrate via the lymphatics to the local lymph nodes. In the abdominal lymph nodes, they undergo the third molt and then go by way of lymph and blood to the lungs. Some larvae accidentally take the portal route and are destroyed in the liver. Some, on reaching the lungs, continue into the systemic circulation and are lost except for those rare ones which pass the placenta and produce intrauterine infections in the fetus. The worms take ~1 month after larval ingestion to reach maturity in the lungs, and it is then that clinical signs are most common because of the development of parasitic bronchitis. Adult worms persist for ~3 months. The life cycle of D. viviparus in cattle is a little shorter than that of D. filaria but is otherwise comparable. Adult worms can continue to lay eggs for 6 months, but most are expelled within 3 months. Dictyocaulus arnfieldi is mostly a patent infection in donkeys, but the worms can develop to maturity if horses or ponies are infected as young foals. The lesions produced by Dictyocaulus spp. depend on the susceptibility of the host and on the number of invading larvae. Cattle and sheep are most susceptible to infection when they are first exposed to contaminated pastures, and therefore severe lesions and the clinical disease they cause are most commonly seen in animals < 1 year of age where infection is endemic. Minor reaction occurs along the path way of larval migration, but the important lesions are found in the lungs. The lesions in the pulmonary tissues can be considered in two main phases, between the time when the larvae reach the lung and the worms reach matu rity (prepatent phase), and when the mature parasites are located in the bronchi (patent phase). In natural infections, these two phases overlap and are associated with hyper plastic lymphadenitis in the related nodes. The larvae ar rive in the lungs from ~5 to 7 days after ingestion. Where they emerge from pulmonary capillaries, they cause mi croscopic foci of necrosis or rupture of alveolar walls with an infiltrate of eosinophils, neutrophils, macrophages, and a few giant cells. With more severe larval invasion, these foci become more numerous and larger. Mononuclear cells thicken the alveolar walls, and there is focal exudation of fibrin into alveoli together with the inflammatory cells. Eosinophils are a prominent feature of the reaction. Vari ous degrees of hyperplasia of alveolar type II epithelial cells also occur. The larvae, some of them dead, can be found in the alveoli. When the number of larvae is large, the foci of acute interstitial pneumonia may be visible grossly as small lobular or sublobular areas which are slightly depressed, purplish, and distributed widely throughout the lungs. By about the tenth day, many of the larvae have gained the terminal bronchioles. Frothy fluid is present in the bronchi and, in very heavy infestations, there is often edema and emphysema of the interlobular septa. Eosino phils invade the septal tissues in large numbers and follow the larvae into the bronchioles. Most of the bronchioles contain plugs of exudate composed largely of eosinophils. Neutrophils, lymphocytes, and macrophages are present in smaller numbers in both the lumina and walls of the bronchioles. Death can occur at this time in very heavy infections. The early bronchiolar epithelial response is of degeneration and sloughing, but subsequently hyperplasia and metaplasia also occur. As the worms reach maturity, beginning ~4 weeks after infection, emphasis shifts to the bronchial lesion, and some resolution of the initial alveolar lesion occurs. The mature, threadlike worms in the bron chi and perhaps caudal trachea are easy to see in moderate to severe infections. Although the early development of lungworms can take place in all lobes, dorsocaudal and ventrocaudal regions are most affected. Mature worms are most numerous in the dorsocaudal bronchi of the caudal lobes, and in light infections may be found only in these regions. The worms are usually bathed in mucinous, foamy bronchial exudate. In some cases, there may be no superficial indications of the worms except for failure of the lungs to collapse. It is usual for gross lesions to be present in patent infections, however. Typically, there are large wedge-shaped areas of dark red or grayish consoli dated lung at the posterior border of the caudal lobes ( Fig. 6 .92). These consolidated areas have firm consistency and are slightly depressed below the surface of surrounding inflated or sometimes hyperinflated lung. Patchy consoli dation may also occur in other dorsocaudal regions and, with severe involvement, can be found on cut section in much of the pulmonary tissue surrounding larger bronchi. There is no pleuritis. The adult worms cause chronic catarrhal and eosino philic bronchitis and bronchiolitis. The epithelium of bron chi is thickened and hyperplastic. Increase in the propor tion of mucus-producing cells is a prominent feature. Elsewhere there may be ulceration or occasionally squa mous metaplasia. The epithelium and lamina propria are infiltrated by mixed leukocytes, with a preponderance of eosinophils, and there is hyperplastic bronchus-associated lymphoid tissue. The lumina contain adult w o r m s , plugs of m u c u s , numerous leukocytes, eggs, and larvae. C o m p o nents of the verminous bronchiolitis are similar, but there is also a tendency for obliterative bronchiolitis to occur. The hyperplasia of bronchiolar smooth muscle, increase in peribronchiolar fibrous tissue, and proliferation of lymphoid cells in bronchiolar walls also a s s u m e relatively greater prominence (Fig. 6 .93). T h e parenchymal lesions which a c c o m p a n y the bron chitis caused by the adult w o r m s are c o m p o u n d e d mostly of atelectasis secondary to the bronchiolitis and of pneu monia which is provoked by aspirated eggs and newly hatched larvae. It is complicated in some cases by bacte ria. Granulomas are frequently present around fragments of discarded cuticle, eggs, or dead larvae. The alveoli, which are partially collapsed, contain many giant cells and vacuolated macrophages. Their walls are thickened by cellular infiltration and slight fibroplasia and may be more or less completely covered by low cuboidal epithelium. Toward the end of the patent period, the alveolar reaction subsides and resolution begins, especially in the periphery of the lobules. Around the bronchioles, however, many of the alveoli are permanently obliterated by the organizing peribronchiolar reaction. The lymphoid nodules which de velop in the walls of bronchi and bronchioles are not generally so conspicuous as those occurring in chronic mycoplasmal infection. In resolving lesions, however, when w o r m s are no longer present, there is no clear mor- phologic distinction. A useful clue to separate these two major causes of lymphoid proliferation is that the airways mainly affected by mycoplasma are in cranioventral re gions, whereas those affected by lungworms in ruminants are dorsocaudal. Two features of the lesions caused by D. viviparus in cattle deserve special mention. The first is that extremely severe damage is associated with pulmonary edema and interstitial emphysema. The interstitial emphysema is sec ondary to severe pulmonary dysfunction and forced expir atory efforts in lungs with nonuniform lobular emptying of air during expiration together with bronchiolar obstruction and probably bronchospasm. In fatal cases, interstitial emphysema may be the most obvious gross finding and therefore lead to confusion with the interstitial emphy sema accompanying acute interstitial pneumonia of toxic origin. This is particularly likely when the pulmonary dam age is caused by massive invasion of larvae, and mature worms are not yet present for gross detection. Micro scopic detection of larvae and immature worms usually provides the diagnosis. The second feature is the presence in the lungs of older animals of scattered nodules 2-4 mm in diameter. The nodules are homogeneously gray, or gray with a greenish center. The gray tissue represents dense accumulations of lymphocytes and possibly plasma cells, and the greenish center is the degenerating larval or adult worm surrounded by eosinophils, macrophages, and giant cells. The nodules are an indication of reinfection of an immune animal, vaccination with x-irradiated larvae or anthelmintic treatment. Dictyocaulus arnfieldi is a lungworm mainly of donkeys and survives for long periods without causing undue clini cal signs. The gross lesions are scattered discrete foci of hyperinflated pulmonary parenchyma, mostly in caudal lobes. In the center of the lesions are small bronchi packed with coiled adult worms. Histologically, the worms are associated with a chronic catarrhal bronchitis. Goblet cell hyperplasia and extensive lymphoid cell infiltration of the walls are the main features. Adult worms cause relatively little luminal response, whereas first-stage larvae stimulate an intense mucopurulent reaction. There is also a chronic catarrhal and eosinophilic bronchiolitis of bronchioles dis tal to affected bronchi. Alveoli are reported to be hyperin flated, but it is uncertain to what extent this reflects true in vivo hyperinflation as opposed to air trapping and failure to collapse when the lungs are examined after death. Infec tion of adult horses with D. arnfieldi usually results in failure of the worm to develop to sexual maturity. The lesions are similar to those described for the donkey and are occasionally associated with chronic coughing and abnormal sounds on auscultation. The most common and important member of the genus is P. rufescens. Whereas Dictyocaulus species have direct life cycles, Protostrongylus rufescens and the other worms to be discussed have indirect life cycles. Protostrongylus rufescens is parasitic in sheep, goats, and deer. The adults are smaller than D. filaria, being from 16 to 35 mm in length. They are reddish and mainly inhabit the bronchioles. The lesions which accompany the infec tion are similar to those produced by D. filaria but are less numerous, lobular in size, and located chiefly in the periphery of the caudal lobes. The lesions are not readily distinguished grossly from those produced by Muellerius capillaris. The first-stage larvae are passed in the feces and enter the intermediate hosts, which are various genera of land snails, by boring through the foot. Two molts occur in the snail and the infective third-stage larvae develop in 2 weeks. Sheep and goats obtain the parasites by eating the snails. linearis is a species comparable to P. rufescens. It is common in western Europe and probably elsewhere, but is confused with other small lungworms of sheep. Cystocaulus ocreatus (C. nigrescens) is little studied, but it is stated to resemble Muellerius spp. in the details of life cycle and pathogenicity. Muellerius capillaris, which is parasitic in sheep and goats, is the most common and ubiquitous of the lung worms. The species is sometimes referred to as the nodu lar lungworm because the adults live in the alveolar paren chyma and almost always provoke an enveloping granulomatous response. The adult worms are found on rare occasions in the bronchioles. There is usually no clinical evidence of respiratory disease in sheep even when the number of nodules is large. Sometimes they become confluent. Diminished weight gains have been recorded in heavily infested lambs, and it has been postulated that the worms predispose to pulmonary bacterial and viral infections. The eggs are laid and hatch in the nodules. This requires that the sexes be paired in the nodules. Often this does not occur, and therefore the examination of feces for lar vae may give no indication of the degree of pulmonary parasitism. The first-stage larvae break out of tissues into the airways and are eventually passed with feces or mucus. The intermediate hosts are various slugs and snails. The infective stage is reached after two molts in the intermedi ate host, and the life cycle is completed when sheep and goats swallow the intermediate hosts. The larvae migrate to the lungs, presumably via the lymphatic pathway, and break out into the alveoli. As a consequence of this type of life cycle, infections are acquired gradually, and large worm burdens are seldom observed in animals <6 months of age. On the other hand, heavy infections are not com mon in old sheep and goats. The nodules produced by these parasites represent le sions of multifocal interstitial pneumonia. They may occur anywhere in the lung, but most of them are located beneath the pleura of dorsal regions of the caudal lobes (Figs. 6.94, 6.95) so that the severity of infestation can be assessed quite accurately by superficial inspection. Why there should be this predilection for the subpleural tissues is not reproduction in a resistant animal. T h e cellular reaction reflects the stage of the parasite present and resistance of the host. T h e earliest form of nodule is produced by the fourth-stage larvae w h e n they enter the lungs, and usually consists of little m o r e than groups of alveoli which are mechanically disrupted. T h e r e may be little cellular reac tion to these larvae of the first infestation, but an eosino philic infiltration may a c c o m p a n y later o n e s . T h e adult w o r m s also disrupt the alveolar septa. T h e eggs and firststage larvae lie in the alveolar spaces and p r o v o k e little inflammatory response, although there is a mild fibrous thickening of the alveolar septa with infiltrated lympho cytes in the septa and around the blood vessels and bron chioles. In older animals, presumably as a result of devel oping resistance, the cellular reaction is m o r e marked, especially to the first-stage larvae and the adults ( Fig. 6 .96). There are intense foci of infiltrated eosinophils around the larvae; the alveolar spaces b e c o m e crowded with macrophages and some giant cells, and the distorted alveolar walls are thickened by fibrous tissue. T h e larvae which escape into small bronchioles are enclosed in plugs of m u c u s and cellular debris. T h e epithelium of the bron chioles is hyperplastic, and the muscularis, m u c h thick ened. W h e n the larvae leave the nodules, the cellular reaction subsides, but the thickening of the alveolar septa persists b e c a u s e of patchy or diffuse fibromuscular hyper plasia. An intense reaction also occurs to the adult w o r m s . There are large n u m b e r s of eosinophils, a n a r r o w zone of epithelioid and giant cells, and peripheral fibroblastic tissue. The cellular debris b e c o m e s calcified, particularly when the w o r m s die, and these calcified nodules persist indefinitely as spherical m a s s e s of calcium salts sur rounded by a fibrous capsule. N o t all the calcification, however, occurs about adult w o r m s . S o m e is precipitated S h e e p . Adults lie in bronchioles and alveolar ducts and are associated with muscular hyperplasia. Eggs and first-stage larvae have p r o v o k e d a chronic interstitial p n e u m o n i a . in the inspissated mucus which collects in obstructed bron chial glands, and some in mucus and debris which accumu late in the bronchioles. An extensive diffuse interstitial pneumonia has been associated with Muellerius infection in goats, but in such cases it is often impossible to assess the possible role of concurrent infection with Mycoplasma spp. or the caprine arthritis-encephalomyelitis virus. There are three important species of the genus, M. elongatus (apri), M. pudendotectus, and M. salmi, and they are all parasitic in the bronchi and bronchioles of pigs. They are believed to be responsible for the occasional transmis sion of the virus of swine influenza. The adult w o r m s are white, threadlike, and from 14 to 60 m m in length, depending on species and sex. In heavy infections, which are mostly in young pigs, they may be found in all lobes of the lung. W h e n there are fewer w o r m s , particularly as occurs in older animals, the w o r m s may be restricted to airways along the ventrocaudal borders of the caudal lobes. T h e s e apparently are areas of predilection or resid ual infestation. T h e eggs are laid in the bronchi, and a few of them hatch there, but most hatch after passing to the exterior in the feces. The first-stage larvae are inactive and are capable of prolonged survival in moist conditions. Their further development depends on ingestion by earth w o r m s , which are the intermediate hosts. T h e larvae de velop to the third, infective stage in -10 days and then remain quiescent unless the e a r t h w o r m is eaten by a pig. The larvae may survive for as long as 18 months in the e a r t h w o r m s and, by that time, some thousands of them may be accumulated by a single w o r m without doing it any harm. Migration within the pig is through the lymphat ics from the intestine to the lungs. Some larvae pass through the liver and produce a focal hepatitis for which the larvae of Ascaris suum are, however, more usually responsible. E v e n with heavy adult infestations, gross lesions are inconspicuous and are seldom as extensive as those pro duced in ruminants by Dictyocaulus spp. In light infec tions, the w o r m s live in the smallest airways, and on superficial examination of the lungs, the presence of the parasites frequently is indicated only by grayish nodules 1-3 m m in diameter and by hyperinflated lobules along the ventrocaudal margins of the caudal lobes ( Fig. 6.97) . Histologically, the lesions are basically the same as those produced by Dictyocaulus spp. T h e initial lesions are multiple foci of intense accumulations of eosinophils surrounding larvae in alveoli. Subsequently, when repro duction is active, a granulomatous alveolar response oc curs to the eggs and larvae. T h e prepatent period for Metastrongylus spp. is -25 d a y s , after which the rate of egg production rapidly reaches a peak and then subsides to a low level. At this later stage, the adults persist mainly in the bronchioles and small bronchi and provoke a chronic This parasite of cats appears to have very limited distribution since it has been recorded mainly from Sri L a n k a . In that its final habitat is the walls of large airways, it resembles Filaroides osleri of dogs (see Parasitic Diseases of the L a r y n x and Trachea, Section I V , E of this chapter). It does not form nodules, however, but causes sinuous thickenings of the bronchial walls. W h e n the infective larvae invade the bronchial walls, they provoke only slight cellular re sponse. T h e adults develop in cystic spaces which are probably dilated lymphatics and which cause displace ment of the surrounding tissues. T h e w o r m s are vivipa rous, and the larvae escape to the bronchiolar lumen where they provoke a catarrhal bronchitis. The adults remain alive for ~1 year, and possibly for much longer. W h e n they die, they provoke an intense infiltration of neutrophils and may calcify. There is residual fibrosis in the bronchial wall. T h e larvae are passed in the feces and develop to the infective stage in a variety of molluscs. They can probably survive for a long time in the intermediate hosts, and the capacity for survival and dissemination is increased by the fortuitous use of transport hosts, such as mice and chickens. There are other species of lungworms in cats which are probably similar to F. rostratus, but virtually the only details concerning them are taxonomic. Vogeloides massinoi (Osleroides massino) lives in the bronchial wall. Vogel oides ramanujacharii occurs in cats in India. Troglostrongylus brevior occurs in cats in the Middle East and is k n o w n to use snails as intermediate hosts. b. Filaroides hirthi T w o similar filarid w o r m s have been recorded as inhabiting the pulmonary p a r e n c h y m a of dogs, Filaroides hirthi and F. milksi. Original reports were of F. milksi, but more recent descriptions have been of a w o r m that, although it closely resembles F. milksi, has been assigned to a separate species, F. hirthi. This description summarizes the current knowledge concerning F. hirthi, leaving the taxonomic and pathogenic uncertainties sur rounding F. milksi for future clarification. Adult F. hirthi, which are 6 -1 0 m m in length, live in alveoli and respiratory bronchioles. Clinical signs of infec tion are rare, and evidence of the w o r m s ' presence is usually limited to the incidental finding at necropsy of tan, green, or gray subpleural nodules 1-5 m m in diameter. T h e nodules are widely scattered over subpleural regions, the n u m b e r s varying with the severity of infection. Histo logically, there is little response to living adult w o r m s (Fig. 6.98A ), but a severe granulomatous response featuring many eosinophils occurs around dead or degenerating w o r m s (Fig. 6.98B ). L a r v a e p r o v o k e a m o r e acute neutro philic reaction. Foci of granulomatous interstitial p n e u m o nia can often be found in which w o r m r e m n a n t s may no longer be identified. Killing the w o r m s with anthelmintic is particularly prone to cause the severe r e s p o n s e . Filaroides hirthi has a direct life cycle, like that of F. osleri. Infective first-stage larvae are passed in the feces and usually the infection is passed from d a m to p u p s . Infection is mostly reported to occur in colonies of beagles reared for experimental studies in which lungs are rou tinely given thorough examinations. T h e incidence of F. hirthi in the canine population at large is not k n o w n . There are a few single-case reports of dogs with lethal infection, however, so it is probably more widespread than realized. larvae. This type of hyperinfection and probable autoinfection seems to occur in dogs with drug-or diseaseinduced immunosuppression. abstrusus is a widespread lungworm of the cat. The adults live in the respiratory bronchioles and alveolar ducts. T h e eggs form nodular deposits in alveoli and hatch to give first-stage larvae which reach the airways and are eventually passed in the feces. The indirect life cycle involves various snails and slugs as intermediate hosts and birds, rodents, frogs, and lizards as transport hosts. The life cycle can be completed if a cat eats either an intermediate host or a transport host. T h e extent to which infective larvae reach the lungs in the blood or by migration through peritoneal and pleural cavities is not certain. W o r m s reach maturity -5-6 w e e k s after ingestion of the third-stage larvae. T h e pulmonary lesions are quite characteristic, usually being in the form of nodules 1-10 m m in diameter, which represent nests of eggs and larvae (Fig. 6.99A ). These nodules, which are yellowish and firm, are scattered throughout the paren c h y m a but are more c o m m o n in the peripheral parts of the lungs and usually project from the surface of the deflated lung. A small amount of creamy exudate containing nu merous eggs and larvae can be expressed from the cut surface of incised nodules. Severe, confluent consolida tion caused by heavy infections of A. abstrusus can pro duce clinical signs of chronic coughing and perhaps pro gressive loss of weight. Occasionally death occurs when there is secondary infection. Microscopically, the eggs and larvae are visible in the alveolar spaces with some disruption of alveolar septa. They are surrounded by dense collections of mixed mono nuclear cells with some giant cells. T h e latter are more numerous around dead or disintegrating larvae. Eosino phils and neutrophils are mostly a feature of early infec tion. L y m p h o c y t i c nodules form around vessels and air ways ( Fig. 6 .99B). Necrosis and calcification seldom occur. In older lesions from which eggs and larvae have disappeared, the alveoli remain epithelialized for a time, and the septa are persistently thickened by fibrous tissue and smooth muscle. This fibromuscular hyperplasia is of ten focal and barely appreciable, but in some cases is diffuse and rigid enough to produce a rubbery consistency. H y p e r t r o p h y and hyperplasia of the smooth muscle in the walls of the bronchioles and alveolar ducts occurs early in the course of the infestation and is progressive, but is not so well developed as is the increase in smooth muscle in the media of small pulmonary arteries and arteri oles. T h e presence of one or m o r e of adult w o r m s , eggs, or larvae in the bronchioles is associated with a chronic catarrhal and eosinophilic bronchiolitis similar to that caused by Dictyocaulus spp. in ruminants. A prominent c o m p o n e n t is the hyperplasia of submucosal glands, which are a usual but generally inconspicuous feature of small airways of cats. The most active phase of the parasite is 6 -1 2 w e e k s after infection, and this is associated with the peak pulmo nary response. Adult w o r m s can persist as long as 9 m o n t h s . Although the granulomatous alveolitis and ca tarrhal bronchiolitis gradually regress, the hypertrophy and hyperplasia of smooth muscle in arteries, bronchioles, and alveolar ducts persist. The association between Aleurostrongylus infection and the dramatic muscular thick ening of the walls of pulmonary arteries has been the subject of controversy. The evidence indicates that hyper plasia and hypertrophy of smooth muscle in pulmonary arteries is a c o m m o n finding in cats of all ages for reasons which are obscure. vasorum is a parasite of the pulmonary arteries and the right ventricle of dogs and foxes. The adult w o r m s are 15-25 m m in length. They cause a proliferative endoarteritis, but the m o r e severe damage is caused by eggs which lodge in arterioles and capillaries. They and the larvae which hatch from t h e m p r o v o k e chronic in flammation in which fibroplasia predominates (Fig. 6.100 ). The larvae break into the alveoli, migrate in the respiratory passages, and are eliminated in the feces. Various snails and slugs serve as intermediate hosts. In the acute form of the disease, with heavy infestations of larvae in alveoli, the fatal o u t c o m e is in large part attributable to pulmonary e d e m a and pneumonia. T h e chronic expression of the disease is largely one of conges tive cardiac failure, secondary to obliterative and throm botic vasculitis, organizing infarcts, and progressive gran ulomatous response to eggs and larvae. Inflammation and scarring of alveolar walls leads to distortion and enlarge ment of remaining airspaces, which can result in a foamrubber a p p e a r a n c e . This is sometimes referred to as em p h y s e m a but is m o r e a form of honeycombing than emphy sema in the conventional sense. Because of their similar location, there is overlap in the types of abnormalities caused by A. vasorum and Dirofilaria immitis (see T h e Cardiovascular System, Volume 3, Chapter 1). Of the t r e m a t o d e s , the only genus which has its final habitat in the lungs is Paragonimus. Several species have been described for the genus. T h e important ones are P. westermanii (the oriental lung fluke) in the F a r E a s t and P. kellicotti in America. F o r the latter species, mink and other fish-eating carnivores are regarded as being the usual hosts. The fluke is not selective in its final hosts, h o w e v e r , and has also been found in h u m a n s , swine, and ruminants. W h e n the crayfish is eaten by the final host, the metacercariae are liberated in the intestine and migrate across the peritoneal and pleural cavities to the lungs. Their passage through the pleura is m a r k e d by multiple small hemor rhages and foci of eosinophilic and fibrinous pleuritis, which heal as small umbilicate scars ( Fig. 6.101 A) . T h e adult flukes are ovoid, reddish b r o w n , and as long as 7 m m . T h e y are found, usually in pairs, in inflammatory cysts in the pulmonary p a r e n c h y m a (Fig. 6 .10IB) and occasionally in the bronchi. T h e cysts are m o r e c o m m o n in the caudal lobes, particularly the right side. T h e y are spherical, -10-15 m m in diameter, and dark red-brown. Their size and the fact that surrounding lung is frequently atelectatic give them a distinctive a p p e a r a n c e . T h e cysts frequently c o m m u n i c a t e with bronchioles. R u p t u r e of cysts on the pleural surface and resulting p n e u m o t h o r a x is a rare complication. T h e cysts b e c o m e progressively surrounded by fibrous tissue and partially lined by bron chiolar epithelium. Eosinophilic, granulomatous p n e u m o nia develops around degenerating eggs adjacent to the cysts containing flukes (Fig. 6.101C ). There is also a chronic catarrhal, eosinophilic bronchiolitis with smooth Primary pulmonary tumors are rare in domestic ani mals. Metastatic lesions are relatively common, however, because of the vulnerability of the lungs to tumor emboli. In view of the much greater frequency of metastatic tu mors, and because their gross and microscopic patterns can sometimes be difficult or impossible to distinguish from those of a primary tumor, an important part of the diagnosis of a primary lung tumor is thorough examination to exclude possible primary sites elsewhere in the body. The rarity of primary pulmonary tumors in domestic animals is in contrast to their frequency in humans. This can probably be accounted for by the lack of carcinogenic stimuli from cigarette smoke or occupationally related chemicals in animals, and by the absence of large numbers of aged individuals. Primary tumors are encountered more often in dogs and cats than in other species. Reported incidence for the dog is -4-5 per 100,000 animals in the population per year. The frequency based on postmortem examination varies with the population sampled, but as many as 1% of dogs necropsied have been recorded as having primary tumors of the lung. Comparable statistics for the cat indicate a frequency of approximately half that of the dog. Neoplasms can arise from any of the tissues present in the lung, but with few exceptions, the significant ones arise from pulmonary epithelium. Classification of epithe lial tumors of the lung is complicated by the recognition that what were once looked on as specific cell types can undergo metaplasia (transdifferentiation) in both inflam matory and neoplastic lesions. The histologic appearance of cells in a tumor is therefore not certain evidence of histogenetic origin. Thus there can be no absolutely rigid histogenetic classification. With this in mind, the following classification provides a useful working basis for categori zation: This classification serves as a framework for categoriz ing primary epithelial lung tumors across a range of spe cies. Modifications are sometimes necessary, especially in domestic animals in which tumors are often well advanced when examined. In dogs and cats, for instance, clinically significant adenocarcinomas have frequently undergone sufficient phenotypic alterations that it is no longer possi ble to classify them as either bronchogenic (arising from major airways) or bronchioloalveolar (arising from small airways or alveolar parenchyma). T h e tumors usually de velop in more peripheral lung regions, which is a feature of bronchioloalveolar tumors. Their distorted, invasive, papillary, and acinar pattern, however, is distinct from the orderly alveolar pattern seen in the typical bronchioloal veolar tumors which are usually found incidentally at nec ropsy. Most pulmonary tumors in domestic animals are adeno carcinomas of bronchogenic or bronchioloalveolar origin. called oat cell carcinoma has ill-defined clusters of small round or oval cells resembling lymphocytes because of their hyperchromatic nuclei and small amounts of cyto plasm. In h u m a n s , the small-cell anaplastic tumors appear to arise from solitary neuroendocrine cells or formed neu roepithelial bodies, as do carcinoids. They are therefore particularly likely to be associated with paraneoplastic s y n d r o m e s caused by secretion of polypeptide h o r m o n e s [e.g., adrenocorticotropic hormone ( A C T H ) , antidiuretic h o r m o n e ( A D H ) , calcitonin] or biogenic amines (e.g., se rotonin). Paraneoplastic syndromes accompanying pri mary pulmonary tumors do not appear to have been identi fied in animals. In general, squamous cell, a d e n o s q u a m o u s , and undif ferentiated carcinomas are more malignant than adenocar cinomas, but all have a strong predilection for spread through intrapulmonary lymphatics. Dissemination through airways to alveoli also o c c u r s . Metastasis can also take place to thoracic lymph n o d e s , abdominal n o d e s , and kidneys, liver, brain, heart, and b o n e s . B r o n c h i o l o a l v e o l a r t u m o r s originate from either secre tory bronchiolar (Clara) cells or alveolar type II epithelial cells. Because of the close phenotypic relationship be tween these t w o cell t y p e s , it is not surprising that histo logic and ultrastructural examination sometimes reveals both cell types in the same tumor. Bronchioloalveolar tumors are found most often in dogs, occasionally as an incidental finding at necropsy. They compose over half the tumors found in some surveys of primary pulmonary tumors of dogs. Typically, they occur as solitary nodules in the periphery of the lung (Fig. 6.103 L e s s frequently, there is a rapidly spreading diffuse or disseminated multifocal type ( Fig. 6.104) . Histologically, the special feature of bronchioloalveolar tumors is the regular alveolar pattern and preservation of pulmonary architecture (Fig. 6.105) . T h e preexisting alveolar stroma b e c o m e s lined by cuboidal or columnar epithelium, often with small papillary projections into the alveolar lumina. As with many t u m o r s , there is difficulty in clearly separat ing benign a n d malignant bronchioloalveolar t u m o r s . Be cause there seems to be potential for eventual develop ment of malignant behavior, there is often n o attempt to categorize them as a d e n o m a s or carcinomas, b u t to regard them all as low-grade carcinomas unless there is clear evidence of highly aggressive behavior. There a r e two major pitfalls in the diagnosis of bronchio loalveolar tumors. O n e is that t h e hyperplasia of bronchio lar and alveolar type II epithelial cells, which is frequently caused by chronic inflammation of the bronchioloalveolar junction, can be mistaken for neoplastic proliferation. T h e other is that rapidly invasive spread of neoplastic cells from either a bronchogenic a d e n o c a r c i n o m a or a metasta sis from elsewhere in the body can sometimes mimic the regular pattern of a bronchioloalveolar carcinoma. Exclu sion of alternative primary sites is therefore an integral part of the diagnosis of bronchioloalveolar t u m o r s , espe cially the multinodular or diffuse varieties. T h e difficulty of classifying a d v a n c e d adenocarcinomas as bronchogenic or bronchioloalveolar w a s referred to earlier. In such cases, t h e tumors should be classified on the basis of morphologic pattern as adenocarcinomas without attempt to specify the site of origin. As an indica tion of how this works in practice, a review of 22 clinically detected pulmonary carcinomas in dogs revealed 13 adenocarcinomas (8 predominantly papillary, 5 mucinsecreting), 5 a d e n o s q u a m o u s carcinomas, 2 bronchioloal veolar adenocarcinomas, 1 bronchioloalveolar a d e n o m a and 1 large-cell undifferentiated carcinoma. A prominent feature of most adenocarcinomas w a s presence of tall columnar neoplastic cells. Five of the 13 adenocarcinomas each had a few small foci where squamous phenotypic expression occurred, even though this w a s not prominent enough to warrant a diagnosis of a d e n o s q u a m o u s car cinoma. Pulmonary adenomatosis of sheep is an infectious form of bronchioloalveolar tumor with the behavioral charac teristics of a low-grade carcinoma. F o r this reason, it is now referred to as pulmonary carcinomatosis. T h e cause is reasonably established as a type B / D retrovirus, but reproduction by purified, cloned virus has not yet been reported. T h e term jaagsiekte appeared in original descrip tions of the disease from South Africa, jaagsiekte being the Afrikaans word for driving sickness. Pulmonary carcinomatosis occurs in many sheep-rai sing areas of the world. It is most important under condi tions of intensive management, which favor aerosol trans mission of the causative virus. T h e disease is less c o m m o n where populations of sheep are dispersed, and it can es cape detection for a time, as happened in the United States. T h e condition belongs in the category of slow virus diseases. Lesions develop slowly with the result that the disease has an insidious onset. Clinical signs are not appar ent for several months to several years and therefore are seen only in adult sheep. Early signs of the disease are coughing and exercise intolerance. L a t e r there are also crackles and wheezes associated with the production of abundant watery e x u d a t e . T h e exudate is discharged from the n o s e , especially w h e n t h e head is lowered, and is an important diagnostic clinical feature. Early gross lesions a r e scattered, small gray-white nod ules, sometimes with surrounding hyperinflated zones ( Fig. 6.106) . Sheep with clinical signs have extensive nod ular a n d confluent firm gray lesions affecting m u c h of the pulmonary tissue. T h e lungs a r e heavy and fail to collapse. T h e cut surface is moist a n d reveals the basic nodularity of the lesion, even in regions w h e r e they coalesce. T h e centers of a d v a n c e d lesions lose their friability a n d be come fibrotic. T h e r e c a n b e coexisting b r o n c h o p n e u m o nia, verminous p n e u m o n i a , chronic progressive p n e u m o nia (maedi) or combinations of these. This h a s been a source of considerable confusion in the past, particularly when the viruses causing chronic progressive p n e u m o n i a and pulmonary carcinomatosis were both present in the same flock. T h e lesions of chronic progressive p n e u m o n i a and pulmonary carcinomatosis are quite different histolog ically. The characteristic histologic lesion of pulmonary carci nomatosis consists of multiple proliferative foci of cuboi dal or columnar cells which line alveoli a n d form papillary projections into their lumina ( Fig. 6.107A,B) . Continued proliferation obscures this pattern, a n d fibroplasia often occurs in more disorganized a n d degenerative regions. Early a n d uncomplicated proliferative lesions a r e not asso ciated with significant accumulations of inflammatory S h e e p . cells, although there is usually some aggregation of macro phages in alveolar lumina. T h e papillary proliferation of cuboidal o r columnar epithelium in the absence of signifi cant interstitial inflammation is in marked contrast to the lymphofollicular interstitial pneumonia of chronic pro gressive pneumonia (maedi) in which alveolar epithelial hyperplasia is an inconstant and relatively minor feature. The papillary proliferations involve both alveoli and bronchioles in many nodules. Ultrastructurally the cuboi dal cells usually have lamellar bodies characteristic of alveolar type II cells, whereas the columnar cells have secretory granules and glycogen compatible with origin from secretory bronchiolar epithelial (Clara) cells. T h e potentially carcinomatous nature of this infectious bron chioloalveolar tumor is confirmed by the occasional find ing of metastatic foci in t h e bronchial or mediastinal lymph nodes. Carcinoids have been reported to occur in lungs of ani mals but have not yet been adequately d o c u m e n t e d . Carci noids in h u m a n s originate from neuroendocrine c o m p o nents of major airways. They have an endocrine pattern of nests or ribbons of uniform cells separated by wellvascularized stroma. T h e cells are round to polygonal. They have relatively small nuclei and abundant, pale, acidophilic cytoplasm. Ultrastructurally their neuroendo crine derivation is revealed by large n u m b e r s of small, d e n s e , secretory granules. Immunocytochemical labeling reveals the presence of functional markers such as gastrin- releasing peptide, neuron-specific enolase, chromogranin, and serotonin. It is probable that carcinoids occur in ani mals, albeit extremely rarely. These are tumors which were originally thought to be derived from myoblasts b u t are n o w believed to originate from a fibroblastlike cell which is related to the progenitor of S c h w a n n cells. Although granular cell tumors can occur in various tissues, there is a difference in predilection sites among species. All granular cell tumors found to date in the lungs of animals have been in horses, a n d in fact this is t h e most frequently reported primary pulmonary tumor of the horse in recent years. T h e tumors have occurred in older horses a n d either were associated with coughing and pulmonary insufficiency or were found as incidental lesions at slaughter. G r o s s lesions are usually multiple discrete or semiconfluent nodules which have a tendency to be associated with major bronchi and to cause obstruc tion by bulging into their lumina. T h e lesions are limited to o n e lung in most instances, more often t h e right o n e . The main histologic feature of the tumor is lobular aggrega tion of large, round to polyhedral cells with abundant acidophilic granular cytoplasm ( Fig. 6.108A,B) . T h e lob ules a r e surrounded and dissected by fibrovascular stroma. T h e cytoplasmic granules in the tumor cells are Lymphomatoid granulomatosis refers to a rare condition of dogs in which there is extensive infiltration of one or more lobes of the lung by accumulations of mixed atypical lymphoreticular cells. The cells have a pronounced ten dency to invade the walls of vessels ( Fig. 6.109A ) and airways. The few reported cases have been in young dogs. Cells composing the neoplasm are of various types. Large histiocytic and plasmacytoid forms predominate ( Fig. 6 .109B), but binucleate cells, eosinophils, lymphocytes, and plasma cells are often also present. A network of fibrous stroma runs throughout the tumor. Mitotic figures are plentiful. The exact nature of the condition is not k n o w n , but evidence is emerging that lymphomatoid gran ulomatosis in dogs is a pleocellular form of T-cell lymphoma. It is important, however, not to use this diag nosis for generally unclassifiable tumors of the lung or for more usual forms of l y m p h o m a in which there is extensive invasion of perivascular and peribronchial regions of the lung by the neoplastic lymphoid cells. M a n y types of malignant tumors can metastasize to the lungs. M a m m a r y carcinomas are among the most frequent in dogs and cats (Fig. 6 .11 OA), uterine adenocarcinomas, in cattle ( Fig. 6. HOB T h e most easily recognizable pattern of metastatic tumors is of multiple nodules scattered throughout the pulmonary p a r e n c h y m a , without great variation in size range ( Fig. 6.110A ). T h e p r e s e n c e of a few gross lesions, especially if there is great discrepancy in size, requires careful analysis of all gross and microscopic findings to provide the best chance of making an unequivocal distinc tion b e t w e e n metastatic foci and primary pulmonary tu mor. T h e probability of neoplastic foci in the lungs being metastases is increased if the animal is a young one. Some times, microscopic examination is needed to differentiate neoplastic nodules and multifocal granulomas. Microscopically, metastatic t u m o r s usually resemble the primary lesions, although they may be either better or less differentiated. Presence of t u m o r cells within arteries is an important indicator of metastatic origin, although this can be difficult to identify in some instances. This is particularly so where scirrhous response around invaded lymphatics gives them a superficial resemblance to thickwalled blood vessels. In some cases w h e r e there is fulminating metastasis, there is n o gross evidence of solid neoplastic infiltrations, merely tan discoloration of the lung and slightly increased firmness. Microscopically, h o w e v e r , widespread vascular embolization by anaplastic cells is seen (Fig. 6 .110C) with early invasion of alveoli and lymphatics. Regardless of source or initial pattern of pulmonary involvement, highly malignant tumors have a predilection for widespread dis semination through intrapulmonary lymphatics. Aetiology of jaagsiekte: Transmission by m e a n s of subcellular fractions and evidence for involvment of a retrovirus. Onders tepoort J Vet Res 47: 275-280, 1980. Pleural abnormalities are usually secondary to lesions in tissues or organs forming the pleural cavity, especially the lung, or are part of more generalized disorders. Congenital anomalies of the pleura and mediastinum are of little significance unless associated with a condition such as congenital diaphragmatic hernia. Congenital cysts may occasionally be found in the anterior mediastinum, mostly of brachycephalic dogs, and are presumed to be vestiges of the branchial p o u c h e s . Usually they are de tected microscopically as cystic spaces lined by a single layer of cuboidal epithelium, often in close association with thymic tissues. Cysts of ~1 cm or more in diameter can be seen grossly as thin-walled structures containing clear, light yellow fluid. Air-or fluid-filled cysts in the caudal mediastinum are m o r e likely to be of bronchogenic origin and can be large enough to cause pulmonary insuf ficiency. Degenerative changes in the pleura occur in some cases of uremia in dogs (see The Urinary System, Chapter 5 of this volume). They are most evident in parietal pleura of the intercostal spaces, particularly the second, third, and fourth. Mineralization centered on degenerate subpleural elastin and collagen fibers is visible as white horizontal striations. Pneumothorax refers to the presence of air or gas in the pleural cavities. Air in the cavities allows the lungs to collapse to a degree proportional to the amount of air present. A normal subatmospheric pressure can be as sumed to have been present at necropsy if the diaphragm m o v e s caudally when the thorax is pierced and air is al lowed to enter. In small animals, p n e u m o t h o r a x can be detected by opening the chest under water and observing the escape of air bubbles. Pneumothorax can be spontaneous or traumatic. Spon taneous pneumothorax is rare. It may complicate any pul monary disease which leads to rupture of pulmonary pa r e n c h y m a at the pleural surface. It is most often associated with rupture of e m p h y s e m a t o u s bullae. L e s s commonly it follows rupture of a cavitated abscess or pyogranuloma that communicates with an airway, or rupture of a parasitic cyst such as can occur in paragonimiasis. Traumatic pneu mothorax is usually the result of accidental perforation of the thoracic wall or rupture of lung and visceral pleura. Air which tracks through the pulmonary interstitium to the mediastinum (pneumomediastinum) does not usually escape into the pleural cavities unless there is traumatic rupture of the mediastinum. Traumatic p n e u m o t h o r a x can also be a complication of cardiac resuscitation or biopsy of the lung. Whatever the cause of p n e u m o t h o r a x , if entry of air stops before there is critical reduction of pulmonary function, the air is slowly resorbed. Hydrothorax is the accumulation of e d e m a fluid in the thoracic cavities. It is usually bilateral and has the same wide range of causes as e d e m a of the lung or elsewhere. The fluid is clear, watery, and ranges from almost colorless to light yellow. Large a m o u n t s of it are present when there is widespread neoplastic involvement of pleural surfaces or w h e n lymphatic drainage is impeded by neoplastic en largement of the thymus or cranial mediastinal lymph nodes. H y d r o t h o r a x may be present in cases of congestive heart failure, particularly in dogs, cats, and cattle. It is also present in severe anemias or in hypoproteinemias associated with the nephrotic syndrome, hepatopathy, protein-losing enteropathy, or malnutrition. H y d r o t h o r a x is also a feature of specific diseases or syndromes such as mulberry heart disease in swine, black disease in sheep, African horsesickness, and A N T U poisoning. Chronic hy drothorax causes pleural opacity because of reactive hy perplasia of mesothelial cells and fibrous thickening of the underlying pleural connective tissue. Chylothorax refers to the accumulation of milky fluid in the thorax (Fig. 6.111 ). T h e fluid is lipid-rich lymph, which can be distinguished from other turbid effusions by extrac tion of the fat with ether or by staining the droplets with a sudanophilic dye. Occasionally the source of the chylo thorax is traced to rupture of the thoracic or right lym- phatic ducts. This is presumed to be the case in the many instances in which the origin is not found. T h e most com mon association of chylothorax is with a traumatic event, bouts of severe coughing, o r tumors in the cranial medias tinum. H e m o t h o r a x is the presence of blood in the pleural cavities. It is most often the result of traumatic rupture of blood vessels, but it can also be caused by erosion of the wall of a vessel by an inflammatory or neoplastic process. L e s s c o m m o n causes are diseases in which there is a clotting disorder. H e m o r r h a g e m a y also arise from highly vascularized tumors (e.g., hemangiosarcoma) or inflam matory processes such as pleural tuberculosis in dogs. Chronic hydrothorax may lead to the development of wellvascularized papillae on the pleura, and rupture of these may cause the effusion to resemble blood. Inflammation of the pleura (pleuritis) is t h e most com monly encountered abnormality. It is usually secondary to pneumonia (see Anatomic Patterns of Pneumonia, Section V I , F of this chapter). Other pathways by which inflamma tory agents reach the pleura are the bloodstream, lym phatic permeation from the peritoneal cavity, traumatic penetration from outside t h e chest or from the esophagus or abdominal viscus such as the bovine reticulum, or direct extension from a mediastinal abscess or esophagitis. T h e agents causing pleuritis as part of blood-borne infections vary with species of animal affected. Haemophilus s p p . are commonly the cause in swine, as are mycoplasmas in swine and goats. Chlamydia psittaci is occasionally involved in ruminants. T h e virus of feline infectious perito nitis is the most c o m m o n cause in cats. Pleural defenses against microorganisms are m u c h less effective than those of the lung. E v e n a few organisms reaching the pleural surfaces are therefore apt t o have serious c o n s e q u e n c e s in contrast to the result of a similar exposure in the lungs. The reactions of the pleura to inflammation are the same as those of the pericardium (see T h e Cardiovascular System, Volume 3, C h a p t e r 1). can occur in any animal, but is of most clinical significance in horses, dogs, a n d cats. It can be caused by pyogenic organisms reaching the pleural cavities by any of the path ways mentioned previously, but t h e relative importance of the pathways and the mix of organisms involved vary with the species of animal. Most cases of serofibrinous effusion or pyothorax in the horse are secondary to either pneumonia or pulmonary abscessation. T h e exudate is usually thin and dirty yellow (Fig. 6 .112) and may be either unilateral or bilateral. Streptococci are the organisms most consistently isolated, sometimes in mixed infections with E. coli, Klebsiella s p p . , Pasteurella s p p . , Pseudomonas spp. o r staphylococci. Pasteurella s p p . , staphylococci, and Bacteroides spp. are isolated in pure culture on occa sion. Mycoplasma felis has been added to the list of possi- ble agents. There is failure to culture organisms from the pleural effusion in as many as 50% of c a s e s , h o w e v e r . In h o r s e s , exudative pleuritis occurs most often in race horses, and in m a n y cases the onset is associated with stress of traveling, training, o r racing. Pyothorax unassociated with significant pneumonia o c curs in dogs, mostly in sporting breeds with access to rural environments. It particularly affects dogs which are used for hunting or are in training. T h e exudate is unilateral or bilateral, more commonly t h e latter. It is usually blood stained and viscous or flocculent b u t m a y b e creamy or darkly serofibrinous. Yellowish sulfur granules m a y be present in the bloodstained p u s . T h e pleural surfaces are thickened and velvety red or grayish yellow a n d fibrotic, depending on age a n d nature of t h e lesion. T h e cranial mediastinum is the main site of thickening. and Bacteroides s p p . are the most frequently recovered organisms, a n d these are commonly associated with t h e presence of sulfur granules a n d a characteristic pyogranulomatous pleuritis a n d mediastinitis (Fig. 6.113 ). Mixed infections are c o m m o n , h o w e v e r , a n d a variety of other organisms c a n be present, including Corynebacte rium s p p . , Pasteurella s p p . , £ . coli, Fusobacterium necro phorum, Pseudomonas spp., and streptococci. T h e patho genesis of the lesion is uncertain, but the circumstantial evidence supports t h e belief that infection reaches the pleural cavity in most instances b y w a y of migrating grass awns or florets. It is next to impossible t o find plant mate rial in the copious pleural e x u d a t e , b u t there is sometimes an association with subcutaneous abscesses or fistulous tracts compatible with migration of grass a w n s , and af fected dogs are those with greatest e x p o s u r e t o t h e species of grasses responsible for invasion of body orifices a n d subcutis. T h e damage caused by the migrating grass awns also seems particularly favorable for growth of the actinom y c e t e s . Pyothorax is fairly c o m m o n in cats (Fig. 6.114) . T h e pus is usually creamy yellow or grayish b r o w n . A s in dogs, it is more often bilateral than unilateral. Various bacteria are responsible, often in mixed infection. Pasteurella mul- Fig. 6 .113 Pyogranulomatous pleuritis caused by Actinomy ces sp. Dog. N o t e the large bacterial colony (arrows). tocida, various Gram-negative enteric bacteria, strepto cocci, and staphylococci have been isolated. and Bacteroides spp. are recovered on occasion, but much less consistently than in dogs. There are few pointers regarding the pathogenesis of the condi tion in cats. Although it is speculated that infection could gain access by penetration of a foreign body from the external surface or esophagus, or by a penetrating bite w o u n d , there are few data available. T Primary pleural tumors are rare. T h e specific type is the pleural mesothelioma, which has been found in the cow, dog, cat, horse, and goat. Mesotheliomas arise from the pericardial and peritoneal surfaces, as well as from the pleura (see T h e Peritoneum, Retroperitoneum, and Mes entery, Chapter 4 of this volume). There is one report of ferruginous bodies being present in significantly greater numbers in the lungs of a small series of dogs with meso theliomas. Ferruginous bodies are fine fibers irregularly coated by ferritin and a m o r p h o u s protein. T h e cores are most commonly asbestos fibers, and therefore the num bers of ferruginous bodies are usually accepted as an index of exposure to asbestos. The finding of increased numbers in the lungs of dogs with mesotheliomas suggests that inhalation of asbestos fibers could be related to the devel opment of mesotheliomas in this species, as it is in h u m a n s . Primary tumors can also arise from the chest wall and mediastinal tissues. T u m o r s of bone and cartilage, nerve sheaths, t h y m u s , lymph n o d e s , and ectopic glandular tis sue are discussed elsewhere. Secondary tumors of the pleura are also u n c o m m o n , but transpleural dissemination of carcinomas and sarcomas occasionally occurs by extension from the lungs, chest wall, or mediastinum. Carcinomas from the abdominal cavity can reach the pleura by penetrating diaphragmatic lymphatics. 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Etiology and diagnostic features Malignant mesothelioma in urban dogs Cytology of diffuse mesothelioma in the thorax of a horse Diffuse pleural mesothelioma in a goat Grass a w n penetration in the dog L a b o r a t o r y diagnosis of pleural and peritoneal effusions Pleuritis and pleural effusion of the h o r s e Pleuritis secondary to p n e u m o n i a or lung abscessation in 90 h o r s e s Pleuritis and pleural effusion in the horse: A study of 37 cases Mesothelioma of the pleura in a horse von Recum, A. F. The mediastinum and hemothorax, pyothorax, and pneumothorax in the dog The pleura: A combined light-microscopic and scanning and trans mission electron microscopic study in the sheep. II. Response to injury and Mycoplasma ovipneumoniae. Vet Microbiol 6: 295-308, 1981 . Gilmour, J. S., Jones, G. E., and Rae, A. G I am grateful to W.L. Castleman for his review of portions of the manuscript and provision of relevant illustrations. I am deeply indebted to Anja Sterner-Kock and Colleen Prather for assistance with bibliographic searches and to Lucy Day for keeping straight the revisions to the manuscript. Much of the credit for the quality of the photographic plates belongs to Andrej T. Mariassy.