key: cord-0040575-2h559p57 authors: Sykes, Jane E. title: Canine Viral Respiratory Infections date: 2013-08-26 journal: Canine and Feline Infectious Diseases DOI: 10.1016/b978-1-4377-0795-3.00017-x sha: 4288ac9c5d348fc0c9e76246dcbba5ea1ca1bb48 doc_id: 40575 cord_uid: 2h559p57 nan Canine viral respiratory disease is a widespread problem where large numbers of dogs are housed indoors together, such as in shelters, commercial dog colonies, and breeding facilities. The longer dogs are housed in a shelter situation, the greater the risk that respiratory illness will occur. 3 In shelter environments, transmissible respiratory disease (or canine infectious respiratory disease complex [CIRDC] , previously referred to as " kennel cough" or canine infectious tracheobronchitis) delays the placement of dogs in homes and can result in unmanageable costs related to treatment, quarantine, and isolation. Transmissible respiratory disease occasionally occurs in owned dogs after a period of contact with large numbers of other dogs at dog parks, dog sporting events such as fly ball, or dog behavior classes. It can also occur after dogs (or dog owners) visit veterinary hospitals, boarding facilities, or pet daycare centers. With the widespread clinical application of molecular diagnostic assays, it is increasingly apparent that the number of viruses that can infect the canine respiratory tract is much larger than previously thought. This has led to exciting new discoveries in the field of canine infectious respiratory disease, and our knowledge of the pathogens involved continues to expand. Co-infections with multiple viruses and bacteria such as Mycoplasma spp., Bordetella bronchiseptica, and Streptococcus equi subspecies zooepidemicus are common and contribute to an increased severity of disease. [4] [5] [6] Viruses believed to play a role in canine respiratory disease include canine herpesvirus-1 (CHV-1), canine adenovirus-2 (CAV-2), canine distemper virus (CDV), canine parainfluenza virus (CPiV), canine pneumovirus, canine respiratory coronavirus (CRCoV), and canine influenza virus (CIV) ( Table 17-1) . CAV-1 may also play a role when vaccination is not performed or when it is performed improperly. 7 Reoviruses may also play a role. 8 CDV, CHV-1, and CAV are discussed in more detail in Chapters 15, 16 , and 18, respectively. The major bacterial causes of canine transmissible respiratory disease are covered in Part II, Section 2 of this book (Chapters 34, 38, and 40) . Although most of the canine respiratory viruses have a worldwide distribution, their relative prevalence varies from year to year and between geographic locations. Even within a state or city, predominant pathogens may differ from one shelter and boarding kennel to another. CDV, CHV-1, CPiV, CRCoV, and CIV are enveloped viruses, so they survive poorly in the environment and are susceptible to a variety of disinfectants. Despite this, contact with virus that persists in the environment may be important for transmission in densely housed populations of dogs. CAV-2 is a non-enveloped virus and has the potential to survive several weeks on fomites. Adenoviruses are icosahedral DNA viruses that infect a variety of animal species. CAV-2 is found worldwide and primarily infects the respiratory tract of dogs. Rarely, it has been implicated as a cause of enteritis in dogs, and it was found in the brains of puppies with neurologic signs. 9 The virus replicates in nonciliated bronchiolar epithelial cells; epithelial cells of the nasal mucosa, pharynx, and tonsillar crypts; mucous cells in the trachea and bronchi; and type 2 alveolar epithelial cells. CAV-2 can also be isolated from retropharyngeal and bronchial lymph nodes as well as epithelial cells of the intestinal tract. Shedding typically ceases 1 to 2 weeks after initial infection. The extent to which CHV-1 plays a role in respiratory disease in dogs has been debated. 10 Experimental infections of dogs can result in rhinitis or signs of tracheobronchitis, and intraocular infection results in conjunctivitis and keratitis. [11] [12] [13] [14] There is evidence of widespread exposure to CHV-1 in dogs worldwide, 10 and a substantial proportion of the dog population may be latently infected. Like other herpesviruses, CHV-1 becomes latent in neurologic tissues, with precipitation of virus shedding by stress. Consistent with the time delay required for reactivation after stress, CHV-1 was most frequently detected 3 to 4 weeks after dogs were introduced to a rehoming center, whereas CRCoV and CPiV were most frequently detected in the first and second week. Dogs infected with CHV-1 were more likely to have severe respiratory disease, although severe respiratory disease itself might predispose dogs to the shedding of CHV-1. 10 Infection with CHV-1 was reported in association with fatal hepatic necrosis in an adult dog that lacked any evidence of immunosuppression. 15 Refer to Chapter 16 for information on CHV-1 infections in neonates. Influenza viruses are enveloped viruses with segmented singlestranded RNA genomes that belong to the family Orthomyxoviridae. Influenza viruses that cause disease in domestic animals belong to the genus Influenzavirus A, whereas influenza B and influenza C viruses primarily circulate among humans. Influenza A viruses are classified based on the genetic composition of their hemagglutinin (H) and neuraminidase (N) genes. To date, 16 H types and 9 N types have been identified, each of which are antigenically distinct. 16 The names of influenza viruses are specified as follows: influenza genus (A, B, or C)/host/geographic origin/strain number/year of isolation and, in parentheses, H and N type-for example, A/canine/Florida/43/2004 (H3N8). 17 Extensive genomic rearrangements that occur within influenza A viruses allow for occasional cross-species transmission among birds and mammals. These rearrangements occur when two different viruses simultaneously infect a host, with subsequent genetic reassortment. Occasionally, cross-species transmission occurs without alteration of the viral genome. In the United States, CIV emerged in racing greyhounds in Florida in 2003 and 2004, 17 where it caused hemorrhagic pneumonia and a high mortality. However, serologic evidence of infection in the greyhound dog population dates back to 1999. 18 Infections spread slowly and were subsequently reported in racing greyhounds and non-greyhounds in at least 38 U.S. states. Outbreaks have continued to occur in shelter situations for nearly a decade after the virus was discovered. The virus that currently circulates in the United States is an H3N8 virus that closely resembles an equine influenza virus, which suggested that an interspecies jump occurred without genetic reassortment. 17 Instead, accumulation of point mutations with minor amino acid changes occurred, with sustained transmission among dogs. The most significant outbreaks of disease due to CIV have occurred in Florida, New England, Colorado, Wyoming, and Texas. In many other states, sustained transmission of the virus from one dog to another has not occurred. The most significant risk factor for infection has been indoor housing. 19 Virtually all cases to date have involved dogs in kennels, animal shelters, or dog daycare facilities. Dogs of all ages and breeds are susceptible, but to date severe hemorrhagic pneumonia has occurred only in greyhounds. 20 The virus is shed for up to 7 to 10 days. CIV has retained the ability to infect horses, but horses develop only mild disease or no clinical signs. 20 Avian-lineage H3N2 CIV emerged in South Korean dogs in 2007, and a similar virus was subsequently isolated from dogs in China. 21, 22 Experimentally, cats are also susceptible to infection by this virus. 23 Korean isolates were associated with epidemics of respiratory disease in kennels within veterinary clinics. 22 A novel H3N1 virus was also detected in South Korean dogs that lacked signs of respiratory disease. 24 A novel H5N2 influenza virus was recently detected in a dog with respiratory disease in China. 25 Dogs are susceptible to infection with human influenza virus H1N1 26, 27 and avian H5N1, 28 but sustained transmission of these viruses in the dog population has not been reported. Limited infection of dogs with equine H3N8 viruses was detected in hounds in England 29 and during an equine influenza outbreak in Australia. 30 In England, disease was so severe that several hounds had to be euthanized, and subacute bronchointerstitial pneumonia was detected at necropsy. 29 The Australian dogs developed inappetence, lethargy, nasal discharge, and a cough that persisted for several weeks, but dog-to-dog transmission was not identified. Experimental transmission of H3N8 influenza virus from horses to dogs was documented in Japan, but infected dogs did not show signs of illness. 31 CDV, CPiV, and canine pneumovirus belong to the family Paramyxoviridae, which are enveloped RNA viruses. CPiV belongs to the genus Rubulavirus. Although previously referred to as canine parainfluenza virus-2, it is probably the same virus as simian virus 5, which was originally isolated from monkey cell cultures. It has been proposed that it be renamed parainfluenza virus 5. 32 Unlike CDV, the outer envelope possesses not only hemagglutinin but also neuraminidase activity (HN attachment glycoprotein). The virus infects dogs worldwide, replicates in epithelial cells of the upper respiratory tract, and often causes no signs or mild respiratory illness. Respiratory disease may be more severe when co-infections with other pathogens such as B. bronchiseptica are present. 33 Viremia seems to be uncommon, but occasionally CPiV has been isolated from the liver, spleen, and kidneys. A strain of CPiV was also isolated from a dog with neurologic signs. 34 There is some evidence that cats may be infected with CPiV or a closely related virus. 35 Virus is shed for up to 10 days after infection. Canine pneumovirus belongs to the genus Pneumovirus. It was first isolated from dogs with acute respiratory disease in shelters in the United States in 2010. 2 The virus is most closely related to a murine pneumovirus and in fact can replicate in mice and cause severe inflammatory pathology. 36 Reoviruses (family Reoviridae, genus Orthoreovirus) are nonenveloped viruses with a segmented, double-stranded RNA genome. Mammalian reoviruses infect a variety of host species and have a worldwide distribution. The prefix reo-stands for respiratory enteric orphan virus, which highlights the tropism of reoviruses for cells of the respiratory and gastrointestinal tract, and their uncommon association with disease. Despite serologic evidence of widespread exposure to reoviruses in dogs, they have been found only rarely in dogs with respiratory disease 8, 37 and dogs with enteritis. 38 There are three mammalian reovirus (MRV) serotypes, and all three have been detected in dogs. The role of reoviruses in disease causation in dogs is unclear, because disease has not been reproducible experimentally. It has been speculated that reoviruses might act synergistically with other respiratory pathogens to cause disease. 10 Coronaviruses are enveloped RNA viruses that possess large, club-shaped spikes on their outer surface, also known as peplomers (see Figure 14-1, B) . CRCoV is a relatively newly identified cause of contagious respiratory disease in dogs. The virus is a group 2a coronavirus (family Coronaviridae, genus Coronavirus) and is distinct from canine enteric coronavirus, a group 1a coronavirus (Box 17-1). 39 Minimal serologic cross-reactivity exists between these two viruses. Group 2a coronaviruses possess a gene that encodes hemagglutinin esterase, an outer membrane protein glycoprotein. This gene is absent in group 1 and 3 coronaviruses. CRCoV is most closely related to a bovine coronavirus but also resembles human coronavirus OC43. 40 CRCoV was first reported in 2003, in a group of dogs with respiratory disease in a rehoming facility in England that had been vaccinated against CAV-2, CDV, and CPiV. 6, 40 Some of the dogs were co-infected with CPiV and CHV-1. 6 CRCoV spread rapidly and primarily was detected in the first week that dogs were introduced to the kennel, after which time CPiV and CHV-1 were detected. Alone, CRCoV causes subclinical infections or mild respiratory disease, but like human respiratory coronaviruses, it can cause reversible damage to, or loss of, the cilia on respiratory epithelial cells (Figure 17-1) . As a result, infected dogs are predisposed to secondary infections. Serologic evidence of exposure to CRCoV is widespread in dogs from North America, Great Britain and continental Europe, Japan, Korea, and New Zealand, 10, [41] [42] [43] and the virus has been detected widely using PCR-based methods in dogs with respiratory disease from many of these countries. To date, there is no evidence that cats can be infected with CRCoV. Feline Infection with pancytotropic strains of canine enteric coronavirus has recently been associated with severe systemic disease in puppies from Europe. Affected pups have fever, mucoid to hemorrhagic enteritis, lymphopenia, neurologic signs such as seizures, and bronchopneumonia. 44, 45 Co-infections with CPV-2 were present in some puppies, but the disease has been reproduced by experimental infection by canine enteric coronavirus alone. Death occurred in some puppies, but others developed transient gastrointestinal signs and recovered. 46 The incubation period for viral respiratory disease is generally less than 2 weeks and can be as short as 2 to 3 days. Influenza virus infections, in particular, have been associated with very short incubation periods. 20 Transmission occurs by aerosol, but direct contact between dogs and fomite transmission (hands, clothing, contaminated food and water bowls, common hallways and exercise areas) are important routes in population-dense environments. Cells of the larynx, trachea, bronchi, and sometimes the nasal mucosa, bronchioles, and alveoli are infected, and although viral shedding patterns differ between pathogens, shedding may occur before the onset of clinical signs. The duration of shedding for CIV and CPiV is very short, typically a few days, and in some dogs, shedding has ceased by the time clinical signs are most apparent. In contrast, CDV can be shed for weeks (see Chapter 15) . Infection with respiratory viruses may be associated with no signs, or complicated pneumonia and death can occur. In general, morbidity is high, but mortality is low. Moderate to severe signs may be more likely to occur in very young puppies, genetically susceptible animals, and when stress and co-infections with multiple viral and bacterial pathogens are present. Infection with CDV is especially effective at predisposing dogs to other respiratory viral infections, because of its immunosuppressive properties, but other viruses that damage ciliated epithelial cells, such as CRCoV and CPiV, also predispose to co-infections. Clinical signs of acute respiratory disease include mild fever, a paroxysmal harsh or "honking" cough, serous nasal discharge, and sometimes sneezing, but usually otherwise affected dogs are often alert, active, and appetent. The cough may be followed by gagging or retching, which may be followed by the production of frothy mucus. An altered bark or stridor may occur in dogs that develop laryngitis, tonsillitis, and/or pharyngitis. CAV-2 and CHV-1 may cause conjunctivitis. 47 In addition, CHV-1 has been associated with ulcerative and nonulcerative keratitis, which may be precipitated by immunosuppression ( Figure 17 -2). [48] [49] [50] Infections with CIV or CDV, or infections with multiple respiratory pathogens, may be more likely to produce systemic signs of fever and lethargy. Dogs that develop secondary bacterial infections may show fever, inappetence, lethargy, a mucopurulent nasal discharge, tachypnea, and a moist, productive cough. On physical examination, dogs with uncomplicated transmissible respiratory disease are typically bright, alert, and active with a paroxysmal cough. The cough is often easily elicited on tracheal palpation. Conjunctivitis and serous ocular and/or nasal discharge may be present, and the tonsils may be enlarged and hyperemic. Dogs with secondary bacterial infections may be pyrexic, lethargic, and tachypneic with increased respiratory effort and A B increased lung sounds on thoracic auscultation. A mucopurulent nasal discharge may also be present. Ulcerative or nonulcerative keratitis may be present in dogs infected with CHV-1. It is not possible to identify the cause of transmissible respiratory disease in dogs based on clinical signs alone, because each pathogen produces a similar spectrum of signs. The high prevalence of co-infections further complicates diagnosis. In addition, other, noncontagious causes of respiratory disease in dogs can lead to signs that closely resemble transmissible respiratory disease. A history of exposure to other dogs can support the diagnosis. Most dogs experience self-limiting disease. Attempts to obtain an etiologic diagnosis should be made when disease persists for longer than 7 to 10 days or is complicated by bacterial pneumonia, with lethargy and inappetence. When outbreaks occur in shelters or the pattern of endemic respiratory disease changes, attempts to make an etiologic diagnosis are also indicated and encouraged (Table 17 -2). Collection of multiple specimen types from several dogs with and without clinical signs in an outbreak situation can facilitate diagnosis and allow interpretation of the significance of positive test results. Organism detection methods, such as PCR assays, are likely to be of highest yield early in the course of illness (e.g., the first 1 to 3 days) or in exposed dogs that have not yet developed clinical signs. Use of a combination of serology and organism detection methods also facilitates diagnosis. In shelter situations or outbreaks where severe disease occurs, necropsies can provide valuable information and should be performed by a veterinary pathologist as soon as possible after death or euthanasia. Tissues should be submitted for histopathology (in formalin), bacterial and virus cultures (fresh tissue), and PCR assay for respiratory viruses and bacteria (fresh or frozen tissue; see Chapter 5). There are no specific abnormalities in the CBC, serum biochemistry profile, or urinalysis that aid in a diagnosis of canine viral respiratory disease. The CBC may be normal or show a mild to moderate neutrophilia. Band neutrophils and neutrophil toxicity may be apparent in dogs with secondary bacterial pneumonia. Severe infections may be associated with leukopenia, which may be followed by leukocytosis in dogs that recover. Transtracheal wash and bronchoalveolar lavage specimens from dogs with viral pneumonia typically show a suppurative or mixed exudate, sometimes with evidence of intracellular bacteria. Culture for aerobic bacterial culture and Mycoplasma spp. are indicated on wash specimens, and antimicrobial susceptibilities should be obtained for any aerobic bacteria isolated. Organisms such as Pasteurella spp., Staphylococcus pseudintermedius, Streptococcus canis, Escherichia coli, Klebsiella pneumoniae, and some Mycoplasma spp. infect the airways as opportunists and are not considered to be primary pathogens. Bacterial culture of nasal swabs is generally not recommended because it often leads to growth of normal flora, which has no clinical relevance. In uncomplicated viral infections, plain thoracic radiography in dogs often shows no significant abnormalities, or there may be a mild diffuse interstitial or bronchointerstitial pattern. Secondary bacterial bronchopneumonia may be characterized by development of peribronchial and alveolar infiltrates or lobar consolidation (Figure 17-3) . Efforts to isolate viruses from dogs with acute respiratory disease have been most useful for identification of novel or reemerging pathogens. 2, 38, 40 Despite the increased availability of molecular diagnostic assays, virus isolation is still offered to veterinarians for routine diagnostic purposes by laboratories that specialize in virology (e.g., the Animal Health Diagnostic Laboratory at Cornell University in Ithaca, NY). Suitable specimens for respiratory virus isolation are nasal and pharyngeal swab specimens, transtracheal or bronchoalveolar lavage specimens, or upper airway or lung tissue obtained at necropsy. If swabs are used to collect specimens, polyester-tipped swabs and specific virus transport media should be used. Cotton swabs should be avoided, because influenza viruses adhere to the cotton, which can lead to reduced sensitivity. 20 Virus isolation is a specialized process that may take several days. As with PCR assays, sensitivity may be low because shedding of respiratory viruses occurs early in the course of illness and may be transient. CRCoV fails to replicate in many cell lines, but was successfully isolated in HRT-18 cells. 51 This may explain its relatively recent discovery relative to other respiratory viral pathogens. Fluorescent antibody can be applied to smears made from swabs from the upper respiratory tract, or tissues collected at necropsy, such as fresh lung tissue. Assays are available for detection of CPiV, CAV, CDV (see Chapter 15), and CHV-1. Attenuated live vaccination with intranasal vaccines for CPiV and CAV has the potential to interfere with fluorescent antibody results, but this requires further study. The sensitivity of fluorescent antibody testing is likely to be lower than that of PCR assays, and inexperienced personnel may misinterpret nonspecific fluorescence as a positive result. Point-of-care ELISAs are available for detection of nucleoprotein antigen of human influenza A viruses. The assays are easily performed and provide rapid results. Unfortunately, such assays have had limited sensitivity and specificity for diagnosis of CIV infections, and so their use is not recommended. False positives may especially be a problem in shelters where canine influenza is not endemic. Panels of real-time PCR assays that detect respiratory pathogens are offered by some commercial veterinary diagnostic laboratories. These may include assays for CRCoV, parainfluenza virus, and CIV, as well as bacterial pathogens such as B. bronchiseptica and Mycoplasma spp. Swabs of the nasal cavity and/or caudal pharynx, or respiratory lavage specimens could be submitted for testing. At necropsy, CRCoV is most readily detected in upper respiratory tract specimens, such as the nasal mucosa, nasal tonsil, and trachea. 52 Lung specimens may also yield positive results. Unfortunately, false-negative PCR results are common, especially in antemortem specimens, because of transient or low-level shedding of many respiratory viruses. In addition, because many respiratory viruses are RNA viruses and RNA is very labile when compared with DNA, false negatives can occur when viral RNA degrades during specimen transport. Bronchopneumonia is present that involves the right cranial, right middle, and left cranial lung lobes. Interestingly, canine herpesvirus DNA was detected in a pooled extract from nasal, conjunctival, and oral swab specimens, as well as a whole blood sample using a PCR assay. In outbreak situations, false-positive PCR results may occur if swab specimens become contaminated with virus from the environment or the hands of personnel. Clean examination gloves should be worn for each dog, and the swab should only touch the anatomic site to be tested. Vaccination with live attenuated vaccines (especially intranasal vaccines) may cause positive test results with real-time PCR assays, but the extent to which this occurs in dogs with respiratory viral illness requires further study. Because CIV vaccines are parenteral inactivated vaccines, they would not be expected to lead to false-positive PCR assay results. The detection of nucleic acid from a respiratory virus in a specimen may not imply disease causation. Diagnostic laboratories that specialize in veterinary virology may offer serologic assays for antibodies to canine respiratory viral pathogens on a commercial basis to practitioners. Serology has limited use for diagnosis because of vaccine titer interference for some organisms, and the high prevalence of subclinical exposure to organisms endemic in the dog population. Titers may be negative in the first 10 days of illness, and some dogs may not show a significant increase in antibody titer after infection. Despite these limitations, serologic assays have been key to identification of infection and disease caused by emerging pathogens such as CIV, when the disease is not endemic. 20 In this situation, analysis of paired serum specimens collected 2 weeks apart can be used to document recent infection. In some dogs, no other diagnostic test may be useful for antemortem diagnosis because virus shedding is so transient and difficult to detect. Serologic assays for CIV exposure are based on serum neutralization or hemagglutination-inhibition (see Chapter 2) . Assays for CIV that use equine influenza virus antigen for antibody detection have suboptimal sensitivity, whereas an assay based on H3N8 CIV antigen was sensitive and specific when compared with serum neutralization. 53 Seroconversion to CRCoV in a bovine coronavirus antigen ELISA assay helped identify the association between infection with this virus and respiratory disease in dogs in the rehoming kennel in the United Kingdom. 6 Serum neutralization assays can be performed for detection of antibodies to CAV-2, CPiV, and CHV-1. Antibodies to CAV-2 and CPiV can also be detected by hemagglutination-inhibition. Necropsy of dogs with viral respiratory infections may show no gross lesions, or pulmonary consolidation and hyperemia of the tracheal mucosa may be present. Purulent exudate may be present in the bronchi. Greyhounds that died of CIV infection had extensive hemorrhage within the lungs, mediastinum, and pleural space, together with mild, fibrinous pleuritis. 17 Histopathology of the airways of dogs with viral respiratory infections may show loss or irregularity of normal respiratory cilia and epithelial necrosis and ulceration within the trachea, bronchi, and bronchioles. With secondary bacterial infection, a neutrophilic or mixed inflammatory infiltrate may be seen in the airway mucosa, submucosa, and alveoli. 54 Bronchial and bronchiolar lumina may contain neutrophils, macrophages, and cellular debris. Thickening of the alveolar walls with type 2 pneumocyte hyperplasia and interstitial edema has also been described. Hemorrhagic interstitial and bronchointerstitial pneumonia, vasculitis, and thrombus formation have been observed in greyhounds with CIV infection. 20 CAV-2 can produce large, basophilic intranuclear inclusion bodies within bronchial, bronchiolar, and alveolar cells. These must be differentiated from the eosinophilic inclusions of CDV (see Chapter 15) . 55 Reoviruses can also produce intracytoplasmic inclusions within bronchial epithelial cells. 8 Use of immunohistochemistry can facilitate definitive identification of viral antigen within cells of the respiratory tract. 5, 55 Like the common cold in humans, contagious respiratory disease in dogs resolves without treatment in the vast majority of dogs, regardless of the underlying cause. For dogs with signs of respiratory disease that have been present for less than 7 to 10 days and that remain bright and appetent, no treatment is indicated. In some dogs, cough persists for as long as 10 to 30 days. Cough suppressants such as hydrocodone could be used for dogs with a nonproductive, honking cough that occurs throughout the day and night. Cough suppressants should not be used in dogs that have productive cough, because they suppress normal clearing mechanisms. Use of a harness or gentle leader for leash walking rather than a neck collar may also reduce cough. The efficacy and optimal dosage of neuraminidase inhibitors such as oseltamivir (see Chapter 7) is unknown, and because of this and the fact that oseltamivir is a first-line treatment for pandemic influenza in humans, it should not be used to treat dogs with respiratory disease, even when CIV infection is present. For dogs with confirmed ocular CHV-1 infections that are associated with corneal ulceration, topical antiviral ophthalmic preparations such as idoxuridine or cidofovir could be considered (see Chapter 7) . 50 Antimicrobial drug treatment could be considered for dogs with signs that persist beyond 7 to 10 days, but is primarily indicated when there is evidence of secondary bacterial bronchopneumonia, such as pulmonary alveolar infiltrates and consolidation on thoracic radiography, lethargy, mucopurulent oculonasal discharges, and/or decreased appetite. Because antimicrobial drug resistance is increasingly reported among secondary bacterial pathogens and B. bronchiseptica, treatment of dogs with secondary bacterial bronchopneumonia is optimally based on the results of culture of a transtracheal wash specimen from each affected dog and antimicrobial susceptibility testing. For dogs with severe pneumonia, initial treatment should involve the use of broad-spectrum parenteral antimicrobial drugs such as a combination of a fluoroquinolone and a penicillin or clindamycin. When infection with B. bronchiseptica or Mycoplasma spp. is suspected, doxycycline may be the best first choice. Indiscriminate use of antimicrobial drugs leads only to widespread bacterial resistance and failure of antimicrobial drug treatment in dogs that develop severe disease. Dogs with pneumonia may also require treatment with intravenous fluids, supplemental oxygen, nebulization, and coupage. Nutritional support in the form of feeding tubes may be required for dogs that are inappetent. Prognosis depends on the virulence of the causative agent(s), the presence of co-infections, and other factors that contribute to host immunosuppression. Prognosis is generally excellent for dogs with uncomplicated infections with a single pathogen. For CIV infection, mortality rates have been less than 8% and could be lower with rapid diagnosis and appropriate treatment. 20 Vaccines are available for reduction of disease due to CPiV, CAV-2, CDV, and CIV. With the exception of CDV vaccines, none of the available vaccines completely prevent infection and shedding, but they can lessen the severity of disease, provided other factors such as overcrowding and appropriate disinfection and reduction of other stressors are also addressed. Parenteral and mucosal (intranasal and oral) attenuated live vaccines are available for CPiV and CAV-2. The vaccine for CIV is an inactivated vaccine. Vaccines for canine transmissible respiratory disease are considered noncore vaccines, so they should be administered to dogs at risk of exposure, such as those that enter shelters, boarding kennels, shows, sporting competitions, popular dog parks, or pet daycare facilities. Mucosal and parenteral vaccines are available for prevention of disease due to CAV-2. Parenteral CAV-2 vaccines also protect against CAV-1 infection. Maternal antibodies persist for up to 12 to 14 weeks after birth. Mucosal vaccines may be useful to overcome maternal antibodies in young dogs that are introduced to shelter environments. However, parenteral vaccines are still required for adequate protection against CAV-1. An inactivated vaccine for CHV-1 is available in Europe for pregnant bitches to protect puppies against neonatal infections (see Chapter 16) . It is not intended to reduce respiratory disease due to CHV-1 infection. Inactivated, parenteral vaccines are available for reduction of disease and shedding caused by H3N8 CIV. 56 One vaccine also reduced the severity of illness caused by co-challenge with CIV and Streptococcus equi subspecies zooepidemicus. 4 The use of these vaccines could be considered for dogs that are likely to contact other dogs in regions where CIV is endemic, especially those that enter boarding or pet daycare facilities. Vaccination against CIV is required for importation of North American dogs to Australia. 57 The initial vaccine can be given as early as 6 weeks of age. Because CIV vaccines are inactivated, two initial doses are required 3 to 4 weeks apart, and maximum immunity does not occur until 1 week after the second dose. As a result, CIV vaccines may not protect dogs that enter shelters where canine influenza is endemic, unless newly introduced dogs are separated from dogs that might be shedding CIV until immunization is complete. Annual boosters are recommended for dogs that remain at risk of infection, but the maximum duration of immunity is unknown. Intranasal vaccination with CPiV significantly reduces clinical signs and virus shedding after challenge. [58] [59] [60] One study showed that intranasal CPiV vaccination reduced clinical signs even when dogs were challenged as long as 1 year after immunization. 58 Few studies have compared the efficacy of parenteral and intranasal vaccines. In a study reported in the early 1980s, the parenteral vaccine was less effective at reducing shedding than the intranasal vaccine, 59 but a study reported in the 1970s showed reduction of clinical signs and shedding after parenteral vaccination. 61 The use of one parenteral CPiV vaccine resulted in antibody titers that persisted for at least 2 years. 62 Use of intranasal CPiV vaccines, as opposed to parenteral vaccines, has been advocated, because they produce local immunity, reduce shedding, and can be used in puppies as young as 3 to 4 weeks of age. 63 However, proper administration of mucosal vaccines may be difficult in aggressive dogs or dogs that refuse to be restrained. Mucosal vaccines may also be associated with transient respiratory illness for 3 to 10 days after immunization in a small percentage of dogs. This may be problematic in shelter and boarding environments, because these signs cannot be distinguished from those that result from natural infection with wild-type viruses. More studies that evaluate the relative efficacy of mucosal and parenteral CPiV vaccines are required. Although vaccination can reduce the prevalence of respiratory disease in dogs, 3 current vaccines do not provide protection against all the organisms that cause respiratory disease in dogs, and immunity is not sterile, so infection and mild clinical signs can still occur. When factors such as stress, immunosuppression, co-infections, and overwhelming challenge doses are present, vaccine-induced protection may be overwhelmed. Prevention of transmissible respiratory tract disease in dogs therefore involves not only vaccination, but also control methods that include quarantine of dogs introduced into densely populated environments, early identification and isolation of dogs with signs of respiratory disease through proper training of shelter personnel, avoidance of overcrowding and mixing of dogs, use of solid walls between runs, reduction of time dogs spend in a shelter environment, optimum nutrition, fomite control, control of noise such as barking, and proper ventilation and disinfection (see . Distances traveled by aerosols generated by dogs are unknown. Dogs with respiratory disease should be separated from other dogs in shelter environments by at least 25 feet (or as far as possible) and ideally placed in an enclosed room with a separate ventilation system. Isolated dogs should not be moved back into the general shelter population, but adopted out of isolation or a separate recovery room. Provided proper cleaning and contact times are used, use of disinfectants with activity against parvovirus should also kill respiratory viruses, with CAV-2 being the respiratory virus that is most resistant to disinfection. The order of inspection of dogs in shelters should be healthy dogs, then quarantined dogs, and finally dogs in isolation. When outbreaks occur, attempts should be made to identify the pathogen(s) involved. This allows potential routes of transmission of infection and shedding patterns to be identified, proper vaccination and control strategies to be implemented, and adequate disinfectants to be selected. For example, quarantine for 2 weeks and isolation or removal of any dogs that develop illness may be effective for diseases such as canine influenza, because of the short incubation and shedding periods. However, it is less likely to be successful for distemper and bordetellosis, which can have prolonged incubation and shedding periods. For some viral respiratory diseases such as canine influenza, discontinuation of intake and adoptions for 2 to 3 weeks may be necessary while the disease runs its course. Exposed dogs could also be transferred to foster care in a household with no other dogs. Because of a lack of adequate resources for treatment, diagnostic evaluation, and management, some shelters have elected to euthanize large numbers of affected dogs. Shelters should provide written information on transmissible respiratory disease to clients who adopt shelter animals, regardless of the presence or absence of clinical signs at the time of adoption, and communicate fully about diseases that are endemic in the shelter. Whenever possible, dogs that leave shelters should be kept away from other dogs for at least 2 weeks (consider 4 weeks if bordetellosis is endemic), and informed about follow-up medical care. Other dogs in the household should be vaccinated before they are placed in contact with the shelter animal. Clients should also be instructed to ensure their local veterinary clinic is aware that their dog is newly adopted from a shelter, so that precautions can be taken to prevent contamination of the hospital environment when the dog is examined a few days after leaving the shelter. Viruses related to simian virus 5 (parainfluenza virus 5) have been detected in humans, but the role of CPiV as a human pathogen is controversial. Reoviruses have a broad host range, and human infection has been associated with enteritis and respiratory disease; MRV-3 infection was associated with meningitis in a child. 64 Thus they represent a potential zoonosis. Although adenoviruses, influenza viruses, coronaviruses, and paramyxoviruses cause respiratory disease in humans, there is no evidence that CAV-2, CIV, CDV, CHV-1, or CRCoV can be transmitted to humans. Human influenza viruses such as H1N1 can cause disease in dogs and may have the potential to spread from infected dogs back to humans. Signalment: "Winnie", a 10-year old male neutered miniature Schnauzer from Sacramento, CA History: Winnie was brought to his local veterinarian because of a 1-day history of serous ocular and nasal discharge, and sneezing. Fever (103.5°F or 39.7°C) was documented on physical examination, and enrofloxacin (2 mg/kg PO q24h), bacitracin-neomycin-polymyxin ophthalmic ointment (both eyes q8h), and diphenhydramine (2.2 mg/kg PO q12h) were prescribed, without clinical improvement. A day later, he became lethargic, inappetent, and polydipsic, and the owners described continuous nasal discharge, and a moist cough. Winnie was brought to the UC Davis VMTH for a second opinion. He had been vaccinated regularly for CDV, CAV-2, CPV, rabies, Bordetella bronchiseptica, and CPiV. He was recently cared for in a boarding facility for a week and had been home for the past 11 days. He also regularly visited dog parks. There were two other miniature Schnauzers at home, and both were currently well. Current Medications: Enrofloxacin, 2 mg/kg PO q24h Other Medical History: Increased activity of serum ALP was noted at a senior care visit 2 months before the onset of respiratory signs. Body Weight: 9.4 kg General: Lethargic but hydrated. T = 100.8°F (38.2°C), HR = 104 beats/min, respiratory rate = 12 breaths/min, mucous membranes pink, CRT = 1 to 2 s. Severe chemosis, hyperemia, and mucoid ocular discharge were present bilaterally. There was also profuse bilateral serous nasal discharge and decreased nasal airflow, hypersalivation, and right tonsillar enlargement. Musculoskeletal: Body condition score 5/9. Respiratory: Stertorous respiratory noises were noted. Increased respiratory effort with a normal respiratory rate was also present. Auscultation revealed referred wheezing noises in all lung fields. Gastrointestinal: Tense abdomen, hepatomegaly was detected on abdominal palpation. No abnormalities were detected. Ophthalmologic Examination: Pupillary light reflexes (PLRs) (direct and consensual) were brisk and complete. There was no evidence of anisocoria. Menace response, dazzle, and palpebral reflexes were all complete. Globe position and movements were normal bilaterally (OU). Periorbital palpation and globe retropulsion were also normal. The dog behaved as if sighted. The eyelids were normal. Both nictitans were hyperemic and edematous, and there was moderate conjunctival hyperemia, chemosis, and mucoid ocular discharge OU. Bilateral iris atrophy and lens nuclear sclerosis were also present. The cornea, anterior chamber, vitreous, and dilated fundic examination were normal OU. In the left eye (OS), a pinpoint incipient anterior cortical cataract was identified just ventral to the center of the lens. In the right eye (OD), a linear pigment deposition on the anterior lens capsule was present at the 5 o'clock position. Thoracic and Cervical Radiographs: A mild to moderate bronchial and interstitial pattern was identified and was most prominent in the caudal lung fields. Cervical radiographs were unremarkable. The pulmonary changes were considered nonspecific, but more significant than those expected due to age. The cranial pole of the right adrenal was mildly to moderately enlarged. The liver appeared sonographically normal. A 3 mm stone was identified in the urinary bladder. Microbiologic Testing: A nasal swab specimen was submitted for real-time PCR panel for canine respiratory pathogens, which included CHV-1, CIV, CDV, CPiV, CAV-2, and B. bronchiseptica. The results were available 3 days later, and the specimen was positive for CHV-1 DNA. Upper respiratory disease and keratitis associated with CHV-1 infection. Winnie was hospitalized in isolation and treated with 0.9% NaCl (30 mL/hr IV), nebulization for 15 min q8h, clavulanic acid-amoxicillin (13.5 mg/kg PO q12h), and lubricating eye ointment (1 inch OU q4h). Clinical improvement occurred a day later, electrolyte abnormalities normalized, and the dog was discharged with instructions to administer topical idoxuridine (0.1% ophthalmic solution, 2 drops OU q4-6h). Unfortunately a caretaker of the dog did not regularly administer the idoxuridine. At a recheck 5 weeks after the dog was first seen, the owner reported 80% improvement in Winnie's respiratory signs, but he continued to sneeze approximately six times a day and was pawing at his eyes. Examination revealed persistent conjunctivitis, and a fluorescein stain showed large, superficial areas of uptake over the central cornea OU (see Figure 17 -2). A Schirmer tear test (STT) was 13 mm/min OS and 8 mm/min OD. A CBC was normal, and the serum biochemistry profile showed persistently increased ALP (835 U/L) and GGT activities (12 U/L) and improvement in the serum ALT activity (124 U/L). The owner was instructed to administer idoxuridine for an additional 2 weeks, as well as lubricating ointment, bacitracin-neomycin ophthalmic ointment (q8h OU), and llysine gel (2 mL [400 mg] q12h PO), separating the ophthalmic medications with administration of the idoxuridine first. At a recheck 2 weeks later, all signs had resolved and there was no fluorescein uptake. STT results were 14 mm/min OS and 10 mm/min OD. The idoxuridine was discontinued. Winnie had another episode of respiratory signs 4 months later, at which time the STT results were 15 mm/min OU. Treatment with lubricating eye ointment and l-lysine was continued. Comments: This was an unusual case of ocular and respiratory herpesviral infection. The early detection of dendritic ulcers allowed a connection to be made between the clinical signs and positive PCR assay result. The negative PCR assay results for other respiratory pathogens did not rule out the possibility of co-infections, because shedding of these organisms may have ceased or been at undetectable levels. Although idoxuridine was used to treat this dog, topical cidofovir may also have been effective. 50 Approximately 2 years later, mild serous nasal discharge and depigmentation of the planum nasale developed. A biopsy of the nasal planum showed epitheliotropic lymphoma. The dog was treated with multiagent chemotherapy for over a year without relapse of herpetic keratitis. 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