key: cord-023689-r03j5u18 authors: Scott, Danny W.; Miller, William H.; Griffin, Craig E. title: Viral, Rickettsial, and Protozoal Skin Diseases date: 2009-05-15 journal: Muller & Kirk's Small Animal Dermatology DOI: 10.1016/b978-0-7216-7618-0.50011-0 sha: doc_id: 23689 cord_uid: r03j5u18 nan Syncytial-type giant cells in the epidermis. Cowpox virus is a member of the Orthopoxvirus genus that has sporadically caused infections of domestic and exotic cats in various European countries." Cats with an uncharacterized poxvirus infection have been recognized in India and the United States, so the geographic area of involvement may be increasing. 1 In one study of 104 healthy cats, 13.5% were serologically positive for poxvirus antigen, suggesting a higher frequency of disease than recognized." The natural reservoir is small wild mammals. The virus circulates in different rodent species, especially voles and wood mice in western Europe.v 11a Cats typically become infected through wounding while hunting these wild mammals. Cat-to-cat, cat-to-human, or cat-to-dog transmission can also occur. G • 45 There appears to be no age, breed, or sex predisposition to infection, and many cases are recognized in the fall of the year." The primary lesion in the disease is an infected "See references I, 5, 8, 19a, 27, 34, 35, 43-45 . Partial alopecia with scaling. Papularto-plaquelike lesions were also present but are not visible. bite wound, typically on the head, neck, or forelimb. Local viral replication worsens the primary lesions and is the point source for the subsequent viremia. During the viremic phase, some cats develop mild pyrexia, inappetence, and depression. Ten to 14 days after the primary lesion, multiple secondary lesions develop over the body. The secondary or pox lesions are initially macular but progress to ulcerated, papular to nodular lesions that crust rapidly (see Fig. 7 -Ie and D). Pruritus is variable, and approximately 20% of infected cats develop oral vesiculation or ulceration. I. 5 Lesions heal slowly over 3 to 4 weeks and may be permanently scarred. During the development and course of the secondary lesions, systemic signs of illness are uncommon unless the cat has some intercurrent immunosuppressive disease. One cat died of necrotizing pneumonia.s> The differential diagnosis includes bacterial and fungal infections, eosinophilic granuloma, and neoplasia (especially mast cell tumor and lymphoma). Definitive diagnosis is made by skin biopsy, serologic testing, and virus isolation." Dermatohistopathologic findings include hyperplasia, ballooning degeneration, reticular degeneration, microvesicle formation, and necrosis of the affected epidermis and the outer root sheath of the hair follicle (see Fig. 7 -IE). Eosinophilic intracytoplasmic inclusion bodies are found within keratinocytes of the epidermis, hair follicles, and sebaceous glands. The diagnosis of cowpox is based on the results of diagnostic tests. Serum samples and fresh biopsy or scab material in viral transport medium are submitted to an appropriate diagnostic laboratory for serologic examination and viral isolation, respectively. Serologic tests cannot differentiate cowpox from other orthopox viruses. Histopathologic examination of secondary lesions usually supports the diagnosis, and orthopoxvirus involvement can be demonstrated by immunohistochemical techniques'' or electron microscopy. Virus isolation is the only method of making a precise diagnosis. There is no specific therapy for cowpox infection. If secondary bacterial infections of the skin or other organs occur, appropriate antibacterial therapy should be instituted. Severely ill animals, which typically have an underlying immunosuppressive disorder, require intense supportive care and may have to be euthanized. Glucocorticoids are contraindicated. Feline cowpox has zoonotic potential for contact cats, dogs, and humans.v-!4, !9a. 44, 45, 45a In humans, these contact infections are uncommon; they can be serious, however, especially if the individual is immunologically compromised. Lesions are typically nodular and occur most commonly on the hands and arms. A fatality in a human receiving corticosteroids has been documented.r' Accordingly, all infected cats should be isolated and handled carefully. The cowpox virus can remain viable under dry temperature conditions for several years, but it is susceptible to various disinfectants, especially to hypochlorite solutions." Dogs develop solitary, asymptomatic, self-healing ulcerated nodules.v- 45 No data are available to indicate whether infection confers long-lasting immunity. To prevent possible reinfection, hunting should be prohibited. Feline infectious peritonitis is a systemic viral disease caused by strains of coronaviruses. Effusive and noneffusive forms are most common.' Skin lesions other than those associated with debility have not been reported. Several cats that have been experimentally infected have developed ulcerative lesions around the head and neck ( Fig. 7-7 ).2 Histopathologic tests showed changes typical of a superficial vasculitis, and viral antigen was demonstrated in blood vessel walls by immunohistochemical techniques. Canine distemper is caused by a paramyxovirus.! In addition to severe respiratory, gastrointestinal, and neurologic disorders, the virus may produce skin lesions in some animals. Because of their general debility, some dogs, and especially very young puppies, develop widespread impetigo (see Fig. 7 -IF). The classic skin manifestation of distemper is the so-called hard pad disease, in which the dog develops nasal ( Fig. 7-8 ) and footpad ( Fig. 7-9 ) hyperkeratosis of varying severity. Although a variety of diseases (e.g., pemphigus foliaceus, lupus erythematosus, drug eruption) induce nasodigital hyperkeratosis, animals with those disorders are often not as systemically ill as dogs with distemper and have more widespread skin lesions. Distemper, leishmaniasis, necrolytic migratory erythema (see Chap. 10), and generic dog food skin disease (see Chap. 17) all can produce the nasodigital lesions and similar systemic signs of illness. The index of suspicion for distemper should be high when the pads are much harder to the touch than the degree of hyperkeratosis would suggest and the dog's vaccination history is poor. Histologically, the skin or pad surface is covered with marked orthokeratotic and parakeratotic hyperkeratosis, and acidophilic cytoplasmic inclusion bodies are commonly seen in keratinocytes." The inclusion bodies are variable in size and are round to irregular in outline. Nuclear inclusions are rare. Occasional multinucleated syncytial giant cells can be seen in the epidermis. Immunohistochemical detection of canine distemper virus in haired skin and footpad epithelium was reported to be very reliable for the antemortem diagnosis of distemper.!" Contagious viral pustular dermatitis (orf, contagious ecthyma) is a disease that is found primarily in sheep and goats and is caused by a parapoxvtrus.f Contagious viral pustular dermatitis was reported in a pack of hounds allowed to feed on sheep carcasses.t" Lesions consisted of circular areas of acute moist dermatitis, ulceration, and crusts, typically around the head. Skin biopsy revealed epidermal hyperplasia, ballooning degeneration, acantholysis within the stratum spinosum, and marked infiltration of neutrophils. Saline suspensions of skin biopsies were applied to the scarified skin of a normal sheep. Crusts removed from the inoculation sites were processed for electron microscopy, and parapoxvirus virus particles were readily seen. One cat with parapoxvirus infection has been documented.F The cat had multiple large crusted lesions over the face and back. Further details were not provided. Therapy for contagious viral pustular dermatitis is topical and varies according to the symptoms involved. The usual course of the disease in animals is 1 to 4 weeks. The disease may be transmitted to humans if broken skin is exposed to lesion material or contaminated objects. Generally, contagious viral pustular dermatitis is a benign disease in humans and results in the formation of a solitary lesion, especially on the hands. Lesions in humans are characterized by maculae that progress through a papular, nodular, and papillomatous stage. The lesions are usually centrally umbilicated and occasionally are bullous. Complications of contagious viral pustular dermatitis in humans include regional lymphadenopathy, lymphangitis, secondary bacterial infection, and rarely, generalized or systemic disease. Pseudorabies is an acute, fatal viral disease caused by an a-herpesvirus. 1 Pigs are the main reservoir of infection. Dogs and cats can be infected by contact with an infected animal or, more typically, by eating raw pork products or offal. Incubation periods range from 2 to 10 days,20a,23 and death typically occurs within 48 hours of the onset of clinical signs. 32 Early work suggested that intense, maniacal upper body pruritus was the cardinal feature of the disease in dogs. 23 More recent work, however, showed that this sign occurred in only 52% of affected dogs. 32 Ptyalism was a universal finding, followed by restlessness, anorexia, ataxia, and a variety of other neurologic abnormalities. When present, the pruritus is intense and leads to self-mutilation, typically of the head and ears. In cats, the neurologic signs seem to predominate and pruritus is rare. 1, 20a The diagnosis can be confirmed by virus isolation. Treatment is usually not attempted; when it is, the result is unrewarding. Prevention by means of strict hygienic procedures is of paramount importance. Mumps is a human viral disease caused by a paramyxovirus, and there are reports of clinical disease in dogs from households where humans had mumps.' One author (WHM) examined a dog with parotid salivary gland enlargement, a probably vesicular cheilitis, and positive antibody titer to the mumps antigen. Only epidermal collarettes were present on the lips, so biopsies were not performed. The skin lesions resolved spontaneously as the salivary gland returned to normal. Feline rhinotracheitis is an infection with an a-herpesvirus resulting in upper respiratory disease." Occasionally, a cat develops oral and cutaneous ulcers. 1, 16. 38 The cutaneous ulcers are usually superficial and multiple, and can occur anywhere on the body, including the footpads. Stress or trauma to the skin might precipitate the development of the ulcers. Skin biopsies reveal epidermal ulceration with subjacent dermal necrosis and a mixed inflammatory infiltrate. Basophilic intranuclear inclusion bodies may be visualized in the keratinocytes or dermal histiocytes. Herpesvirus can be cultured from the skin; more diagnostically, it can be seen in the keratinocytes via electron microsoopy.P An ulcerative and necrotizing facial dermatitis or stomatitis has been associated with herpesvirus 1 infection in cats.s'- 42c, 47 Affected cats mayor may not have active or historical ocular or respiratory signs. The disorder is recognized most often in adult cats but kittens can be affected. Typically, crusted skin lesions involve the nasal planum, bridge of the nose, and periocular skin (see Fig. 7 -IG). When the crusts are removed, the exposed skin is inflamed and ulcerated (see Fig. 7-1H ). Similar lesions can be found elsewhere on the body. Exfoliative erythema multiforme has occurred in cats following upper respiratory infections. Generalized exfoliation and erosions occur that histologically showed individual cell apoptosis and lymphocytic epitheliotropism. The lesions spontaneously resolve after the infection is cleared." With intercurrent respiratory signs, the diagnosis is straightforward. In the absence of respiratory signs, the differential diagnosis would include the FeLV dermatitis, drug reaction, erythema multiforme, pemphigus vulgaris, and systemic lupus erythematosus. Diagnosis is via skin biopsy. Serologic test results do not confirm active infection nor that the skin disease is due to the virus. In skin biopsies, an ulcerative, often necrotic, dermatitis and suppurative folliculitis and furunculosis is seen ( Fig. 7-10 ). Demodex cati mites may be visible within the follicular lumen.f" There is a perivascular-to-interstitial mixed inflammatory cell dermatitis with many eosinophils. In the surface and follicular epithelium, multinucleated keratinocytic giant cells can be seen ( Fig. 7-11 ) and amphophilic intranuclear (Cowdry type A) inclusion bodies can be seen in the giant cells ( Fig. 7-12 ) and other keratinocytes. A unique feature of this disease is necrosis of epitrichial sweat glands ( Fig. 7-13 ). Ultrastructural studies demonstrate intranuclear virions consistent with herpesvirus. Polymerase chain reaction (PCR) testing in affected cats was strongly positive for herpesvirus 1,21. 42c However, the use of PCR as a diagnostic test for feline herpesvirus-associated disease is of limited value because of the occurrence of healthy carriers." An immunohistochemical test was reported to be accurate.f" In adult cats, the disorder can be triggered by stress or corticosteroid usage. Correction of these problems with the use of antibiotics and other symptomatic treatments may allow for spontaneous healing. Other agents suggested include lysine (250 mg of the formulation without propylene glycol orally q24h), a-interferon, and acyclovir. 38 • 47 These treatments mayor may not be beneficial. Oral ulceration is reported to be more common with calicivirus infection than with rhinotracheitis.' Sporadic reports associate infection with skin lesions of the feet or perineum.P: 25 The tissues are swollen, tender, and ulcerated. Although calicivirus was isolated from the skin in one case, no histopathologic tests were performed to demonstrate whether the virus was causal or a contaminant. Because some infected cats can develop a presumed immune-mediated arthropathy." it is reasonable to assume that the virus can induce primary skin lesions. Papillomaviruses belong to the papovavirus family and are either known to cause or suspected to cause oral papillomatosis, cutaneous papillomas, and cutaneous inverted papillomas in dogs (see Chap. 20).34b At least two strains of virus and probably more exist in the dog. 24a In classic oral papillomavirus infection, self-cure is the rule, provided that the host is immunocompetent.w Two additional syndromes have been recognized that are probably associated with papillomavirus infection in dogs. The first syndrome involves the development of multiple warts on the footpads of young dogs." Affected dogs are 1 to 2 years of age at the onset of symptoms. They develop discrete, firm, hyperkeratotic, often hornlike lesions on multiple pads of two or more paws (Fig. 7-14A ). In the dogs studied, lesions were not detected elsewhere. If the lesions are large or involve the weight-bearing surface of the pad, lameness can occur. The lesions wax and wane in severity, and individual lesions may spontaneously resolve but new ones develop. Histologically, the lesions have the characteristics of viral papillomas; to date, however, efforts to demonstrate the virus have been unrewarding. Treatment with topical keratolytic or softening (e.g., water and petrolatum) agents removes the hyperkeratotic debris, softens the lesions, and decreases the dog's discomfort, but it does not appear to alter the course of infection. Topical dimethyl sulfoxide (DMSO) and oral etretinate have been of no benefit in the few dogs treated. Spontaneous resolution of all lesions has not been recognized and it is unknown whether immunotherapy would be of benefit." The second syndrome involves the development of multiple discrete and pigmented papules, plaques, or nodules ( Fig. 7-15 ). The cases recognized have occurred in young adult dogs (3 to 5 years) with no prior history of skin disease.v 17, 24a, 33 In one dog, lesions developed while the dog was receiving a corticosteroid and spontaneously regressed within 3 weeks of drug withdrawal." Lesions can be singular but typically are multiple from the onset, involved any skin surface, and became more numerous with time. Histologically, the lesions are sharply demarcated and characterized by surface and infundibular follicular epithelial pseudocarcinomatous hyperplasia and dysplasia. No koilocytosis or inclusion bodies were seen. A novel papillomavirus was demonstrated in one dog37 and probably is responsible for the lesions in the other dogs. The lesions can persist unchanged for over 18 months, but transformation to intraepidermal carcinomas may occur.l": 33 No effective treatment is reported. Although papillomas are occasionally recognized in cats, there was no evidence for their viral induction in cats until 1990. 1O , 42b Two aged Persian cats were described with multiple hyperkeratotic plaques (see Fig. 7 -14B).9 The lesions were of variable size, predominately truncal in location, and hyperpigmented in one case. Histopathologic studies showed surface and follicular infundibular epithelial hyperplasia and dysplasia with koilocytosis. Intracytoplasmic inclusion bodies were seen and papillomavirus-like particles were demonstrated on electron microscopy. Immunohistochemical staining demonstrated papillomavirus antigen that had characteristics of a novel feline papillomavirus. Other cases with similar features were subsequently reported.12. 15 The cats were assumed to be immunocompromised. Many cases of multicentric squamous cell carcinoma in situ have been recognized in the cat since 1990 4 . 18, 24, 31 (see Chap. 20). The lesions from these cats also showed surface and follicular hyperplasia and dysplasia, but there was far more cellular atypia and 24 Ultrastructural studies in six cats showed intranuclear particles that were compatible with papillomavirus, These data would suggest that the feline papillomavirus induces long-lasting dysplastic lesions that eventually become neoplastic. Therapeutic options are limited. Surgical removal is usually impractical because of the numbers of lesions, their location, or both, and because new lesions appear after surgery. Topical treatment with 5-fluorouracil, which can be effective in humans and dogs,31 is contraindicated in cats because of its neurotoxicity. Preliminary work suggests that Bradiation therapy (strontium-Btl plesiotherapy) is an effective treatment for early Iesions'", as with surgery, however, it does not prevent new lesions. Anecdotal reports suggest that treatment with interferon alfa may be effective (see Chap. 20). Papovaviruses cause cutaneous and mucosal papillomas (warts) in the dog (see Chap. 20). Feline sarcoma virus produces cutaneous fibrosarcomas in young cats (see Chap. 20). FeLV and feline sarcoma virus have been associated with the development of lymphosarcoma, liposarcoma, melanoma, hemangioma, and multiple cutaneous horns in cats (see Chap. 20). Rocky Mountain spotted fever is caused by the rickettsial agent Rickettsia rickettsii and is transmitted by ticks.I. 52. 55, 56 It is a seasonal disease in the United States, with cases occurring between April and September. Infected dogs develop fever, anorexia, lethargy, peripheral lymphadenopathy, and signs of neurologic dysfunction. Approximately 20% of cases will develop skin lesions of erythema, petechiation, edema, and occasionally, necrosis and ulceration of the oral (see Fig. 7-14C) , ocular, and genital mucous membranes and the skin of the nose, pinnae, ventrum, scrotum (see Fig. 7-14D) , and distal limbs and feet. 51 . 56 Edema of the extremities is frequently seen and is the earliest cutaneous sign. The epididymis of male dogs may be painful and swollen. Hematologic changes may include anemia, leukopenia, or leukocytosis and thrombocytopenia. Skin biopsy reveals necrotizing vasculitis (Fig. 7-16) . Dogs with Rocky Mountain spotted fever have a fourfold rise in serum antibody titer to R. rickettsii. Direct immunofluorescence testing for R. rickettsii antigen in formalinfixed skin biopsy specimens is often positive (antigen seen within vascular endothelium)'! Therapy includes tetracycline (22 mglkg q8h orally), doxycycline (10 to 20 mglkg q12h orally), or chloramphenicol (20 mglkg q8h orally) for 1 to 2 weeks and supportive care. 1. 59 Intercurrent use of high-dose corticosteroids to treat the skin lesions can prolong the rickettsemia and course of treatment but otherwise has no detrimental effects/" The dog presents a potential public health danger when infested with R. rickettsii-infected ticks; there is also a danger when blood or tissues from rickettsemic dogs are handled without suitable protection. Ehrlichiosis is caused by the tickbome rickettsial agent Ehrlichia canis. 1 Systemic signs of illness predominate and include fever, weight loss, depression, lethargy, and anorexia. Hematologic and clotting abnormalities, vasculitis, and monoarthropathy or polyarthropathy also can be seen. Skin lesions are very rare and include a crusting facial dermatitis involving the bridge of the nose.P' pustular and purpuric lesions due to vasculitis, and an intensely pruritic papulocrustous dermatitis." With its immunosuppressive nature, some German shepherd dogs develop recurrent German shepherd pyoderma until the ehrlichiosis is resolved (see Chap. 4). The facial dermatitis had histologic features seen in lupus erythematosus, but the dog was antinuclear antibody (ANA) negative and positive for Ehrlichia canis. Doxycycline, an antibiotic with very little direct effect on the skin, resulted in resolution of the skin lesions This highlights the need to consider infectious agents when the skin lesions clinically and histologically resemble those seen in lupus. Feline haemobartonellosis (feline infectious anemia) is an acute or chronic disease of domestic cats characterized by fever, depression, anorexia, and macrocytic hemolytic anemia.' It is caused by the rickettsial agent Haemobartonella felis. Cutaneous hyperesthesia and alopecia areata have been reported to occur in cats with acute and chronic haemobartonellosis'P, however, no pictures, photomicrographs, or details of any kind were provided to substantiate these cutaneous diagnoses . Toxoplasmosis is a multisystemic disease caused by the coccidian Toxoplasma gondiP' 99 Toxoplasmosis has been rarely reported to cause various cutaneous lesions in humans'" and in cats.v 78 Histopathologic findings in cats were reported to be necrotizing dermatitis and vasculitis with Toxoplasma ( Fig. 7-17 ). PCR-based techniques are available for the rapid and accurate diagnosis of toxoplasmosis.P" Coccidia of the genus Caryospora have a complicated life cycle involving rodents, reptiles, and raptors.'-76 Infection occurs by ingestion of an infected host and results primarily in diarrhea. These organisms have been suspected'<-123 or identifled?" in puppies that developed pustules, plaques, or nodules on the skin of the trunk. The tissue reaction was pyogranulomatous with eosinophils, and numerous organisms in various stages were identified in macrophages and connective tissue cells (Fig. 7-18 ). Neosporosis is caused by Neospora caninum.s- 58, 75, 80, 99.,108,120 Because its tachyzoites and tissue cysts resemble those of Toxoplasma gondii, the organism has doubtless existed unrecognized for years. Its complete life cycle is unknown. Infection occurs via vertical transmission or postnatal inoculation, the latter being most important,58, 117 Exposure to cats may increase the risk of infection.'!" In one study, about 15% of normal dogs were serologically positive. Sporozoites penetrate cells and change into tachyzoites, which divide rapidly and cause tissue damage. Tachyzoites then become bradyzoites within tissue cysts. Dogs of any age can be infected, but clinical signs are more severe in young dogs. Neurologic and muscular signs predominate, but pneumonia, hepatitis, myocarditis, or dermatitis can also be seen. 89. 120 Skin disease has been described in a small number of dogs. Most had widespread draining nodules.?" 87. 99a, 112, 113. 115 but one had a rapidly spreading, ulcerative dermatitis of the eyelids, neck, thorax, and perineurrr" The lesions may be pruritic. Histologically, nodular lesions are characterized by a pyogranulomatous dermatitis. Tachyzoites can be seen within keratinocytes, macrophages, neutrophils, and rarely, in endothelial cells. The dog with ulcerative lesions had an eosinophilic necrotizing dermatitis with severe congestion, thrombosis, and infarction." To differentiate neosporosis from toxoplasmosis, immunohistochemical or ultrastructural studies are needed. Serologic tests are available to determine the rate of infection.U? A titer of~1:800 by indirect fluorescent antibody testing is considered strongly suggestive of active infection.P" Susceptibility testing of N. caninum to various antimicrobial agents has been performed but detailed studies on the in vitro versus in vivo correlation of these data are not available." Susceptibility testing suggests that sulfamethoxazole, azithromycin, canthromycin, erythromycin, doxycycline, minocycline, and clindamycin hydrochloride can be of benefit. Several cases were treated with a 21-day115 or 45-day79 course of clindamycin (12.5 to 18.5 mglkg, orally, ql2h) with resolution of the lesions.79.99a Combination therapy with pyrimethamine (0.25 to 0.5 mglkg, orally, ql2h) and sulfadiazine (30 mglkg, orally, ql2h) is also reported to be effective. 99a When this combination is used, folinic acid (5 mg/day) or brewer's yeast (100 mg/kg/day) is given to prevent bone marrow suppression.P'" Sarcocystis organisms are widespread in nature, especially in cattle and sheep.' Dogs and cats become infected by ingesting tissue cysts (sarcocysts). Sarcocystis species are typically not pathogenic for dogs and cats, although there has been one report of a dog with chronic diarrhea who developed multiple cutaneous abscesses over the whole body and especially on the hind limbs."? Biopsy showed severe necrotizing, fibrinosuppurative dermatitis with numerous neutrophils and fewer eosinophils and macrophages. Vessels were congested and plugged, and numerous protozoal organisms were seen within macrophages and, occasionally, in endothelial cells of vessels. Canine babesiosis is a tickborne hematozoan disease caused by three species of Babesial. 101 : Babesia canis, which is worldwide in its distribution, and Babesia gibsoni and Babesia vogeli, which are more restricted. Infection induces a parasitemia that results in varying clinical signs. Asymptomatic carriers exist. Aside from the oral or cutaneous petechial and ecchymotic hemorrhages associated with thrombocytopenia or disseminated intravascular coagulation, skin lesions are rare. Skin lesions are due to subjacent leukocytoclastic vasculitis with or without vascular necrosis." Clinical signs include edema, ecchymosis, ulceration, and necrosis (see Fig. 7-14E ), which can be seen on the pinnae, axillae, groin, limbs, or scrotum.F" 69 As in ehrlichiosis, dogs with babesiosis can have some of the clinical features of systemic lupus erythematosus and may have a positive ANA titer. Accordingly, all dogs with suspect lupus erythematosus should have serologic tests for appropriate rickettsial or protozoal diseases before the diagnosis of systemic lupus is made. Treatment with pentamidine isothionate resolved the skin lesions in the reported case/" Other babesiacides may also be effective. Leishmaniasis is a serious protozoal infection caused by a variety of Leishmania spp.! 82, 94, 122 Disease is most common in humans and dogs but can be seen in cats and other domestic animals. The disease is worldwide in distribution. In the Old World, most cases in dogs occur in the Mediterranean basin and Portugal, but reports have originated in France, Germany, Switzerland, the Netherlands, and other countries. In the New World, the disease is endemic in South and Central America; endemic foci have been reported in Texas, Oklahoma, Ohio, Michigan, and Alabama." Dogs imported from endemic areas may develop the disease months or years later, so cases could be recognized anywhere. The disease is transmitted to humans and animals by bloodsucking sandflies of the genus Lutzomyia in the New World and Phlebotomus in the Old World. The frequency of infection increases during warm months when the vector load is high. 57 Domestic and wild dogs, rodents, and other wild mammals are the reservoir. Twenty percent of seropositive asymptomatic dogs have Leishmania organisms in clinically normal skin. 84a Because of the occurrence of open lesions, some investigators have expressed concern regarding the possibility of direct or mechanical transmission from dog to dog or from dog to humans. Leishmaniasis in HIV-positive humans is an emerging disease.P'" The possibility that humans act as a reservoir for other humans and animals has been put forth." In general, tissue damage in leishmaniasis is due to granulomatous inflammation and immune complex deposition. It has been hypothesized that dogs with subclinical or latent leishmaniasis may develop cutaneous lesions at the sites of external trauma and resultant inflammatory processes, because amastigotes in blood cells are transported to the inflamed areas. 1l 5a This mechanism could partly explain the distribution of inflammatory and ulcerative lesions at pressure points, which is common in canine leishmaniasis. The incubation period varies from weeks to several years with a gradual onset of signs and continual progression. The disease primarily affects dogs less than 5 years old. Rural animals, especially those who spend the night outdoors, are at an increased risk 133 From 10 to more than 50% of seropositive dogs have no clinical signs of disease and may remain healthy for prolonged periods of time, if not perrnanently.sv-94a. 123a Skin lesions occur in over 80% of dogs with visceral involvement.1, 72, 73, 94. 110, 116 The most common finding is an exfoliative dermatitis with silvery white, asbestos-like scaling. The exfoliation can be generalized but usually is most pronounced on the head, pinnae, and extremities (see Fig. 7-14F ). Nasodigital hyperkeratosis may accompany the scaling, and the involved skin can be hypotrichotic to alopecic. Periocular alopecia (lunettes) is common. The next most common presentation is an ulcerative dermatitis (see Fig. 7-14G and H) . Other findings include onychogryposis (Fig. 7-19) , paronychia, sterile pustular dermatitis, nasal depigmentation with erosion and ulceration, and nodular dermatitis.s" 94a Secondary bacterial pyoderma occurs in about 25% of the dogs. 94a Systemic signs of illness are many and varied. Over 50% of involved dogs show decreased endurance, weight loss, and somnolence. I, 71, 72, 94, 94a Because of the parasitemia and the host's immunologic response to the organism, physical abnormalities are varied, Generalized lymphadenopathy and hepatosplenomegaly are common findings. Other abnormalities include muscle wasting, cachexia, intermittent fever, keratoconjunctivitis, and lameness. Because of the Leishmania-induced cell-mediated immunodeficiency, these dogs can be predisposed to generalized demodicosis in all of its forms. I06a Cats are resistant to experimental infection, and reports of spontaneous cases are rare,59, 93, 96, III The majority of cases had a nodular or crusting dermatitis of the lips, nose, eyelids, and pinnae. A generalized exfoliative dermatitis can also be seen. Because immunodeficiency is not a prerequisite for infection, dogs with leishmaniasis show an immunologic response to the organism. Resistance or susceptibility to clinical leishmaniasis appears to be associated with the stimulation of a T helper-lor T helper-2 cell response, respectively.P" IL-2 and TNF-a seem to playa protective role,94a With infection, serum levels of anti-Leishmania IgG, IgM, IgA, and circulating immune complexes increase and, with high titer, predispose to renal disease. 102, 103, 105 With infection, the number of C021 +, C05+, C04+, and C08+ cells decreases and the degree of incompetence seems to influence the severity of clinical signs. 62, 63, 66, 106 Early in experimental infection, the dog develops a cell-mediated immune response to the organism but this can disappear with the onset of clinical signs.ll B With a persistent cell-mediated response, the dog's clinical signs are absent or milder and the number of organisms found in the tissues is fewer. 62, 66, 85 The differential diagnosis includes pemphigus foliaceus, systemic lupus erythematosus, zinc-responsive dermatosis, necrolytic migratory erythema, sebaceous adenitis, and lymphoma. Laboratory findings usually include nonregenerative anemia, hyperglobulinemia, hypoalbuminemia, and proteinuria. Tests for immune-mediated diseases (Coornb's tests, ANA, lupus erythematosus preparation, rheumatoid factor) can be positive in dogs with Ielshmaniasis.P: 94a The frequency of a clinically insignificant positive ANA titer varies from 16% to over 80% of dogs tested.P 94, 104 Because many of the clinical signs of leishmaniasis overlap with those of systemic lupus erythematosus, immunodiagnostic test results must be interpreted carefully when a dog comes from an endemic area. Demonstration of anti-Leishmania antibodies, positive skin test reaction," or the organism itself confirms the diagnosis. Although dogs can have positive serologic test results in the absence of clinical disease, spontaneous elimination of the parasite is rare; therefore, positive test results indicate infection.' Various serologic tests are available (IFA, ELISA, Dot-ELISA) and the published sensitivity and specificity vary with the test, population being studied, and investigator.50, 84, 94, 118., !27, !28 No test is 100% accurate, with false-negative results reported in more than 10% of infected dogs tested. The test method also dictates whether the test can be used to monitor response to treatment. For that purpose, the indirect immunofluorescence test (IFA) is recommended.s-!3! Amastigotes are most easily seen with Ciemsa's stain and are found most often in smears from lymph nodes or bone marrow (Fig. 7-20) . Identification in other tissues is more difficult and often unrewarding. Lymph node cytology is positive in about 85% of the clinically ill dogs, whereas IFA is positive in about 97%.94. In early clinical disease, cytology may be positive when serology is negative. 94 ' There is no correlation of severity of clinical signs with serological titer. 94 • Skin biopsy findings vary considerably, Orthokeratotic and parakeratotic hyperkeratosis are usually prominent; the inflammatory infiltrate typically consists of macrophages with fewer numbers of lymphocytes and plasma cells. Granulomatous perifolliculitis (Fig. 7-21 ), interstitial dermatitis, superficial and deep perivascular dermatitis, lichenoid interface dermatitis, nodular dermatitis, lobular panniculitis, suppurative folliculitis, and intraepidermal pustular dermatitis ( Fig. 7-22 ) are the nine inflammatory patterns that have been recognized in leishmaniasis; this large number reflects the clinical variability of the disease.?' The three most common patterns are granulomatous perifolliculitis, superficial and deep perivascular dermatitis, and interstitial dermatitis. It is common for a dog to have more than one pattern of inflammation present. In the perifollicular pattern, total obliteration of the sebaceous glands occurs in approximately 45% of the cases. This sebaceous destruction no doubt contributes to the high frequency of clinical exfoliation. The Leishmania organisms are found intracellularly and extracellularly in approximately 50% of cases. They are round to oval, 2 to 4 /-Lm in size, and contain a round, basophilic nucleus and a small, rodlike kinetoplast. Although they are visible in routine stains, Leishmania organisms are best seen when Giemsa stain is used. Immunohistochemical techniques facilitate the identification of the organlsm." peR is at least as sensitive as immunohistochemical detection of Leishmania in biopsy specimens, and may be positive when the latter is negative.n 9 • Dogs with visceral leishmaniasis show increased levels of IgG-2 specifically directed against O-acetylated sialic acids during active disease, and these antibodies have 96.6% sensitivity and 75% specificity." At present, canine leishmaniasis is considered an incurable disease in the vast majority of cases. Treatments can bring about a clinical cure, but relapses months to years after treatment are to be expected. These relapses are probably due to incomplete eradication of the parasite, but could also represent reinfection. Accordingly, with the poor prognosis for cure and the possible reservoir status of the dog for human infection, euthanasia may be indicated. In endemic areas, insect control measures can be beneficial in reducing the rate of insect feeding and, hopefully, infection.P When treatment is indicated, the most widely used treatment is meglumine antimonate. 1, 82 Dosages vary with the study and range from 20 to 50 mglkg given subcutaneously twice daily to 200 to 300 mglkg given intravenously every other day.73., 118b, 124, 126 Remission rates approaching 85% can be achieved with a large number of injections.P: 124 but parasitologic cure rates are much lower. Studies in humans and dogs have suggested that the antileishmanial activity of liposome-encapsulated meglumine antimonate is vastly superior to that of the unencapsulated drug. 70, 125 Other drugs that have been used in canine leishmaniasis include aminosidine, 114, 132 amphotericin B,95 allopurinol,67.,97, 129, 130 metronidazole, and ketoconazole. Allopurinol has been receiving widest attention because of its low cost and safety."? With daily dosages of 11 to 15 mglkg, clinical cure is achieved in most cases, but parasitologic cure is rare. Various drug combinations have been studied, with meglumine antimonate and allopurinol receiving widest usage. 73, 73., 88, 109 In one study, the combination of meglumine and allopurinol was more effective than either product alone.P' The addition of allopurinol improves the clinical response rate, and its use on a daily basis for 1 week each month appears to prevent relapse. However, the rate of parasitologic cure is not impacted. The most helpful new treatment is an admixture of chemotherapy and immunotherapy with LiF2 antigen, an antigen derived from L. infantum. 107 Simultaneous use of this antigen and meglumine resulted in parasitologic cure in all cases tested. There is no correlation between serologic titers and clinical signs in treated or untreated dogsY4. High titers often persist in clinically cured animals and cannot be used to monitor progress of therapy or to confirm complete cure. 94• Antigen-specific lymphoproliferative responses do reappear in successfully treated dogs.ll s, Leishmania organisms can often be demonstrated cytologically, by culture, or by peR in successfully treated dogs. 67., 11Sb Thus, these dogs remain important carriers and reservoirs. Successful treatment of feline leishmaniasis has not been reported. 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