Infection with the pathogenic fungus Histoplasma capsulatum can result in systemic disease in several species of animals, including dogs and cats. While the exact prevalence of this infection is unknown for these animals, large areas of endemicity exist throughout the world. In the United States, the largest number of cases occurs in the Ohio, Missouri, and Mississippi river valleys. One study reported histoplasmosis as the second most common fungal infection in cats.1 Infected dogs and cats may present with a myriad of clinical signs, commonly including pyrexia, anorexia, and lethargy. Histoplasmosis is an important differential diagnosis to consider in animals from endemic areas.
Histoplasmosis was first described at the Panama Canal in 1905 by the American physician Samuel Darling.2 During an autopsy of a patient suspected of having miliary tuberculosis, microscopic examination revealed intracellular organisms in many tissues, including the lungs. Because of the organisms' encapsulated appearance, resemblance to plasmodia, and location within histiocytes, Darling named the agent Histoplasma capsulatum. Thinking that he had identified a new form of visceral leishmaniasis, Darling incorrectly identified the organism as protozoal. In 1912, the Brazilian physician and pathologist Henrique da Rocha-Lima reviewed Darling's slides and suspected the organism was a yeast.2
Histoplasmosis may have an acute or chronic clinical course.7-9 Depending on the fungal inoculum size and host immunocompetence, H. capsulatum infections may result in subclinical infection, dormant infection with subsequent reactivation and dissemination, or pulmonary or disseminated histoplasmosis.10-13
Although histoplasmosis has been reported in dogs from 5 months to 11 years old,8,9 it is most commonly seen in dogs < 4.11 No consistent sex predilection has been documented. Male dogs have been reported to be 1.2 times more frequently affected than females,11,14 while in other reports, females are more frequently affected than males.8,9 One study reported that pointers, Weimaraners, and Brittany spaniels had an increased risk of histoplasmosis.11,14
Once thought to be rarely affected, cats are now considered as likely as dogs to develop clinical histoplasmosis.10,11,15 In a retrospective study of 571 cats with deep mycotic infections, histoplasmosis was the second most commonly reported fungal infection (16.7% of cases) after cryptococcosis (46.1% of cases). The reported age of cats with histoplasmosis ranged from < 2 months to > 15 years, with most cases occurring in cats < 2 years old. Males and females were affected in about equal numbers, which1 contrasts with a previous study of 18 cats with pulmonary histoplasmosis in which females outnumbered males 2 to 1.16 Thus, as in dogs, conclusions regarding sex predilection in feline histoplasmosis cannot be drawn.
In a review of 96 cats with histoplasmosis, Persians and Siamese were found to be overrepresented and underrepresented, respectively; this has not been reported elsewhere in the literature.1 Of these 96 cats, 15% had positive test results for feline leukemia virus (FeLV) infection.1 In contrast, a previous retrospective study of 12 cats with disseminated histoplasmosis revealed no association between FeLV infection and histoplasmosis.15
The clinical signs seen in dogs and cats with histoplasmosis vary depending on which form of infection has taken root.
Acute pulmonary histoplasmosis in dogs and cats is thought to be uncommon. In dogs, this form is characterized by a rapid onset of dyspnea and cyanosis. Dogs with chronic pulmonary histoplasmosis are presented for evaluation of a mild, chronic cough and a history of weight loss and inappetance.7 Coughing may be due to partial airway obstruction secondary to hilar lymphadenopathy.17 Most affected cats have disseminated disease, and, even with evidence of pulmonary involvement, they seldom cough.10,11,18 Other clinical signs of respiratory tract involvement include dyspnea and tachypnea.11
Canine disseminated histoplasmosis
Acute disseminated histoplasmosis affects multiple organs, with a history of illness of only a few days' duration in experimental animals.19 Gastrointestinal involvement was reported in 28 of 36 (78%) dogs with chronic disseminated histoplasmosis.8,9 Large bowel diarrhea, characterized by hematochezia, mucus, and tenesmus, is common.11 With disease progression into the small intestine, diarrhea may become watery and voluminous, and protein-losing enteropathy may occur.8-11
In addition to gastrointestinal signs, common nonspecific clinical signs of chronic disseminated histoplasmosis in dogs include weight loss, inappetence, and fever of unknown origin that is nonresponsive to antibiotic therapy.7-11,20
Abnormal lung sounds, with or without accompanying cough or dyspnea, are noted in fewer than 50% of dogs with disseminated histoplasmosis.11 Infiltration of the organism into other organs, including the liver, spleen, and bone marrow, may result in hepatomegaly, splenomegaly, or pallor associated with anemia.8,9 Less commonly reported clinical findings of canine disseminated histoplasmosis include
Feline disseminated histoplasmosis
Clinical signs of feline disseminated histoplasmosis are often chronic and nonspecific. Weight loss, pale mucous membranes, lethargy, pyrexia, anorexia, and dehydration were the predominant findings in 12 cats with disseminated histoplasmosis. Five of the 12 cats were tachypneic with abnormal lung sounds.15 A review of 96 cases reported weakness, lethargy, emaciation, dehydration, and pyrexia as the most common signs.1 Respiratory signs such as dyspnea, tachypnea, and occasional coughing were noted in 39% of the cats.1
While sometimes reported to be uncommon, ocular involvement may occur in disseminated histoplasmosis more often than in other systemic mycoses in cats.1,36 In a review of 96 cats with histoplasmosis, 24% of the cats had ocular involvement including chorioretinitis, anterior uveitis, or retinal detachments.1 Granulomatous chorioretinitis occurs, possibly because of H. capsulatum in the choroid and retina.34,37 Additional ocular involvement may include retinal hemorrhage, optic neuritis, and fungal granulomas.15,38,39
About one-third of affected cats may have lymphadenopathy, splenomegaly, or hepatomegaly, occasionally accompanied by icterus.11 In contrast to dogs, primary intestinal histoplasmosis is unusual in cats; in one cat, this form of histoplasmosis caused vomiting and watery diarrhea with hematochezia.40
Cutaneous lesions, infrequently reported, are nodular or ulcerated and may exude serosanguineous fluid.11,32,38,41-44 Neurologic signs also occur.45 Rare clinical findings include nasal polyps and oral and lingual ulceration.10,11
CLINICAL PATHOLOGY AND DIAGNOSTIC IMAGING FINDINGS
The results of routine diagnostic tests such as a complete blood count, a serum chemistry profile, a urinalysis, and radiographic or ultrasonographic examinations may raise your suspicion of histoplasmosis.
Complete blood count
The most common hematologic abnormality in dogs and cats with disseminated histoplasmosis is a normocytic, normochromic nonregenerative anemia.10,11,46 Anemia in dogs is usually mild to moderate; the packed cell volume (PCV) ranges from 20% to 37% (reference range = 35% to 57%47).8 In a report of 12 cats, anemia ranged from moderate (PCV = 20% to 25%) to severe (PCV < 20%) (reference range = 30% to 45%47).15 Causes of anemia may include intestinal blood loss, chronic inflammation, or bone marrow infiltration.8,11,30
Other hematologic abnormalities reported in dogs include monocytosis, neutrophilia, eosinopenia, and, less commonly, neutropenia, eosinophilia, basophilia, or a degenerative left shift.8-11,35,48,49 While infrequently observed, histoplasmosis is reported as a risk factor for neutropenia.48 Mild to severe thrombocytopenia may occur in as many as half of affected dogs.11 In a report of three dogs with histoplasmosis, platelet counts ranged from 5,000 to 81,000/mm3 (reference range = 211,000 to 621,000/mm3). Thrombocytopenia may be caused by increased platelet consumption or, possibly, sequestration in association with splenomegaly and hepatomegaly.46
A wide range of other hematologic abnormalities also occur in cats. Both neutropenia and neutrophilia have been reported,1,18,38,50 and pancytopenia was documented in one cat with toxic changes to the neutrophils.18 Thrombocytopenia may be observed in as many as one-third of affected cats.11 Chronically infected cats may not show any hematologic abnormalities.38
Serum chemistry profile
Hypoalbuminemia was reported in five of five cats and nine of 11 dogs with disseminated histoplasmosis.8,15 The hypoalbuminemia may result from intestinal blood loss, decreased synthesis associated with inflammation, liver dysfunction, or protein-losing enteropathy.8-11,15 Hyperglobulinemia secondary to inflammation is reported in dogs and cats.8,10,15,33,38 Hepatic involvement can result in increased serum alanine aminotransferase (ALT) activity, alkaline phosphatase activity, and total bilirubin concentration.8,9,11,38 Hypercalcemia has been reported in cats with histoplasmosis.38
While proteinuria has been reported,8,38 urinalysis results in dogs and cats with histoplasmosis are usually within reference ranges.10,50
Cats. Unspecified thoracic radiographic abnormalities were present in 27 of 31 (87.1%) cats with disseminated histoplasmosis.1 An interstitial miliary pattern was the most common radiographic abnormality in a study of 12 cats.15 Radiographic patterns in cats with pulmonary histoplasmosis include a fine, diffuse or linear interstitial infiltrate; nodular interstitial infiltrate; or, rarely, alveolar pattern.16,53,54 Enlarged or mineralized tracheobronchial lymph nodes were not a feature of feline pulmonary histoplasmosis.16 Areas of pulmonary consolidation were reported in one cat.54
Abdominal radiography and ultrasonography
Abdominal radiographs in dogs and cats may show hepatomegaly or splenomegaly; ascites was reported in one dog.9,10,15,35,55 On abdominal ultrasonographic examination, the affected liver may have a hyperechoic appearance, as well as nodular lesions.10,36,55 Lymphadenomegaly may also be observed.9
Dogs. Bony lesions of histoplasmosis are rarely reported in dogs; affected sites include the tibia and tarsal, carpal, and metacarpal bones.26,27,56,57 Radiographic abnormalities include soft tissue swelling and joint effusion with osteolysis and proliferative sclerosis.26,56
Cats. In a review of 96 cases of feline histoplasmosis, all seven cats with lameness had changes consistent with osteomyelitis on long bone radiographs.1 Multiple long bones, as well as carpal and tarsal bones, may be affected.38,43,44,58 A predilection for sites distal to the elbow and stifle joints exists.43 Lesions are predominantly osteolytic, with periosteal and endosteal proliferation seen in some cases.43 Bone weakening can result in pathologic fractures that heal after treating the disease.43,44 Additional radiographic changes reported in one cat included soft tissue swelling and subchondral bone collapse.58
Histoplasmosis is commonly diagnosed by identifying the H. capsulatum organism.7,11,51,59
Cytology and histology
When a peripheral blood smear is examined, identifying H. capsulatum is enhanced by examining the buffy coat.7,10,18,38,53 Histoplasma capsulatum has been documented in the neutrophils (Figure 3), monocytes, and, rarely, eosinophils of affected dogs.10,30,35,46,49 A review of cats with histoplasmosis reported the organism within phagocytic cells in peripheral blood smears in 11 of 56 (19.6%) cases.1 In a separate study, examination of peripheral blood smears revealed the organism in four of 12 (33%) feline cases.15
Histologic evaluation of affected tissues often shows granulomatous or pyogranulomatous inflammation with intracellular organisms. Histoplasma species organisms are not well-visualized with routine hematoxylin-eosin stain. Periodic acid-Schiff, Gridley's fungal, or Gomori methenamine silver stains should be used to enhance detection.10,11 Histoplasma capsulatum has been identified antemortem by histologic examination of several tissues (Table 1).
Polymerase chain reaction testing
To date, polymerase chain reaction (PCR) testing has been used primarily in research settings to confirm a diagnosis of histoplasmosis. A nested PCR technique has been applied in situ to DNA extracted from pus and paraffin-embedded tissue samples of dogs with histoplasmosis.64,65 PCR testing is not commercially available for diagnostic testing for histoplasmosis in cats and dogs.
In people, standard serologic tests include complement fixation and immunodiffusion, which use yeast and mycelial antigens to detect antibodies against H. capsulatum.61 Complement fixation is more sensitive.62 However, when complement fixation was performed in nine cases of canine histoplasmosis, only one titer of 1:8 was obtained.9 Similarly, serologic testing performed in nine cats with histoplasmosis had positive results in only four of the cats (44%).1 Because of a myriad of false negative and false positive results, serology for antibody detection is not considered a reliable method of diagnosis in cats and dogs.10,11
Antigen detection tests are used to detect histoplasmosis in human serum, urine, bronchoalveolar lavage fluid, and cerebrospinal fluid.63 Cross reactivity occurs with other agents of disseminated mycoses, such as Blastomyces species.66 Research on the use of antigen detection tests to diagnose canine and feline histoplasmosis is limited. Full validation of these tests for dogs and cats is pending.
Even though itraconazole is reportedly the treatment of choice for histoplasmosis in dogs and cats,10,38 few reports of specific studies of its efficacy in these species exist. One report indicated good efficacy in eight cats treated with itraconazole (5 mg/kg orally b.i.d.) for 60 to 130 days, with two cats relapsing and requiring additional therapy to achieve complete remission.38 Because of marked variability in the oral absorption of itraconazole, some cats may require twice-daily dosing at 10 mg/kg.68 Different formulations of itraconazole exist (Table 2); of these, the oral suspension has the greatest bioavailability.22,68,69 Use of the intravenous formulation of itraconazole may be considered in animals that cannot be treated with an oral formulation. However, little data exist on the use of intravenous itraconazole in dogs and cats.22,69
Successful treatment of feline histoplasmosis with varying dosages of ketoconazole has been reported.18,44,50 However, because of its reduced spectrum of activity against Histoplasma species and increased relative toxicity, ketoconazole is not a first-choice treatment.10
Voriconazole and posaconazole
Voriconazole, a triazole structurally related to fluconazole,72 and posaconazole, a triazole structurally related to itraconazole, also have activity against H. capsulatum. There are not sufficient data regarding the safety and efficacy of these newer agents in dogs and cats to warrant recommending their use. They may be considered as rescue therapy for patients in which other treatments have failed. Pharmacokinetic data for these agents in dogs are available.73,74
In dogs and cats with severe disseminated or pulmonary histoplasmosis, amphotericin B or combination therapy with amphotericin B and itraconazole may provide more effective control.10 Itraconazole treatment is started at the same time as amphotericin B and is continued for the normally recommended duration of treatment (Table 2) after amphotericin B treatment is terminated. Although typically administered intravenously, subcutaneous amphotericin B has been used to treat cryptococcosis.75
Nephrotoxicosis is an important adverse effect of amphotericin B therapy, particularly when the deoxycholate form is used. Since urine changes may precede serum elevations in urea nitrogen and creatinine, serial evaluation of urine specific gravity and monitoring for evidence of casts, protein, or hematuria should be performed.22 Because of their comparatively reduced nephrotoxicity, the lipid and liposomal forms of amphotericin B are preferred, and should be considered when amphotericin B treatment is indicated.76,77
While the lipid and liposomal forms of amphotericin B are more expensive, this increased expense must be considered in light of increased safety. The financial and health costs of toxicosis related to using the deoxycholate form may be as much or more of a burden than the additional cost of the lipid forms.78
Because of the risk of immunosuppression and subsequent dissemination of infection, glucocorticoids are generally not recommended in treating histoplasmosis. However, airway obstruction from enlarged hilar lymph nodes and inflammation associated with proliferation of the organism in the lungs can be life-threatening.10 In a study of dogs with enlarged hilar lymph nodes secondary to chronic pulmonary histoplasmosis, corticosteroid administration (prednisone 2 mg/kg orally every 12 to 24 hours) resulted in the resolution of the clinical signs of airway obstruction in less than one week, compared with 8.8 weeks in dogs treated with antifungal therapy.17 Only consider using corticosteroids if there is marked respiratory compromise and if no organisms are found on cytologic or histologic evaluation. Additional supportive therapy for pulmonary histoplasmosis may include oxygen supplementation and antibiotics, if clinically indicated.11
TREATMENT DURATION AND MONITORING
While the duration of therapy is variable, most patients treated with antifungal drugs will receive these medications for a minimum of four to six months or two months after resolution of all clinical signs.10 Patients should be rechecked at monthly intervals. In addition to physical and ocular examinations, a serum chemistry profile is recommended to monitor hepatic enzyme activity while an animal is receiving azole antifungal therapy.11 In a study of 112 dogs treated with itraconazole, anorexia was the most common adverse effect and was usually associated with an increase in ALT activity. The anorexia resolved within three or four days after the medication was stopped, and therapy was reinstituted one week after discontinuation.79 In dogs, if the serum ALT activity is > 250 IU/L, consider discontinuing itraconazole therapy.80 In dogs and cats with anorexia and increased ALT activity, treatment can be resumed at half the original dose once the anorexia resolves or the hepatic enzyme activity returns to reference values.22,81 Similar recommendations apply for animals exhibiting signs of cutaneous vasculitis.81
Response to therapy should be evaluated through the resolution of clinical signs, hematologic and biochemical abnormalities, and radiographic lesions.10 Treatment is continued for a minimum of one month past resolution of clinical signs, and animals should be reevaluated for evidence of relapse three and six months after therapy is discontinued.11
The prognosis depends primarily on the extent and severity of infection. Pulmonary histoplasmosis may resolve without specific antifungal therapy,82 and dogs and cats with pulmonary histoplasmosis can have a good prognosis. The prognosis for disseminated histoplasmosis depends on the degree of dissemination and severity of clinical signs.10,11 While central nervous system involvement often carries an unfavorable outcome,33,34 recovery of neurologic function is possible.45
With ocular involvement, the prognosis for return of vision is guarded to poor.37 One recent report of feline ocular histoplasmosis documented return of vision with complete resolution of retinal hemorrhages six months after the initiation of systemic itraconazole therapy in a cat.39
Vaccination against histoplasmosis is not available in cats and dogs, so the recommended method of protection is preventing exposure to potentially Histoplasma species-laden areas, such as chicken coops, bird and bat roosts, and construction and excavation sites.4,10
Histoplasma capsulatum is a saprophytic, dimorphic fungus that affects people and animals. The primary route of transmission is by inhaling conidia from the soil. It is thought that most infections are self-limiting, but pulmonary or disseminated disease may occur. Clinical signs in cats are often chronic and nonspecific, while dogs often display gastrointestinal signs. Definitive diagnosis is based on cytologic or histologic identification of H. capsulatum. The treatment of choice in cats and dogs is the azole antifungal agent itraconazole. The prognosis depends on the extent of disease and can range from guarded to excellent. The best method of prevention is to avoid exposure to contaminated areas. Horizontal or zoonotic transmission has not been documented, but common-source infection has been observed.
The authors wish to thank Dr. Craig Thompson, DACVP, for obtaining and providing the digital photomicrographs and Dr. Jacob Rohleder, DACVR, for interpreting the radiographic images used in this manuscript.
Kelly Gingerich, DVM
Lynn Guptill, DVM, PhD, DACVIM
Department of Veterinary Clinical Sciences
School of Veterinary Medicine
West Lafayette, IN 47907
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