We report a case of subacute to chronic mucocutaneous histoplasmosis in a dog without evidence of underlying immunocompromise. Geographically, this dog lived in the Texas Gulf Coast area, a temperate region where the thermally dimorphic fungus H. capsulatum is endemic and is commonly found in the environment [10, 11]. Potential sources of infection in this case include household dust or contaminated soil (e.g., potted plants, flower beds) [3]. An increased risk of infection has also been reported with the renovation of older buildings or basements [1, 3, 12, 13], which was not obvious from the patient history. The true prevalence of histoplasmosis in companion animals in this geographic region is difficult to determine because of the endemic status of the fungal organism [2, 7, 14].
An increased risk for severe clinical disease following H. capsulatum infection is reported in immunosuppressed individuals [1,2,3], although – in contrast to human patients – many dogs with clinical signs related to infection with H. capsulatum are not known to be immunosuppressed [7]. Infection of dogs typically occurs via inhalation or – less commonly – via ingestion of H. capsulatum spores [1,2,3, 15, 16].
Histoplasmosis has been reported in dogs ranging in age from 2 months to 14 years, but most affected dogs are younger than 5 years of age [2, 7, 17]. At 4.5 years of age, the dog in this case was in the age range – but not the typical breed or breed type – of dogs with an increased risk for contracting systemic histoplasmosis [7, 17]. The dog presented at the end of July with a three-month history of clinical signs. Thus, the infection likely happened in the spring, which concurs with the seasonal spike of histoplasmosis cases in dogs [17].
The case presented shows that cytological and/or histological examination of tissue specimens are suitable for diagnosing nasal histoplasmosis. Cytological examination of the affected tissues in this case suggested infection with H. capsulatum, although the yeast forms were only noted extracellularly. True infection, rather than contamination with environmental H. capsulatum organisms, was subsequently confirmed by both histopathological examination – where yeast forms of H. capsulatum were present within macrophages – and antigen detection via ELISA [15, 18].
Routine hematology and serum biochemistry profiles are typically normal with mycoses affecting the nasal cavity [4]. Peripheral eosinophilia may be seen with fungal infections (particularly aspergillosis) but was not present in this case. Thrombocytopenia and hyperglobulinemia, as seen in this case, are common in dogs with histoplasmosis [1, 2, 7].
The MVista H. capsulatum quantitative antigen ELISA (MiraVista) has been validated for use in dogs and can be performed on serum or urine. This quantitative test detects a component of H. capsulatum galactomannan, a component of the fungal cell wall. The test has a high sensitivity (95%) in dogs [8, 16], but false-negative results are possible, particularly with localized histoplasmosis [12, 16]. A higher sensitivity has been reported for the urine antigen test compared to the detection of antigenemia in people [8, 19], dogs [16], and cats [15], and this finding is consistent with the results reported for the patient described here. In human patients, lower antigen levels are routinely noted in immunocompetent versus immunocompromised individuals, those with a localized versus disseminated disease, and patients with subacute or chronic infection versus acute histoplasmosis [19].
Cross-reactivity of the MVista H. capsulatum antigen test with other endemic mycoses is reported [19]. Although possible, cross-reactivity with Blastomyces dermatitidis is very unlikely in this case given both the cytological findings and the geographical location. H. capsulatum produces a small (2–4 μm diameter) yeast with a thin and clear capsule, whereas the yeast form of B. dermatitidis is larger (8–15 μm diameter) and can demonstrate broad-based budding [1, 20]. Also, blastomycosis is not prevalent in the Texas Gulf Coast area [20]. PCR analysis would have been most specific for fungal identification [1, 15], but it is not routinely available. Fungal culture (which takes over 10–20 days) was not performed due to the high zoonotic risk. Still, potential cross-reactivity of the antigen test is of minor clinical relevance as similar antifungal treatment regimens are used for both infections [1,2,3,4, 20, 21].
Localized bone lysis is typically seen in dogs with sino-nasal aspergillosis, whereas intact nasal turbinates were seen on CT in the dog described in this report. Lameness, arthralgia, and joint swelling have been reported in dogs with H. capsulatum infection [1, 16]. Whether this is due to the presence of H. capsulatum organisms within musculoskeletal structures or reflects a secondary immune-mediated response is unclear, although a series of cats with bone and joint infection was recently reported [22]. The rapid resolution of lameness and swelling with antifungal treatment in the dogs reported here would be compatible with either mechanism, but the recurrent nature of the clinical signs would favor a secondary immune-mediated etiology.
A varying prognosis in dogs with histoplasmosis is described [1]. Survival rates for dogs with pulmonary, gastrointestinal, or disseminated histoplasmosis range from 33 to 78%; better outcomes are generally reported for patients with localized disease [2, 7]. The rapid and sustained response to treatment in the dog described here suggests that nasal mucocutaneous infection may be highly amenable to treatment and conveys a good prognosis.
The treatment of choice for histoplasmosis is systemic or topical triazole antifungal therapy (itraconazole or fluconazole) and/or amphotericin B, and long courses of antifungal treatment (at least 4–6 months) are usually required [1, 2, 4, 7, 9, 13, 21, 23]. Itraconazole is widely regarded as the preferred choice, and appears to be a safe and efficacious treatment option for nasal histoplasmosis [9, 23]. This triazole blocks fungal ergosterol synthesis leading to increased cell membrane permeability and interference with intracellular processes [9]. The long half-life of itraconazole (51 h) allows for once-daily dosing with higher steady-state concentrations [9] but an increased risk of adverse effects. Oral bioavailability of itraconazole capsules is approximately 20% in dogs [9], and generic pelletized itraconazole capsules as used in this case are pharmacokinetically similar to brand-name itraconazole capsules [21, 24]. In the case presented here, this treatment resulted in a significant clinical improvement within 13 weeks (3 months). However, the effects of treatment were likely much longer given the high volume of distribution and long half-life of itraconazole [9].
Hepatic injury appears to be a dose- and duration-dependent side effect of itraconazole treatment [1, 3, 9]. Periodic evaluation of serum liver enzyme activities (especially hepatic leakage enzyme activities) and liver substrates is therefore recommended during itraconazole treatment [3, 7, 9, 25]. In the case presented, serum ALT activity increased to 2.8-times above the upper reference limit 2 weeks after starting itraconazole treatment but normalized in 3 weeks following a 40% dose reduction (13 mg/kg q24h to 8 mg/kg q24h). The lower dose was achieved by resizing the pellet-containing original capsules by weighing to obtain lower-dose capsules [21]. This approach was preferred over switching to the brand-name itraconazole liquid solution due to the costs involved. Therapeutic drug monitoring [21] was not performed in this patient, thus information regarding trough levels achieved with the lower dose was not available.
Ulceration of the external nares is routinely noted in dogs with fungal infection within the nasal cavity [4, 26]. Nasal infection with H. capsulatum is unusual in dogs and cats [1, 4, 7, 16], and involvement of the mucocutaneous area has not been described. This patient’s history and disease course led us to a presumptive diagnosis of primary nasal histoplasmosis. However, the possibility of an underlying disease (e.g., idiopathic lymphoplasmacytic rhinitis) or an injury to the nose cannot be discounted. It is also possible that prior antimicrobial and/or anti-inflammatory treatment predisposed this dog to subsequent infection with H. capsulatum. As previously reported, this case supports that antibiotic treatment should be used sparingly in nasal discharge cases in dogs [26].
Histoplasmosis typically presents as a systemic mycosis in dogs [1, 2, 7]. While the disease appeared to be localized primarily to the nasal cavity in the case presented, carpal swelling and lameness, as well as mild splenomegaly might have indicated extra-nasal involvement. Absent the results of any further diagnostics (e.g., synovial and/or splenic aspirates), this possibility can neither be confirmed nor excluded. This dog’s mild initial antigenuria (< 4 ng/mL [19]), along with his rapid and sustained clinical resolution with only 3 months of antifungal treatment, make a disseminated mycosis less likely, as systemic infections typically require longer courses of treatment [1,2,3].
Monitoring of H. capsulatum antigen levels has been reported as effective means to monitor response to treatment in human and veterinary patients with histoplasmosis [8, 27]. It is noteworthy that this dog’s H. capsulatum urine antigen test was negative after just 2 weeks of itraconazole. The authors attributed this to the localized nature of the infection, and therefore relied on the appearance of the affected area to guide treatment decisions.
Because the test was repeatedly negative during follow-up evaluations, the improvement and resolution of clinical signs appeared to be the best means of monitoring the dog during treatment with itraconazole.
We acknowledge a few limitations to this case report. Most importantly, diagnostics pertaining to the concurrent lameness were limited to radiographic studies. Infection of the carpal bones or joints with H. capsulatum cannot therefore be excluded. Carpal arthrocentesis with joint fluid cytology may have provided additional useful information, as organisms were routinely identified in synovial fluid in a recent series of cats with histoplasmosis and bone or joint involvement [22]. In addition, it is the opinion of the authors that this dog was not immunocompromised, as he had not received any immunomodulatory therapies prior to the onset of clinical signs and appeared otherwise systemically well. However, an occult disease process impacting immune responses (e.g., a congenital immunodeficiency syndrome such as selective immunoglobulin deficiency) cannot be completely excluded. During the dog’s physical examination, a heart murmur (grade II/VI) was noted and presumed to reflect a mitral valve regurgitant jet due to degenerative mitral valve disease or mitral valve dysplasia. Further diagnostics (i.e., echocardiogram, systemic blood pressure) to evaluate the murmur were recommended but declined by the owner. Concurrent endocarditis was therefore not excluded, but seems highly unlikely.
This case suggests that dogs with nasal mucocutaneous histoplasmosis may respond well to systemic antifungal therapy, and experience excellent long-term outcomes. H. capsulatum antigenemia and antigenuria may be absent or modest, and clinicians must therefore rely on the appearance of the affected area to guide treatment decisions.
