Blastomyces dermatitidis (Blastomycosis)

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MICROBIOLOGY

Originally described in 1894 by Gilchrist, blastomycosis is an important pyogranulomatous systemic mycosis caused by Blastomyces dermatitidis, a thermally dimorphic fungus which grows as a yeast at 37°C and as mycelia at 25°C. The perfect or sexual stage is Ajellomyces dermatitidis. In the yeast form, the organism is round, measures 5-15 µm in diameter, and has a thick doubly-refractile cell wall. Broad-based budding is characteristic . At room temperature, the imperfect stage of the organism grows as a fluffy white mold on Saboroud's media , and at 37°C, it grows as a brown folded colony of yeast (4).

EPIDEMIOLOGY

Areas which are endemic for B. dermatitidis in the United States include the south central and midwestern portions of the country, especially those areas around the Great Lakes and the Ohio and Mississippi river valleys (22, 38). Outside of the U.S., well-documented cases have been reported most commonly from the Canadian provinces of Ontario and Manitoba, where incidence rates equal or exceed those in certain hyperendemic sites in the United States (27). Fewer well-documented cases have been reported from Central and South America, and Western Europe, but the disease seems to be widespread in Africa. Cases occurring outside of the traditional endemic area are increasingly recognized. For instance, cases occurring in eastern Colorado have been reported (13).

Current evidence indicates that the organism exists in warm, moist soil enriched by organic debris including decaying vegetation and wood. In endemic areas, small point source outbreaks have been associated with recreational and occupational activities occurring in wooded areas along waterways (21,25). There is a striking male predominance among clinical cases of blastomycosis, and there is usually a recent history of occupational or recreational exposure, especially heavy equipment operation, forestry, farming, or hunting (25). Lacking sensitive and specific screening methods such as skin tests and serology, the actual number of infected individuals is unknown, but asymptomatically-infected persons likely comprise the vast majority of these individuals.

CLINICAL MANIFESTATIONS

Patients with acute pneumonia due to B. dermatitidis most often present with non-specific flu-like symptoms, non-productive cough, and chest radiographic findings that are either non-specific or entirely negative . Most cases go unrecognized and untreated with specific antifungal therapy (3,5,25). Rarely, cases of acute overwhelming pulmonary blastomycosis with respiratory failure and acute respiratory distress syndrome have been reported and are associated with an extraordinarily high mortality (26). Outside of an epidemic setting, it has been difficult to determine how often the acute pneumonic syndrome occurs relative to the number of cases which progress to chronic pulmonary or extrapulmonary disease, but current understanding suggests that the majority of patients exposed to B. dermatitidis develop a self-limited illness (3,5,25).

Chronic Pulmonary Infection

Chronic pneumonia is the single most common clinically entity associated with blastomycosis, and is recognized in 60-90% of patients with proven disease. The disease is typically indolent with low-grade fever, weight loss, other constitutional symptoms, chronic cough, and sputum production (3,5,33). Hemoptysis is uncommon. The disease is most often mistaken for tuberculosis, other bacterial and fungal causes of chronic pneumonia, and primary lung malignancy

Skin and Subcutaneous Tissue

The skin and subcutaneous tissues are the second most common site involved with blastomycosis, occurring in 40-80% of cases. Two types of skin lesions are generally seen: papulosquamous, eruptive, and verrucous lesions and cutaneous ulcers . Subcutaneous nodules are also common, and may occur alone or with either verrucous lesions or cutaneous ulcers. Nodules may suppurate and drain spontaneously, evolving into chronic ulcerative lesions (25).

Osteoarticular

The bones and joints are the next most frequently involved sites, occurring in approximately 5-50% of patients. Osteoarticular disease is one of the most indolent forms of blastomycosis, and most frequently involves long bones, vertebrae, ribs, and cranium (1,12). Patients may present with pathologic fractures due to destructive bony lesions or with localized bone pain. Extension from a destructive bony lesion into the soft tissue causing localized abscesses (e.g., psoas abscess) is not uncommon (36). Joint involvement is usually limited to larger joints such as the knees, ankles, and hips. Synovial fluid is purulent with a predominance of polymorphonuclear cells on fluid analysis.

Genitourinary

Genitourinary involvement occurs in 10-30% of patients with blastomycosis, and is most often manifest in the male as prostatitis or epididymitis. The testes may also be involved. Males with prostatic involvement usually present with symptoms of obstruction and a tender mass on prostate exam. Genitourinary blastomycosis in women may involve the uterus and adnexa, and may be misdiagnosed as tuberculosis or cancer (25).

Central Nervous System

The central nervous system (CNS) is involved in up to 5% of non-immunocompromised patients with blastomycosis. CNS blastomycosis may present as either a mass lesion(s) or as chronic meningitis (2,16,25). The diagnosis of chronic meningitis due to B. dermatitidis is suggested by the presence of a substantial number of neutrophils in the cerebrospinal fluid of a patient with chronic meningitis and an appropriate epidemiologic history, and is confirmed by the presence of the typical morphologic appearance of the organism on histopathologic specimens of CSF or tissue (19).

LABORATORY DIAGNOSIS

Definitive diagnosis of blastomycosis requires isolation in culture of B. dermatitidis from a clinical specimen . A presumptive diagnosis is made on the basis of histopathology revealing characteristic, broad-based, budding yeasts with a doubly-refractile cell wall demonstrated from a clinical specimen . B. dermatitidis can usually be distinguished from other yeasts on the basis of these distinctive morphologic characteristics.

The process of obtaining specimens is dependent on the site of involvement. Among patients with presumed pulmonary disease, expectorated sputum will reveal organisms on KOH preparation or special stains approximately 50-70% of the time (3,5). Bronchoscopy should be reserved for those patients unable to produce sputum, and who have no extrapulmonary lesions that are readily accessible for examination. Examination by wet prep or special stain of exudate from cutaneous or subcutaneous lesions, synovial fluid, and soft tissue abscesses usually reveals the organism. By contrast, direct examination of CSF among patients with suspected blastomycotic meningitis is usually negative for yeasts.

Serologic assays for blastomycosis are available in several reference laboratories. A urine and serum assay for Blastomyces antigen has been approved and is broadly available in the United States (9,35). The assay is reasonably sensitive, but has significant cross-reactivity with the Histoplasma antigen assay, thus the assay is non-specific and of limited usefulness in the specific diagnosis of blastomycosis. Despite the availability of this and other assays, the diagnosis of blastomycosis primarily rests on clinical, pathologic and traditional microbiologic findings(14,18).

PATHOGENESIS

Primary infection with B. dermatitidis occurs when aerosolized conidia are inhaled, and once in the lungs at body temperature, these conidia transform to the yeast phase. A self-limited infection develops in the majority of persons. In a smaller group of patients, chronic infection limited to the lungs, or disseminated infection involving extrapulmonary sites develop. Blastomycosis may occur in the laboratory after accidental inhalation, or percutaneous inoculation. Outside of very unusual circumstances, person-to-person transmission of B dermatitidis does not occur (11). Likewise, perinatal transmission of the organism is exceedingly uncommon (40).

Most cases of blastomycosis occur in individuals who are living in an endemic area at the time of diagnosis, though several cases of endogenous reactivation have been documented among patients who had not lived in nor visited an endemic area for prolonged periods. The majority of recent cases of endogenous reactivation blastomycosis have been reported among patients with the acquired immunodeficiency syndrome who have not lived in an endemic area for several years, providing new insight into long-term latency potential of B dermatitidis (29,31).

SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo

Single Drug

Susceptibility testing for dimorphic fungi remains poorly standardized, but in vitro and in vivo data exist concerning the susceptibility of B. dermatitidis to various antifungal agents. Amphotericin B has the best in vitro activity, and consistently demonstrates fungicidal activity in animal models and is generally regarded as the most active compound. Among available systemic azole antifungal agents, all have excellent in vitro activity and in animal models against B. dermatitidis. Currently available azoles are fungistatic (Table 1). The echinocandins do not have significant activity against B dermatitidis.

Among the azoles, posaconazole and isavuconazole demonstrate the greatest activity in vitro, but there are few animal data and very limited data from isolated case reports in humans (12,34,39).. Despite the availability of these highly active compounds, a vast amount of clinical experience and the IDSA clinical treatment guidelines continue to support itraconazole as the drug of first choice for most cases of non-life-threatening blastomycosis (8).

Combination Drugs

There are no clinically relevant data concerning combination drug therapy for blastomycosis.

ANTIMICROBIAL THERAPY

General

There are currently 7 antifungal agents which have demonstrated efficacy in the treatment of human blastomycosis including amphotericin B, ketoconazole, itraconazole, posaconazole, isavuconazole, voriconazole and fluconazole. There have been no published therapeutic trials comparing different antifungal agents in blastomycosis, thus our understanding of what constitutes the most effective therapy for this disorder is largely based on small to moderate sized clinical trials, case reports, retrospective reviews and anecdotal experience. Historically, conventional (deoxycholate) amphotericin B (AmB) has been the mainstay of therapy for all forms of blastomycosis since its availability in 1958. Clinicians generally prefer a lipid formulation of AmB over the deoxycholate formulation due to less nephrotoxicity, and this approach is endorsed by the most recent IDSA guidelines for the treatment of blastomycosis (8,10). The published efficacy of AmB in all forms of blastomycosis ranges between 66% and 93% depending on the dose of drug, duration of therapy, underlying illness and disease severity. For mild to moderate disease, efficacy generally exceeds 90%. Unfortunately, all formulations of AmB must be administered by the intravenous route and they have significant renal, electrolyte, hematologic, and infusion-associated toxicities. Consequently, orally administered and less toxic azole antifungal agents are an attractive alternative to AmB.

Ketoconazole was the first of the azoles to be extensively studied and widely used for the treatment of non-life threatening, non-central nervous system blastomycosis. The first large study of ketoconazole for blastomycosis compared different doses (400 and 800 mg daily) in 80 patients, and demonstrated a successful outcome in 78% and 100% of patients who received at least 6 months of therapy with 400 mg or 800 mg of ketoconazole daily, respectively (28). A second study evaluated ketoconazole 400 mg daily in 44 patients with blastomycosis and led to a successful outcome in 80% (6). Dose-limiting toxicity due to ketoconazole was seen in both studies and included nausea, vomiting, rash, pruritus, decreased libido, impotence, and gynecomastia. Recently, ketoconazole received an FDA warning restricting its use, and is now not considered first line therapy for any fungal infection because of potential liver and adrenal toxicity.

Itraconazole, an orally available antifungal, is the drug of choice for most patients with mild to moderate non-life-threatening blastomycosis that does not involve the central nervous system. Dismukes and colleagues reported the efficacy and toxicity of itraconazole in 48 patients with non-life threatening non-central nervous system blastomycosis (14). Patients were started on 200 mg daily. For those patients who had persistent or progressive disease at this dose, the dose could be increased to 300 mg or 400 mg daily. Among 48 evaluable patients, 43 (89%) were successfully treated. Furthermore, 38 of 40 (95%) of patients who received at least 2 months of therapy had successful outcomes. These results are similar to the efficacy seen with amphotericin B for mild to moderate disease. The median duration of treatment of successfully treated patients was about 6 months. Itraconazole was well tolerated at both low and higher doses, and nausea and vomiting were the most common drug-related toxicities.

Despite its very favorable pharmacokinetics and safety profile, there are relatively few data concerning the use of fluconazole for the treatment of blastomycosis. An early study of fluconazole in blastomycosis evaluated 200 mg and 400 mg daily in 23 patients with non-life threatening, non-central nervous system disease (30). Overall efficacy in this trial was 65% (15 of 23 patients successfully treated) including 8 of 13 (62%) patients receiving lower dose and 7 of 10 (70%) receiving higher dose fluconazole. Median duration of therapy was about 6 months, and the drug was well-tolerated. Interestingly, in 6 patients who had failed prior antifungal therapy with ketoconazole or amphotericin B, all six eventually responded to fluconazole. Because of these encouraging results, a subsequent study was conducted to evaluate higher doses of fluconazole (400 and 800 mg) in patients with mild to moderate blastomycosis (32). Overall success in this study was 87%, including 17 of 19 (89%) patients receiving 400 mg daily and 17 of 20 (85%) patients receiving 800 mg daily. The efficacy of higher-dose fluconazole in this study approaches that of itraconazole at 200 to 400 mg daily. Further, it equals or exceeds the published efficacy of ketoconazole and is generally much better tolerated. Thus, fluconazole at a daily dose of 400 to 800 mg represents a reasonable alternative among patients cannot tolerate conventional antifungal therapy with itraconazole or in whom previous therapy has failed.

Voriconazole, has good in vitro activity against B. dermatitidis, but there is very few prospective clinical data to support its use in this disease (15). However, emerging observational clinical data suggest an important role for voriconazole in CNS blastomycosis, and this agent appears to be a effective alternative to fluconazole in this setting (2,8). Despite excellent in vitro activity versus B. dermatitidis, there are only anecdotal reports which provide insight into the potential use of posaconazole and isavuconazole for treatment of blastomycosis (12,34).

Special Circumstances

A lipid formulation of AmB is the drug of choice for patients with severe or life-threatening blastomycosis. A daily dose of 3-5 mg/kg for at least 2 weeks or until the patient has demonstrated a significant clinical response is the preferred approach to these patients (8). There are few published data on the use of the lipid formulations of AmB in the treatment of blastomycosis, however, these formulations generally provide much more safety than the conventional formulation.

Acute Pulmonary Blastomycosis

As most cases of acute blastomycosis improve spontaneously without antifungal therapy, many clinicians have elected to observe these cases without initiating specific therapy. While there are no compelling data which strongly favor treating all patients with acute pulmonary blastomycosis, currently most clinicians treat these patients with an azole for 6-12 weeks, usually itraconazole, given its safety, patient tolerance, and efficacy. Patients who do not receive systemic antifungal therapy must be followed carefully to observe for evidence of disease activity (3,5,8).

Central Nervous System

Most patients with proven or suspected CNS involvement should receive aggressive therapy with a lipid formulation of AmB 3-5 mg/kg daily, and should receive at least 2-6 weeks of induction therapy (8). There is limited published experience with fluconazole in this setting, and it appears to be an effective agent for CNS infection due to B. dermatitidis as de-escalation therapy. The efficacy of fluconazole in this setting probably relates to its excellent penetration into the cerebrospinal fluid. Fluconazole should be given in higher doses (800 mg/d) for at least 6 months when given for CNS blastomycosis (8). More recently, there have been favorable results with voriconazole in CNS blastomycosis, and it has become the preferred oral azole for this complication (2,8). There is no role for itraconazole in this setting, indeed, there have been several reports of relapsing infection in the CNS following successful treatment of pulmonary and dermatologic blastomycosis with ketoconazole and itraconazole (10,42).

Ocular

Keratitis, conjunctivitis, and endophthalmitis are rare complications of human infection with B. dermatitidis (23,24). Therapy for ocular blastomycosis is not well described, but should probably include both systemic and local antifungal therapy. All successfully managed patients have been treated with systemic amphotericin B (8). The role of the azoles as adjunctive therapy remains unclear, but fluconazole and voriconazole both appear to achieve therapeutic concentrations in an aqueous humor and vitreous body (28).

Special Populations

Children

Sporadic cases of blastomycosis are recognized uncommonly in children, though the spectrum of disease reflects that of adults with blastomycosis (7,37). Some authors have suggested that children respond poorly to therapy with azoles when compared with adults (37). A possible explanation for this poor response is a delay in diagnosis with more advanced and aggressive disease at the time of diagnosis.

Immunocompromised Patients

The number of patients with blastomycosis and significant underlying disorders of immune function has increased markedly in recent years, due in part to the large number of solid organ transplant recipients, patients with AIDS, hematologic malignancies, chronic glucocorticosteroid recipients, and other miscellaneous disorders (17,18,20,29,31). Among these patients, infection with B. dermatitidis can be usually severe, characterized by multiple visceral organ dissemination, frequent involvement of the central nervous system, and an overall mortality of approaching 30% despite antifungal therapy (29). Consequently, most immunocompromised patients should receive aggressive initial therapy with amphotericin B, and this should be continued until the patient has experienced significant clinical improvement. Primary therapy with itraconazole should be given only to patients with limited disease and a mild, stable underlying condition associated with immune dysfunction. Among patients who have disorders characterized by ongoing immunosuppression, lifelong suppressive therapy with itraconazole may be necessary to prevent relapsing disease (8).

ADJUNCTIVE THERAPY

Except in cases of large pockets of undrained purulence (e.g., pleural empyema), there is little role for surgery as adjunctive therapy in blastomycosis. Few cases of truly refractory focal disease unresponsive to systemic antifungal therapy occur. As with other invasive fungal infections, there is a potential role for interferon gamma and interleukin-12, but there are no data to support this therapeutic approach to therapy.

ENDPOINTS FOR MONITORING THERAPY

For patients with blastomycosis, the efficacy of therapy is generally based on clinical and radiographic (usually pulmonary and bone) findings. Follow-up cultures from involved sites, where available, become negative within one month of initiating therapy in most circumstances. Persistently positive cultures after at least 2 months of antifungal therapy indicate an inadequate response to therapy and should prompt strong consideration for changing therapy unless there has been a significant clinical and radiographic response. When cultures are unavailable or difficult to access (e. g., bone involvement, pulmonary nodule), then clinical and radiographic evaluation are usually the only means of determining a response to therapy. Therapy should be continued for a minimum of 6 months for pulmonary and cutaneous/subcutaneous disease, and for at least 6-12 months for other forms of disease.

VACCINES

At present, there is also no vaccination available to prevent blastomycosis. The recent work of Wuthrich et al., suggests the potential of a live recombinant vaccine strain of B. dermatitidis that is highly immunogenic in laboratory animals (41). The potential target population for such a vaccine includes individuals at high risk of developing blastomycosis, for example veterinarians, woodsmen, certain laboratory workers, and individuals living in endemic areas who are at high risk of complications due to this disease such as patients with AIDS, solid organ transplant recipients, and patients receiving chronic glucocorticosteroids. While the animal studies investigating this vaccine have been promising, efficacy data in humans are unavailable.

PREVENTION

There are no formal recommendations to prevent exposure to B. dermatitidis. The disease is unusual and sporadic, and epidemiologic studies performed to date do not clearly suggest that modifying behavior will significantly alter the incidence of disease.

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