Are You Confident of the Diagnosis?
What you should be alert for in the history
Blastomycosis is a systemic pyogranulomatous disease caused by Blastomyces dermatitidis, an endemic mycosis that is commonly encountered in North America. More specifically, it is endemic in US states that border the Ohio and Mississippi River valleys, as well as US states and Canadian provinces that border the Great Lakes and Saint Lawrence River.
Blastomycosis infection should be strongly considered in a patient who has characteristic skin lesions and has spent a significant amount of time in an area endemic for B dermatitidis. A clue to the diagnosis should be considered if a pet dog is diagnosed with blastomycosis–not because it is transmissible from dogs to humans (except through a bite wound) but because of common exposures.
Unlike histoplasmosis, there is no reliable test for blastomycosis that can be used to accurately determine prevalence and geographic distribution of human disease.
Characteristic findings on physical examination
Skin disease is the most common extrapulmonary manifestation of blastomycosis. Skin involvement may occur alone, but usually occurs concurrently with active pulmonary disease. Skin disease is frequently a marker for disseminated infection. Cutaneous blastomycosis can present as either verrucous or ulcerative lesions.
Verrucous lesions are more common and usually appear on exposed areas of the body. Verrucous lesions tend to start as pustulopapular lesions (Figure 1) ; eventually, they develop a heaped-up and crusted appearance, and the borders tend to be sharp and irregular (Figure 2and Figure 3). Removal of the crust reveals purulence in which yeast forms are usually seen. They are grey to violaceous in color, and older lesions may be depigmented and scarred.
Ulcerative cutaneous lesions also start as papules, which eventually develop into ulcers with heaped-up borders (Figure 4). There may be exudate at the base; the central area tends to have friable tissue that can bleed readily (Figure 5).
The exudative nature of the skin lesions are due to the development of microabscesses in the subcutaneous tissue. Lesions may be solitary or multiple in presentation; their number may be a function of the immune status of the host. A patient may have both types of lesions. Subcutaneous lesions without a verrucous surface or ulceration may occur. These lesions are tender and may resemble other panniculitides.
Expected results of diagnostic studies
Biopsy of the skin lesion is key in the diagnosis of blastomycosis infection. Histopathologic examination of tissue using a variety of staining methods (H & E, PAS, Grocott-Gomori methenamine silver nitrate) will reveal a round multinucleate yeast with a double refractile cell wall (Figure 6). Typically, there will be a single broad-based bud. Other histopathologic findings include polymorphonuclear leukocytes, noncaseating granulomas, microabscesses, and pseudoepitheliomatous hyperplasia.
Tissue samples should also be inoculated on fungal medium; growth depends on the organism burden from the sample. Once there is growth, the diagnosis of B dermatiditis can be confirmed with a DNA probe specific for this organism.
An adjuvant test that can be utilized to confirm infection with B dermatiditis is the MVista® Blastomyces Quantitative Antigen test, which targets the polysaccharide cell wall antigen. This test, an enzyme-linked immunoassay, can be performed on serum, urine, bronchoalveolar lavage, and cerebral spinal fluid (CSF) samples.
Other cutaneous infections can mimic cutaneous blastomycosis including other endemic mycoses such as histoplasmosis and coccidioidomycosis. Cutaneous blastomycosis may also resemble pyoderma gangrenosum or keratoacanthoma or malignancies such as basal cell carcinoma or squamous cell carcinoma. Skin biopsy is important to differentiate blastomycosis infection from these other disease entities.
Who is at Risk for Developing this Disease?
Traditionally, persons with blastomycosis infection are young to middle-aged men who lived in areas endemic for B dermatiditis and engaged in outdoor activities near bodies of fresh water. However, male predominance may be more associated with outdoor exposure in endemic areas.
Immunocompromised hosts are also recognized for being at risk for disease, albeit not to the extent of the other endemic mycoses, and are more likely to present with fulminant disseminated disease. Cell-mediated immunity is thought to be important in controlling disease progression; thus, HIV-infected individuals, transplant recipients, and hosts on other immune-modulating agents are at higher risk of disease.
What is the Cause of the Disease?
B dermatiditis, a thermal dimorphic fungus, has been recovered in soil and rotting organic material. B dermatiditis has been linked to several epidemics, many of which involved populations living near waterways. However, the exact correlation between B dermatiditis and its ecologic niche is yet to be determined.
Initial infection occurs when the host inhales B dermatiditis conidia into the lungs. Primary cutaneous blastomycosis has been reported following dog bites and after inoculation in the laboratory. Host immune defenses are important in containing infection to the alveolar space and preventing further hematogenous dissemination. From the lungs, dissemination to other organs can occur.
The skin is the most common extrapulmonary site of infection, followed by bone, genitourinary, and central nervous system (CNS). Because cell-mediated immunity is thought to control progressive infection, hosts with impaired cell-mediated immunity are at particular risk of disseminated disease and severe infection.
Systemic Implications and Complications
Although the initial portal of entry is usually via the lungs, patients may not typically exhibit signs and symptoms of pulmonary blastomycosis. Other than the skin, B dermatiditis has the propensity to disseminate to the bones, genitourinary system, and CNS. If patients exhibit signs and symptoms that may indicate other sites of infection, appropriate testing should be performed.
For acute pulmonary blastomycosis, a chest x-ray may reveal pneumonia that is indistinguishable from bacterial infection; symptoms include fever, chills, and productive cough. Chronic symptoms such as weight loss, night sweats, productive cough, and fever may signify chronic pulmonary blastomycosis. Sputum or bronchial washings should be obtained and examined for the presence of the organism.
Osseous blastomycosis typically shows osteolytic lesions on imaging studies; infection may spread to adjacent joints and cause synovitis and septic arthritis. Synovial fluid analysis as well as biopsy of affected bone should be performed to assess for blastomycosis.
CNS blastomycosis usually presents as meningitis or mass lesions. Cerebrospinal fluid (CSF) analysis may reveal pleocytosis; however, fungal culture may not yield the organism. Antigen testing of the CSF may be helpful in establishing the diagnosis.
In immunocompromised hosts, it is imperative that other sites suspected for infection be carefully examined to determine if this is the case.
Mild to Moderate Disease (Not Involving CNS)
–Oral itraconazole solution 200mg 3 times daily for 3 days, then once or twice daily for 6 to12 months
Moderately Severe to Severe Disease
–Initial therapy: amphotericin B formulations (either lipid formulation amphotericin B, 3 to 5 mg/kg per day; OR amphotericin B deoxycholate, 0.7 to1.0 mg/kg per day) for 1 to 2 weeks with no CNS involvement; or 4-6 weeks if concomitant CNS involvement. Of the lipid preparations, liposomal amphotericin B is preferred because of higher CNS levels in animal models. Step down therapy to an oral azole should be initiated when there is clinical improvement.
Maintenance therapy: oral itraconazole solution 200 mg 3 times daily for 3 days, then twice a day; total duration of therapy for at least 12 months.
Alternate Antifungal Agents
–Fluconazole: less effective than itraconazole but better CSF levels
–Voriconazole and posaconazole: excellent in vitro and in vivo activity; not approved by the Food and Drug Administration but encouraging case reports and case series for voriconazole including in CNS disease and refractory disease. Less reported information for posaconazole.
Optimal Therapeutic Approach for this Disease
In patients with mild to moderate cutaneous blastomycosis, outpatient therapy with oral itraconazole can be used. Careful medication review should be done before starting itraconazole to ensure that there are no drug-drug interactions. Length of therapy is highly individualized; treatment may be extended for a few months after skin lesions have resolved.
Patients with moderately severe to severe disease usually require hospitalization; if a patient exhibits hemodynamic instability, signs of meningitis, or respiratory distress, immediate hospitalization is recommended. If a patient is suspected to have cutaneous blastomycosis and has severe illness, therapy with amphotericin B should be started even before skin biopsy results are available. A thorough evaluation of other possible sites of blastomycosis infection should be performed if the patient exhibits localizing symptoms.
Duration of therapy with amphotericin B formulations depends on whether the CNS is involved. When the CNS is not involved, amphotericin B should be administered for 1 to 2 weeks; with concomitant CNS involvement, amphotericin B is given for 4 to 6 weeks. For cutaneous blastomycosis, improvement in skin lesions is usually seen shortly after starting treatment with amphotercin B formulations. Once therapy with amphotericin B is complete, maintenance therapy with itraconazole is recommended.
Fluconazole at higher doses (400 to 800mg), as well as ketoconazole (400 to 800 mg) are alternative therapies for cutaneous blastomycosis. Ketoconazole is rarely used because of its side effect profile and variable absorption. However, these azoles have not been as successful in treating cutaneous blastomycosis as itraconazole. Fluconazole, voriconazole, or posaconazole can be used for individuals who are unable to tolerate itraconazole.
Oral itracoazole is the drug of choice for mild to moderate disease, as well as for maintenance therapy. Itraconazole solution is preferred over capsules due to better absorption and patient tolerability. Itraconazole affects the cytochrome P-450 system, specifically CYP3A4; it is a potent inhibitor, and can cause increased plasma concentrations of other medications that are metabolized by this pathway. Also, other medications can increase the metabolism of itraconazole, leading to subtherapeutic levels. Careful review of concomitant medications should be performed before starting itraconazole; this is especially important in patients taking immunomodulating agents, such as transplant recipients.
Itraconazole serum levels should be measured after 2 weeks of therapy to ensure adequate therapeutic drug levels, and periodically thereafter. As with other azoles, itraconazole can cause hepatitis and gastrointestinal upset. Itraconazole should be used with caution in patients with congestive heart failure, as it may cause a syndrome of hypertension, edema, and hypokalemia.
In immunosuppressed hosts who are unable to reverse their immunosuppression, lifelong treatment with oral itraconazole may be necessary to ensure that there is no recurrence of infection. Transplant recipients on several immunosuppressive agents are at particular risk for relapse.
For moderately severe to severe disease, amphotericin B formulations should be administered for 1 to 2 weeks. All formulations of amphotericin B are administered via the intravenous route. Amphotericin B deoxycholate is associated with several side effects, including infusion-related symptoms (fever, chills, rigors, headache, GI upset), renal toxicity, electrolyte imbalance, hepatotoxicity, cardiac arrhythmias, and bone marrow suppression.
The lipid formulations of amphotericin B are less likely to cause these toxicities, especially renal insufficiency. Because amphotericin B can cause irreversible nephrotoxicity, a careful review of the patient’s medications should be performed; other potential nephrotoxic agents that are not essential should be withheld while on amphotericin B. Frequent monitoring of electrolytes and renal function should be obtained while on therapy regardless of formulation; aggressive electrolyte supplementation is important to ensure that the patient is not at risk for cardiac disturbances.
Surgery has little role in the treatment of blastomycosis except for drainage of large abscesses and debridement of devitalized tissue. Even if drainage is performed, antifungal therapy is necessary.
Unusual Clinical Scenarios to Consider in Patient Management
Since blastomycosis can occur in any organ, unusual manifestations including breast masses and ocular involvement have been described. Skin lesions of blastomycosis have initially been misdiagnosed as condyloma acuminatum surrounding the anus, or giant keratoacanthoma of the nasal and maxillary area skin and soft tissue.
The clinical syndrome associated with subcutaneous nodules differs from that seen with other skin lesions. They usually occur with pulmonary or extrapulmonary disease, and are actually cold abscesses. Patients frequently have systemic symptoms and are acutely ill. Therapy should be initiated promptly in this situation. Lesions may drain spontaneously. The diagnosis is quickly established by microscopic examination of aspirated or drained pus, which is teeming with organisms.
What is the Evidence?
Castillo, CG, Kauffman, CA, Miceli, MH. “Blastomycosis”. Infect Dis Clin N Am. vol. 30. 2016. pp. 247-264. (A comprehensive and up-to-date review of blastomycosis, including epidemiology, clinical manifestations, diagnosis, and treatment options.)
Chapman, SW, Dismukes, WE, Proia, LA, Bradsher, RW, Pappas, PG, Threlkeld, MG. “Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 46. 2008. pp. 1801-12. (Evidence-based treatment guidelines for blastomycosis, prepared by an expert panel. Included in the guidelines are recommended and alternate therapies for blastomycosis, as well as a discussion of side effects and use of antifungals.)
Bradsher, RW, Bennett, JE, Dolin, R, Blaser, MJ. “Blastomycosis”. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 2015. pp. 2963-2973. (A thorough overview of blastomycosis; including historical, mycologic, and epidemiologic background. Disease in special hosts is also reviewed.)
Saccente, M, Woods, GL. “Clinical and laboratory update on blastomycosis”. Clin Microbiol Rev. vol. 23. 2010. pp. 367-81. (Another excellent review of blastomycosis, with an emphasis on the microbiologic, histopathologic, and molecular tests for diagnosis.)
Freifeld, A, Proia, L, Andes, D, Baddour, LM, Blair, J, Spellberg, B. “Voriconazole use for endemic fungal infections”. Antimicrob Agents Chemother. vol. 53. 2009. pp. 1648-51. (A retrospective review of voriconazole use in patients with endemic fungal infection; which included 8 patients with blastomycosis. Six of the 8 patients were successfully treated with voriconazole; all patients had toxicity or tolerance issues with either amphotericin B or other azoles.)
Lambert, HP, Farrar, WE. “Unit 6 Cutaneous manifestations of infections III”. Slide atlas of infectious diseases. 1982. (Reprints of slides as noted.)
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