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BLASTOMYCOSIS

Carol A. Kauffman, MD

University of Michigan


MYCOLOGY

Blastomycosis is caused by Blastomyces dermatitidis, a thermally dimorphic fungus. In the environment, the organism grows as a mould that produces conidia, which are responsible for transmission of infection to humans. In the laboratory on Sabouraud's agar at 25-28°C, the organism grows as a fluffy white mould, whose conidia are not distinctive. In tissues and in the laboratory at 35-37°C, B.dermatitidis assumes the yeast form. The yeast form is distinctive, appearing as an 8-15 micron, thick-walled yeast that produces a single, broad-based daughter bud.

EPIDEMIOLOGY

B. dermatitidis is endemic in the Mississippi and Ohio River valleys and also occurs in those states and Canadian provinces that border the Great Lakes and the St. Lawrence Seaway[1-6]. B. dermatitidis is difficult to isolate from the environment, and thus its environmental niche is not well defined. It is postulated that moist soil enriched with decaying vegetation encourages the growth of B. dermatitidis.Newer techniques, such as PCR, might prove helpful in the future to better define the environmental reservoir [7].

Most cases of blastomycosis are sporadic although outbreaks have been well described. Outbreaks are often associated withactivities that take place around rivers and lakes [1-2]. Blastomycosis is more common among men, presumably because they are more likely than women to be exposed to the organism in the course of their everyday activities.However, in outbreaks, men and women are equally represented.

Blastomycosis also occurs commonly in dogs in the highly endemic areas [8]. The diagnosis of blastomycosis in a pet dog can be a valuable clue to the cause of a patient's unknown skin lesion or pulmonary infiltrate.

PATHOGENESIS

In the environment, the conidia produced by the mould are aerosolized into the alveoli, at which point the mould converts to the yeast phase by mechanisms not completely understood.Alveolar macrophages are able to phagocytize conidia, and both neutrophils and macrophages can phagocytize the yeast phase organisms [9,10]. Ultimate control of infection with B. dermatitidis depends on T lymphocytes that are sensitized to Blastomyces antigens and produce cytokines that allow macrophages to kill the yeasts[11].The host response noted in tissue samples is both pyogenic and granulomatous. Although the lungs are the primary organ involved initially, hematogenous dissemination is common and can lead to focal manifestations at a distant site or to disseminated infection. Not all organisms are eradicated by the immune response in some patients, and reactivation, sometimes many years after the initial infection, has been reported [12].

CLINICAL MANIFESTATIONS

Pulmonary Infection

Primary infection is asymptomatic in more than 50% of infected individuals [3,13-15]. When symptomatic infection does develop, it most often presents as a mild self-limited lower respiratory tract infection with cough, low-grade fever, and fatigue. Patients are often diagnosed as having community-acquired pneumonia due to bacteria, and they are treated with antibiotics. Only after the symptoms fail to respond to antibacterial therapy is the possibility of blastomycosis entertained. Chest radiographs reveal patchy infiltrates or nodules [16-18]. Mediastinal and hilar lymphadenopathy occur less commonly than they do with histoplasmosis.

The chronic form of pulmonary blastomycosis progresses over months and mimics tuberculosis [19,20]. Symptoms include cough, purulent sputum, hemoptysis, fever, malaise, and weight loss. Chest radiographs can show mass-like lesions, nodules, or upper lobe cavitary infiltrates.

Acute respiratory distress syndrome (ARDS) is a dreaded complication of pulmonary blastomycosis. ARDS can occur in presumably healthy hosts, as well as in those who are immunosuppressed [21-24].The diagnosis of blastomycosis is often delayed, contributing to the progression to ARDS. In one report, over 60% of patients who died of blastomycosis-associated ARDS were not suspected of having a fungal infection, and the diagnosis was not made until they were severely ill [23]. ARDS complicating blastomycosis has a mortality rate that varies from 50-89%.

Disseminated Infection

Any focus of blastomycosis outside the lungs is a manifestation of hematogenous dissemination. Almost every organ has been reported to be involved in occasional patients, but those most commonly involved, in order of decreasing frequency, are skin, osteoarticular structures, the genitourinary system, and the central nervous system. Some patients will have a single cutaneous lesion with no other obvious manifestations of disease, but others, especially those who are immunosuppressed, may be acutely ill with multi-organ involvement. Early series noted rates of symptomatic dissemination in as many as 60% of patients, but recent studies have shown rates of only 20-25%[3,23].Disseminated infection may accompany pulmonary manifestations or appear after the pulmonary findings have resolved.

The classic skin lesion is verrucous and crusting with central punctate draining microabscesses. However, pustules, nodules, and ulcers also can occur [25]. A single lesion may be the sole manifestation, but many patients have several lesions and a few have hundreds of lesions.

Osteoarticular involvement can be contiguous with cutaneous lesions or occur in separate areas [26]. When vertebral osteomyelitis occurs, epidural extension into the cord can occur. Radiographs usually show well-circumscribed osteolytic lesions; in vertebral osteomyelitis, the disc space and the vertebral body are involved, and a paraspinous abscess is commonly noted.

Genitourinary tract involvement, especially with prostate infection, is the third most common extra-pulmonary site in men [3]. Symptoms include dysuria, perineal pain, and obstructive symptoms. A prostate nodule or a diffusely tender prostate are found on examination.

Central nervous system (CNS) infection is uncommon. It is likely to be a manifestation of widely disseminated infection in those who are immunosuppressed. In those who are immunocompetent, CNS blastomycosis is more likely to present as chronic meningitis without other manifestations of disseminated infection. In addition to meningitis, abscesses in brain and cord can occur [27]. The typical cerebrospinal fluid findings are those of a lymphocytic meningitis with elevated protein and moderately decreased glucose levels. Mortality remains high for CNS blastomycosis.

Blastomycosis in Immunocompromised Hosts

The greatest risk for severe infection is in patients who have defective cell-mediated immunity; such patients include those who have HIV infection and less commonly, patients who have been treated with TNF antagonists or are solid organ transplant recipients [28-32]. Severe pneumonia with hypoxemia, widely disseminated infection, and CNS involvement are all more common in this population.

DIAGNOSIS

Culture

Growth of B. dermatitidis in vitro is the definitive diagnostic technique. However, it may take as long as 4-5 weeks for the organism to grow [33]. Thus, a positive culture usually provides confirmation that the patient has blastomycosis, but other means are required to establish an early diagnosis if one is to provide appropriate and timely care for patients [34].

Smears and Histopathology

The simplest method to achieve a rapid diagnosis is to seek the organism in a smear from a respiratory or tissue sample [33]. B.dermatitidis is a distinctive 8-15 um thick-walled yeast that forms a single broad-based bud. The specimen is usually stained with calcofluor white that contains KOH, which highlights the thick fungal cell wall. Papanicolaou stain, used in cytological examinations, also shows the distinctive characteristics of B. dermatitidis. In tissue sections, the organisms are poorly seen with hematoxylin and eosin stain, but are readily seen with methenamine silver or periodic acid Schiff (PAS) stains.

Antigen Assay

An assay that detects the cell wall polysaccharide of B. dermatitidis in urine is available through MiraVista Laboratories in Indianapolis, Indiana [35]. The test is not specific for blastomycosis; cross-reactivity occurs in patients who have histoplasmosis and paracoccidioidomycosis. An early report noted a sensitivity of 93% and a specificity of 79% using stored samples, but performance in the clinical setting is not yet established. It appears that this assay is most useful for patients who have severe pulmonary or disseminated infection [36].

Antibody Assays

The currently available assays for detecting antibodies to B. dermatitidis by complement fixation and immunodiffusion are not useful for diagnosis because both sensitivity and specificity are poor.

TREATMENT

The Infectious Diseases Society of America (IDSA) has published guidelines for the treatment of blastomycosis [37] (Table 1). Patients who have mild-to-moderate pulmonary or disseminated blastomycosis can be treated with an azole agent. Those patients who have severe pulmonary or disseminated blastomycosis, those who have central nervous system involvement, and those who are immunosuppressed should be treated initially with an amphotericin B formulation.

Amphotericin B

In the years before azole agents were introduced, amphotericin B deoxycholate (AmB-d) was the standard therapy. The dosage of AmB-d is 0.7-1.0 mg/kg daily. Currently, many physicians prefer to use a lipid formulation of amphotericin B, either liposomal amphotericin B  (AmBisome) (L-AmB) or lipid complex amphotericin B (Abelcet) (ABLC), because these formulations are less nephrotoxic than the deoxycholate formulation. The dosage of L-AmB is 3-5 mg/kg daily and of ABLC is 5 mg/kg daily. Once the patient has responded to treatment with an amphotericin B formulation, usually after several weeks, step-down therapy with an azole agent is recommended [37].

Azole Agents

Itraconazole is the recommended azole for treatment of mild-to-moderate blastomycosis and for step-down therapy after initial amphotericin B treatment  [37,38]. The recommended dosage is 200 mg given thrice daily for 3 days as a loading dose, followed by 200-400 mg daily. If 400 mg daily is prescribed, the drug should be given as 200 mg twice daily. Drawbacks of itraconazole include variability in absorption and drug-drug interactions. The oral suspension, given on an empty stomach, provides more predictable absorption but is tolerated less well by many patients. The capsule formulation requires both food and gastric acid for maximum absorption, and thus the patient cannot take proton pump inhibitors or H-2 blockers. Serum concentrations of itraconazole should be monitored because of the highly variable absorption that is seen from patient to patient.

Fluconazole is not as effective as itraconazole for blastomycosis, and should be used only if the patient cannot tolerate itraconazole [37,39]. Voriconazole has been reported to be effective for blastomycosis in anecdotal case reports [40-43]. There are no reports on the use of posaconazole for blastomycosis.

Pulmonary Blastomycosis

All patients who have pulmonary blastomycosis should be treated with an antifungal agent [37]. Patients who have mild-to moderate illness are usually treated with itraconazole for a total of 6-12 months. Those who have severe illness should receive an amphotericin B formulation until signs of improvement have occurred and then therapy can be switched to oral itraconazole to continue therapy for 6-12 months. Patients who develop ARDS clearly should be treated with amphotericin B, and some physicians would also add corticosteroids. Corticosteroids are not recommended in the IDSA Guidelines, but there are anecdotal reports that use of these agents is helpful in patients with blastomycosis-associated ARDS [24].

Disseminated Blastomycosis

All patients who have disseminated blastomycosis, even those who have only a single skin lesion, should be treated with an antifungal agent [37]. Those who have mild to moderate infection and localized lesions can be treated with itraconazole for 6-12 months. If they have osteoarticular involvement, 12 months of therapy is recommended. For those patients who are severely ill, initial therapy should be with amphotericin B until a clinical response is seen, at which point, itraconazole can be used a step-down therapy for a total of at least 12 months of therapy.

Central Nervous System Blastomycosis

For patients with CNS blastomycosis, either L-AmB or ABLC at a dosage of 5 mg/kg daily is recommended for the initial 4-6 weeks, and this is followed by therapy with an azole for a total of a least a year [37].Azoles that are suggested by the IDSA Guidelines include: itraconazole, 200 mg 2 to 3 times daily; fluconazole, 800 mg daily; or voriconazole, 200-400 mg 2 times daily. All of these regimens are based entirely on anecdotal reports [40-43]. Depending on the response to therapy and the immune status of the patient, azole therapy may have to be continued for life to prevent relapse of the infection [37].

Immunosuppressed Patients

Immunosuppressed patients should be treated with an amphotericin B formulation initially, until a response is noted. Then step-down treatment with itraconazole, 200 mg twice daily for a total of 12 months is recommended. For patients in whom the immunosuppression cannot be reduced, life-long suppressive therapy with 200 mg daily of itraconazole is recommended [37].




References

1. Klein BS, Vergeront JM, DiSalvo AF, Kaufman L, Davis JP. Two outbreaks of blastomycosis along rivers in Wisconsin. Isolation of Blastomyces dermatitidis from riverbank soil and evidence of its transmission along waterways. Am Rev Respir Dis 1987; 136:1333-8.

2. Baumgardner DJ, Steber D, Glazier R, Paretsky DP, Egan G, Baumgardner AM, Prigge D. Geographic information system analysis of blastomycosis in northern Wisconsin, USA: waterways and soil. Med Mycol 2005; 43:117-25.

3. Chapman SW, Lin AC, Hendricks KA, Nolan RL, Currier MM, Morris KR, Turner HR. Endemic blastomycosis in Mississippi: epidemiological and clinical studies. Semin Respir Infect 1997; 12:219–28.

4. Dworkin MS, Duckro AN, Proia L, Semel JD, Huhn G. The epidemiology of blastomycosis in Illinois and factors associated with death. Clin Infect Dis 2005; 41:e107-11.

5. Cano MV, Ponce-de-Leon GF, Tippen S, Lindsley MD, Warwick M, Hajjeh RA. Blastomycosis in Missouri: epidemiology and risk factors for endemic disease. Epidemiol Infect 2003; 131:907-14.

6. Crampton TL, Light RB, Berg GM, Meyers MP, Schroeder GC, Hershfield ES, Embil JM.. Epidemiology and clinical spectrum of blastomycosis diagnosed at Manitoba hospitals. Clin Infect Dis 2002; 34:1310-6.

7. Burgess JW, Schwan WR, Volk TJ. PCR-based detection of DNA from the human pathogen Blastomyces dermatitidis from natural soil samples. Med Mycol 2006; 44:741-8

8. Baumgardner DJ, Paretsky DP, Yopp AC. The epidemiology of blastomycosis in dogs: north central Wisconsin, USA. J. Med. Vet. Mycol 1995; 33:171-6.

9. Sugar AM, Picard M. Macrophage- and oxidant-mediated inhibition of the ability of live Blastomyces dermatitidis conidia to transform to the pathogenic yeast phase: implications for the pathogenesis of dimorphic fungal infections. J Infect Dis 1991; 163:371-5.

10. Sugar AM, Picard M, Wagner R, Kornfeld H. Interactions between human bronchoaveolar macrophages and Blastomyces dermatitidis conidia: demonstration of fungicidal and fungistatic effects. J Infect Dis 1995; 171:1559-62.

11. Klein BS, Davis JP, Bradsher RW, Vergeront JM. Development of long-term specific cellular immunity after acute Blastomyces dermatitidis infection: assessments following a large point-source outbreak in Wisconsin. J Infect Dis. 1990; 161:97-101.

12. Ehni W. Endogenous reactivation in blastomycosis. Am J Med 1989; 86:831–2.

13. Bradsher RW, Jr. Pulmonary blastomycosis. Sem Respir Crit Care Med 2008; 29:174-81.

14. Vaaler AK, Bradsher RW, Davies SF. Evidence of subclinical blastomycosis in forestry workers in northern Minnesota and northern Wisconsin. Am J Med 1990; 89:470-6.

15. Sarosi GA, Davies SF, Phillips JR. Self-limited blastomycosis: a report of 39 cases. Semin Respir Infect 1986; 1:40-4.

16. Brown LR, Swensen SJ, Van Scoy RE, Prakash UBS, Coles DT, Colby TV. Roentgenologic features of pulmonary blastomycosis. Mayo Clin Proc 1991; 66:29-38.

17. Sheflin JR, Campbell JA, Thompson GP. Pulmonary blastomycosis: findings on chest radiographs in 63 patients. AJR 1990; 154:1177-80.

18. Winer-Muram HT, Beals DH, Cole FH Jr. Blastomycosis of the lung: CT features. Radiology 1992; 182:829-32.

19. Davies SF, Sarosi GA. Epidemiological and clinical features of pulmonary blastomycosis. Semin Respir Infect. 1997; 12:206–18.

20. Kralt D, Light B, Cheang M. Clinical characteristics and outcomes in patients with pulmonary blastomycosis. Mycopathologia 2009; 167:115–24.

21. Lemos LB, Baliga M, Guo M. Acute respiratory distress syndrome and blastomycosis: presentation of nine cases and review of the literature. Ann Diagn Pathol 2001; 5:1-9.

22. Meyer KC, McManus EJ, Maki DG. Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome. N Engl J Med 1993; 329:1231-6.

23. Vasquez JE, Mehta JB, Agrawal R, Sarubbi FA Blastomycosis in northeast Tennessee. Chest 1998; 114:436-43.

24. Lahm T, MD, Neese S, Thornburg AT, Ober MD, Sarosi GA, Hage CA. Corticosteroids for blastomycosis-induced ARDS; a report of two patients and review of the literature. Chest 2008; 133: 1478-80.

25. Body BA. Cutaneous manifestations of systemic mycoses. Dermatol Clin 1996; 14:125-35.

26. Johnson MD, Perfect JR. Fungal infections of the bones and joints. Curr Infect Dis Rep 2001; 3:450-60.

27. Friedman JA, Wijdicks EFM, Fulgham JR, Wright AJ. Meningoencephalitis due to Blastomyces dermatitidis: case report and literature review. Mayo Clin Proc 2000; 75:403-8.

28. Pappas PG, Pottage JC, Powderly WG, et al. Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1992; 116: 847-53.

29. Pappas PG, Threlkeld MG, Bedsole GD, Cleveland KO, Gelfand MS, Dismukes WE. Blastomycosis in immunocompromised patients. Medicine (Baltimore) 1993; 72:311-25.

30. Gauthier GM, Safdar N, Klein BS, Andes DR. Blastomycosis in solid organ transplant recipients. Transpl Infect Dis 2007; 9.310-7.

31. Kauffman CA. Endemic mycoses after hematopoietic stem cell or solid organ transplantation. In: Bowden RA, Ljungman P, Snydman DR, (eds). Transplant Infections, 3rd edition, Lippincott, Williams & Wilkins, 2010. p 607-16.

32. FDA Alert September 4, 2008, Tumor necrosis factor-alpha blockers (TNF blockers), Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab) (www.fda.gov/cder/drug/InfoSheets/HCP/TNK_blockersHCP.html)

33. Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev 2010; 23:367-81.

34. Martynowicz MA, Prakash UB. Pulmonary blastomycosis: an appraisal of diagnostic techniques. Chest 2002; 121:768-73.

35. Durkin M, Witt J, LeMonte A, Wheat B, Connolly P. Antigen assay with the potential to aid in diagnosis of blastomycosis. J Clin Microbiol 2004; 42:4873-5.

36. Mongkolrattanothai K, Peev M, Wheat L, Marcinak J. Urine antigen detection of blastomycosis in pediatric patients. Pediatr Infect Dis J 2006; 25:1076-8.

37. Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America Clin Infect Dis 2008; 46:1801-12

38. Dismukes WE, Bradsher RW, Cloud GC, et al. Itraconazole therapy of blastomycosis and histoplasmosis. Am J Med 1992; 93:489-97.

39. Pappas PG, Bradsher RW, Chapman SW, et al. Treatment of blastomycosis with fluconazole. Clin Infect Dis 1995; 20:267-71.

40. Freifeld A, Proia LA, Andes D, et al. Voriconazole use for endemic fungal infections. Antimicrob Agents Chemother 2009; 53:1648-51.

41. Borgia SM, Fuller JD, Sarabia A, El-Helou P. Cerebral blastomycosis: a case series incorporating voriconazole in the treatment regimen. Med Mycol 2006; 44:659-64.

42. Bakleh M, Askamit AJ, Tieyjeh IM, Marshall WF. Successful treatment of cerebral blastomycosis with voriconazole. Clin Infect Dis 2005; 40:e69-71.

43. Bariola JR, Perry P, Pappas PG, et al. Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era. Clin Infect Dis 2010; 50:797-804.

Treatment of blastomycosis


Type of Blastomycosis

Preferred Therapy

Comments

Pulmonary, mild to moderate severity

Itraconazole, 200 mg thrice daily for 3 days, then once or twice daily for 6–12 months

Fluconazole less efficacious;
Voriconazole or posaconazole may be effective, but little experience

Pulmonary, moderately severe to severe

Lipid AmB, 3–5 mg/kg daily for several weeks until improved, then step down to an azole; consider addition of corticosteroids for ARDS

Itraconazole, 200 mg thrice daily for 3 days, then 200 mg twice daily for 6–12 months is preferred step-down therapy

Disseminated, mild to moderate severity

Itraconazole, 200 mg thrice daily for 3 days, then once or twice daily for 6–12 months

Fluconazole less efficacious;
Voriconazole or posaconazole may be effective, but little experience

Disseminated, moderately severe to severe

Lipid AmB, 3–5 mg/kg daily for several weeks until improved, then step down to an azole

Itraconazole, 200 mg thrice daily for 3 days, then 200 mg twice daily for at least 12 months is preferred step-down therapy

Central nervous system disease

Lipid AmB, 5 mg/kg daily for 4–6 weeks, then step down to an azole

Step-down therapy with:
Itraconazole, 200 mg 2 to 3 times daily, OR Fluconazole, 800 mg daily, OR Voriconazole, 200–400 mg twice daily for at least 12 months; resolution of CSF findings required; some patients may require life-long suppressive therapy

Immunocompromised patients

L- AmB, 3-5 mg/kg daily for several weeks until improved, then step down to an azole

Itraconazole, 200 mg thrice daily for 3 days, then 200 mg twice daily for 12 months is preferred step-down therapy; life-long suppression with itraconazole, 200 mg daily, if immunosuppression cannot be reversed

AmB = amphotericin B; Lipid AmB = liposomal AmB (Ambisome) or lipid complex AmB (Abelcet); CSF = cerebrospinal fluid



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