blastomycosis - university of wisconsin–madison · blastomycosis jeannina a. smith1 and carol a....

Blastomycosis

Jeannina A. Smith1 and Carol A. Kauffman1

1Division of Infectious Diseases, University of Michigan Medical School, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan

Blastomycosis is an endemic mycosis that occurs predominantly inNorth America in the north central United States and provinces ofCanada, southern states, and those midwestern states that borderthe Mississippi River basin. It causes acute and chronic pneumoniasand disseminated infection with cutaneous lesions as the majorextrapulmonary manifestation. However, the vast majority ofinfected persons are asymptomatic or have mild respiratory symp-toms that are not diagnosed as being caused by a fungal infection.Rarely, patients develop severe pulmonary infection that progressesto acute respiratory distress syndrome (ARDS), which has a highmortality rate. A urinary antigen test is now available to aid indiagnosis, but it is not specific and is positive in patients who havehistoplasmosis as well as blastomycosis. Antibody assays remainnonspecific and insensitive, and the confirmatory diagnostic test isstill growth of the organism in culture. Updated guidelines from theInfectious Diseases Society of America are available to aid cliniciansin the management of the various forms of blastomycosis.

Keywords: endemic mycoses; Blastomyces dermatitidis; fungal pneu-monia

Blastomycosis is caused by Blastomyces dermatitidis, a thermallydimorphic fungus that grows as a mold in the environment andas a yeast in tissues. The infection is most commonly noted incertain areas of the United States and Canada. Blastomycosis isprimarily a pulmonary infection, but dissemination occursfrequently and leads to involvement of skin, osteoarticularstructures, the genitourinary tract, and other organs. Neweraspects of clinical manifestations, diagnostic methods, and treat-ment regimens for blastomycosis will be emphasized in thisreview.

EPIDEMIOLOGY

The epidemiology of blastomycosis is less well defined than thatof histoplasmosis and coccidioidomycosis. This is partly due tothe fact that the organism is difficult to isolate from theenvironment (1, 2). During a recent investigation of an outbreakin dogs, a PCR-based technique successfully identified B.dermatitidis from environmental samples, giving hope that thistechnique might prove useful in the future to help define theenvironmental niche (3). In contrast to histoplasmosis, forwhich skin testing facilitated screening of large populationsfor past exposures, there have been no reliable means to screenfor exposure to B. dermatitidis. Mandatory public healthreporting of blastomycosis is required in only a few states orprovinces, namely Illinois, Wisconsin, Mississippi, Manitoba,and Ontario. Thus, the extent of occurrence of blastomycosis isundoubtedly underestimated.

B. dermatitidis is endemic in the Mississippi and Ohio Rivervalleys, the Midwestern states and Canadian provinces that

border the Great Lakes, and the area of New York and Canadaadjacent to the St. Lawrence Seaway (2, 4–6). Sporadic humancases of blastomycosis have been reported from other areas,including Hawaii, Israel, India, Africa, and Central and SouthAmerica (7, 8). In states that have a high incidence of blasto-mycosis, such as Mississippi and Wisconsin, certain countiesreport a disproportionate number of cases (9). For example, onesurvey in Wisconsin noted that the incidence of symptomaticinfection in 10 different counties ranged from 5.1 to 41.9 casesper 100,000 persons (10). Activities in watershed areas appear tocarry a higher risk for acquisition of B. dermatitidis (2, 11, 12). Itis thought that the moist soil enriched with decaying vegetationin these areas encourages the growth of the organism. In mostseries, men are more commonly infected with B. dermatitidis; thepresumption is that they have a greater risk for exposure to theorganism in the course of outdoor activities (5, 6, 13). Blasto-mycosis also occurs in dogs in the same endemic areas (14), andnot infrequently, humans and dogs are ill with the disease at thesame time, having experienced the same exposure.

PATHOGENESIS

The conidia produced in the environmental mold phase causeinfection when aerosolized and inhaled into the alveoli, whereconversion to the yeast phase occurs. Several local host factorsare triggered after inhalation of the conidia. Alveolar macro-phages can phagocytize and kill conidia, which can inhibittransition of some of the inoculum to the yeast phase (15, 16).Neutrophils and macrophages can phagocytize the yeast phaseorganisms, leading to a mixed pyogenic and granulomatous hostresponse that is seen in tissue samples. Ultimately, control ofinfection with B. dermatitidis is primarily dependent on Tlymphocytes that have become sensitized to Blastomyces anti-gens arming the macrophages to kill the phagocytized yeasts(17, 18). Humoral immunity develops, but is not crucial tocontainment of the infection. The primary, and in many casesthe only, clinical manifestation of blastomycosis is pneumonia.However, hematogenous dissemination is common and can leadto focal disease at a distant site or disseminated infection. Notall organisms are eradicated by the immune response, andreactivation has been reported up to 40 years after the initialinfection (19).

CLINICAL MANIFESTATIONS

Pulmonary Blastomycosis

Pulmonary infection is the most common manifestation ofinfection with B. dermatitidis. Infection is asymptomatic inmore than 50% of infected individuals (13, 20–22). Of thepatients who are symptomatic, illness typically begins 30 to 45days after exposure, and the illness most often manifests asa mild self-limited pulmonary infection or ‘‘summer cold.’’Several studies have suggested a seasonal predilection, withisolated pulmonary disease presenting in the late summer andautumn, and disseminated and extrapulmonary disease present-ing in winter through late spring (23). Patients ill enough to seekmedical care are often thought to have bacterial community-acquired pneumonia, and they are treated with antibiotics. It is

(Received in original form June 12, 2009; accepted in final form July 18, 2009)

Correspondence and requests for reprints should be addressed to Carol A.

Kauffman, M.D., Veterans Affairs Ann Arbor Healthcare System, 2215 Fuller

Road, Ann Arbor, MI 48105. E-mail: [email protected]

Proc Am Thorac Soc Vol 7. pp 173–180, 2010DOI: 10.1513/pats.200906-040ALInternet address: www.atsjournals.org

not until the patient’s symptoms fail to respond to antibacterialtherapy that the diagnosis of pulmonary blastomycosis issuspected. In one series of 118 people who were found to havepulmonary blastomycosis, cough (90%) was the most commonsymptom, followed by fever (75%), night sweats (68%), weightloss (68%), chest pain (63%), dyspnea (54%), myalgias (50%),and hemoptysis (18%) (24). Chest radiographs reveal a patchypneumonitis, a mass-like infiltrate, or nodules (25–27) (Figure1). Mediastinal and hilar lymphadenopathy is not commonlyseen and helps differentiate blastomycosis from histoplasmosis.Although pulmonary infection can be self-limited (21, 22), it iscurrently recommended that all patients in whom the diagnosisis made and who are symptomatic be treated with an antifungalagent to prevent progressive infection.

Chronic pulmonary blastomycosis is clinically indistinguish-able from tuberculosis. Symptoms include cough productive ofpurulent and sometimes bloody sputum, fever, malaise, andweight loss (13, 28, 29). Chest radiographs reveal mass-likelesions that are often mistaken for a malignancy, upper lobeinfiltrates with cavities, or scattered nodules (25–27) (Figures 2and 3). These patients may or may not have skin lesions or othermanifestations of disseminated infection. This form of blasto-mycosis is progressive if not treated.

Rarely, patients with pulmonary blastomycosis develop acuterespiratory distress syndrome (ARDS) (Figure 4). A recentevaluation of hospitalized patients who had pulmonary blastomy-cosis noted that 10% received some care in the intensive care unitand that more than a third of patients who developed respiratoryfailure died, usually within several days of admission (29). Severepulmonary involvement can be seen in patients with defectivecell-mediated immunity, including patients who have a hemato-logic malignancy, have received a transplant, or have AIDS. Inone series from a hyperendemic area, 3 of 9 patients with

blastomycosis-associated ARDS had at least partial immunosup-pression (30). However, just as frequently, the patient whodevelops this severe form of blastomycosis is a previously healthyperson (30–33). In some patients, presentation is that of a typicalcommunity-acquired pneumonia, and then a few days to a weeklater acute decompensation occurs with hypoxemia requiringintubation. Others have fulminant pneumonia and appear to beseptic on admission. The diagnosis of blastomycosis is oftendelayed, contributing to the progression to ARDS. In one report,over 60% of patients who died of blastomycosis-associated ARDSwere not suspected of having a fungal infection, and the diagnosiswas not made until they were desperately ill (32). Blastomycosis-associated ARDS is associated with mortality rates of 50 to 89%,even in patients receiving appropriate therapy (30–33).

Disseminated Infection

B. dermatitidis can disseminate to many different organs, but theskin, osteoarticular structures, and the genitourinary system arethe most frequently involved. It is likely that dissemination occursearly in infection before the development of specific cell-medi-ated immunity, but most patients remain asymptomatic and willnever develop systemic manifestations. Studies reported prior tothe availability of antifungal agents noted rates of symptomaticdissemination in almost two-thirds of patients, but recent studiesreport dissemination rates of 20 to 25% (6, 13, 32). By the timeextrapulmonary manifestations appear, the chest radiograph mayshow resolving pneumonia or no infiltrates.

Cutaneous lesions often appear on the exposed areas of thehead, neck, or extremities, but they can appear anywhere. Theclassic lesion is verrucous and crusting with central punctatedraining microabscesses, but violaceous nodules, ulcerativelesions, and pustules have been observed (13, 34) (Figures 5–7). Although single lesions have been described, most patientsmanifest several lesions and uncommonly, a large number oflesions. Bone involvement can underlie the cutaneous lesions,

Figure 1. Acute pulmonary blastomycosis in a college student whoattended a soccer camp in upper Wisconsin.

Figure 2. Chronic pulmonary blastomycosis in an elderly man who

had fevers, cough, hemoptysis, and weight loss; this patient had severalskin lesions, as well.

174 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7 2010

but can also be present at multiple distant sites as well. Drainingsinus tracts can develop over bony lesions. Radiographs usuallyshow well-circumscribed osteolytic lesions (35).

Genitourinary tract involvement is most common in men,and the prostate is the usual target organ (13). Symptomsinclude dysuria, perineal discomfort, and obstructive symptoms.Central nervous system (CNS) infection is rare. Meningitis,brain abscesses, and cord lesions can occur (36). CNS involve-ment can be one manifestation of disseminated infection; this isusually the case in immunosuppressed patients. Immunocom-petent patients are more likely to develop isolated chroniclymphocytic meningitis. Mortality remains high for CNS blas-tomycosis, especially when it is accompanied by disseminatedinfection.

Blastomycosis in Immunocompromised Hosts

Patients who have defective cell-mediated immunity have beenshown to have an increased risk of developing symptomaticprimary disease after exposure to B. dermatitidis. Most cases havebeen reported in patients who had AIDS (37). Acquisition hasbeen from the environment, but it has been estimated that asmany as 25% of AIDS-related cases may be due to reactivationinfection (37). The manifestations of blastomycosis in patientswith AIDS are generally more severe than those in immuno-competent hosts. Severe pneumonia with hypoxemia, widelydisseminated infection, and CNS involvement are all morecommon in this population. CNS manifestations were presentin 40% of cases in patients who had AIDS. The mortality ofblastomycosis in the pre-HAART era was nearly 40%, and mostdeaths occurred within 3 weeks of diagnosis (37).

Blastomycosis has been reported uncommonly in solid organtransplant recipients and patients with hematologic malignan-cies (38–40). In transplant recipients, the disease is frequentlyassociated with severe infection accompanied by ARDS andwidespread dissemination (39, 40).

Seven patients with blastomycosis have been reported to theFDA registry of fungal infections in patients receiving TNF-ainhibitor therapy (41). There are no published case reports onthese patients. However, blastomycosis is listed in the warningissued by the FDA on September 4, 2008 regarding increased

Figure 3. Chronic pulmonary blastomycosis appearing as a mass-like

lesion that was initially thought to be carcinoma.

Figure 4. Severe pulmonary blastomycosis causing acuterespiratory distress syndrome in a middle-aged man.

Smith and Kauffman: Blastomycosis 175

risk of fulminant infections with endemic mycoses in patientsreceiving TNF-a inhibitor therapy.

DIAGNOSIS

The diagnosis of blastomycosis is often elusive, and delays indiagnosis are common (13, 42, 43). For example, in Mississippi,which has the highest reported prevalence of blastomycosis inNorth America, only 5% of patients with pulmonary blastomy-cosis were correctly diagnosed at initial presentation. Whenpulmonary disease was associated with cutaneous involvement,the initial diagnosis was improved to 64%, as clinicians recog-nized the classic skin lesions of blastomycosis. A delay indiagnosis of more than 1 month was reported in half of thepatients (13).

Culture

The difficulty in making the correct diagnosis of pulmonaryblastomycosis is not so much the inadequacy of the availableculture techniques, but rather the failure to consider thediagnosis. An appraisal of diagnostic techniques in patientswith pulmonary blastomycosis noted that culture eventuallyyielded B. dermatitidis in 86% of patients (43). The diagnosticyields for sputum samples, tracheal secretions, and gastricwashings were 75%, 100%, and 67%, respectively. Whenbronchoscopy was performed, the yield was even greater. Themain drawback to culture methods is that it may take as long as4 to 5 weeks for the organism to grow (44). For most clinicalsituations, this means that culture results provide confirmationof the diagnosis, but other techniques that give a more rapidanswer must be pursued.

Figure 5. Verrucous, plaque-like lesion

showing central microabscesses and the

well-demarcated, heaped-up border typ-ical of blastomycosis.

Figure 6. Painful, ulcerated lesion on thelower leg of a patient who had several

other cutaneous ulcerations and also

a pulmonary infiltrate; B. dermatitidiswas grown from sputum and the cuta-

neous ulcers.


Smears and Histopathology

The importance of immediately looking for the organism ina smear from a respiratory or tissue sample has been empha-sized. In one series of patients who had pulmonary blastomy-cosis, a smear and culture for fungus was ordered for only 24%of sputum samples and 55% of samples obtained by bronchos-copy (43). B. dermatitidis has distinctive features that includelarge size (8–15 mm), thick wall, and distinctive budding(daughter cell is close to the same size as the mother cell beforedetachment). Thus, a rapid diagnosis of blastomycosis can bemade by microscopic examination of smears of respiratorysecretions or histopathologic examination of tissue specimens(44). Respiratory secretions can be treated with KOH or withcalcofluor white, which causes fluorescence of the fungal cellwall, and is more sensitive. Papanicolaou stains that are used for

cytology preparations also show the distinctive characteristics ofB. dermatitidis (Figure 8). The organisms are poorly seen intissue stained with hematoxylin and eosin, but are readily seenwith methenamine silver or periodic acid Schiff (PAS) stains.

Antigen Testing

A urine antigen assay for the cell wall polysaccharide of B.dermatitidis has been reported to have a sensitivity of 93% anda specificity of 79% (45). It is a relatively new test, and its role indiagnosis is still unclear. Currently, it appears that this assay isuseful for patients who have either severe pulmonary or dissem-inated infection, but whether it will be helpful in those withmilder infection is not known. It is also not clear if urinaryantigen levels can be followed as a means of assessing theresponse to treatment, as has been demonstrated with urinary

Figure 7. Large pustular lesions thatevolved over the course of 1 to 2 weeks

in a young man who died with widely

disseminated blastomycosis; smear taken

from one of these lesions revealed nu-merous budding yeasts typical of B.

dermatitidis.

Figure 8. Papanicolaou stain of sputum

from a patient with blastomycosis, show-

ing the thick-walled yeast that has a sin-

gle daughter bud attached by a broadbase.


Histoplasma antigen testing (46). The test is not specific forblastomycosis, and cross-reactivity occurs in patients who havehistoplasmosis, paracoccidioidomycosis, and penicilliosis (45). Insome patients with severe infection, the Histoplasma urinaryantigen level is higher than that for the Blastomyces antigen,emphasizing the cross-reactivity between these two assays.

Serological Testing

Serological testing in blastomycosis is problematic because oflow rates of sensitivity and specificity (44). For example, in onelarge series of 25 patients with pulmonary blastomycosis, theimmunodiffusion assay was positive in 40% and complementfixation in 16% (43). Extensive work has gone into trying toestablish more specific and sensitive assays using differentantigens specific to B. dermatitidis (47), but none are currentlyavailable. The commercially available assays for complementfixation and immunodiffusion are not useful for diagnosis.

TREATMENT

Updated practice guidelines for the treatment of blastomycosishave been published by the Infectious Diseases Society ofAmerica (IDSA) (48) (Table 1). All patients with blastomyco-sis, even those with a single cutaneous lesion, should be treatedwith an antifungal agent because of the high likelihood ofprogression or recurrence of the infection if not treated. Ingeneral, initial therapy for patients who have mild-to-moderatepulmonary or disseminated blastomycosis will be with an azoleagent and for patients who have severe pulmonary or dissem-inated blastomycosis will be with an amphotericin B formula-tion. Immunosuppressed patients and those with central ner-vous system disease should be treated initially with anamphotericin B formulation (48). The major changes that havebeen incorporated in the 2008 IDSA guidelines as comparedwith the 2000 IDSA guidelines are noted below.

Amphotericin B Therapy

Lipid formulations of amphotericin B, either liposomal ampho-tericin B or lipid complex amphotericin B, are recommended asalternatives to amphotericin B deoxycholate, which was theonly formulation recommended in 2000. There are no con-trolled trials proving the benefit of lipid formulations comparedwith standard amphotericin B deoxycholate, but in many in-

stitutions the lipid preparations are preferred for most indica-tions that require amphotericin B therapy because they areclearly less nephrotoxic. The dosage is 3 to 5 mg/kg daily forsevere pulmonary or disseminated infection. The recommenda-tion to use amphotericin B for the entire course of therapy hasbeen changed to encourage step-down therapy to an azole whenthe patient has had a satisfactory clinical response to initialamphotericin B therapy.

Despite antifungal therapy, the mortality rate of blastomyco-sis-associated ARDS is still 50 to 89% (30–33). The IDSAguidelines note that corticosteroids have been used in an attemptto improve the outcomes in patients with this complication, butno recommendation was made in regard to the use of theseagents (48). Anecdotal case reports have shown benefit, but thereare no controlled studies assessing corticosteroid use (33). Onereport of only two patients showed rather dramatic improvementwhen methylprednisolone was added to amphotericin B therapy.Extracorporeal membrane oxygenation (ECMO) has also beenused in an attempt to maintain oxygenation and permit lowerventilation pressures in one patient who ultimately died ofblastomycosis (49). This case was instructive in that it wasdocumented that the serum levels of amphotericin B remainedwithin the expected range and were not affected by changes ofthe membrane oxygenator or circuit tubing.

Azole Therapy

Itraconazole remains the azole of choice for mild-to-moderateblastomycosis and for step-down therapy after initial amphoter-icin B treatment for severe blastomycosis (48, 50). Cure ratesare as high as 95% for nonmeningeal mild-to-moderate disease.The usual dosage is 200 mg once or twice daily after an initialloading dose of 200 mg three times daily for 3 days. When thedaily dosage of itraconazole is 400 mg, absorption is enhanced ifthe drug is given as 200 mg twice daily. The main drawbacks ofitraconazole are the variability in absorption and the manydrug–drug interactions. The preferred formulation is the oralsuspension because absorption is more predictable with thisformulation. The suspension is administered on an emptystomach; unfortunately, gastrointestinal upset is common andnot all patients are able to tolerate this formulation. The capsuleformulation of itraconazole requires both food and gastric acidfor maximum absorption. Thus, acid-inhibiting drugs cannot beprescribed when the capsule formulation is used.

Wide inter-patient variability of serum concentrations isevident with either formulation. Because of this, serum itraco-

TABLE 1. SUMMARY OF TREATMENT RECOMMENDATIONS FOR BLASTOMYCOSIS

Type of Blastomycosis Initial Therapy Step-down Therapy

Pulmonary, mild to

moderate severity

Itraconazole, 200 mg thrice daily for 3 d,

then once or twice daily for 6–12 mo

Same as initial

Pulmonary, moderately

severe to severe

Lipid AmB, 3–5 mg/kg daily OR AmB-d, 0.7–1.0 mg/kg

daily for 1–2 wk until improvement noted


then 200 mg twice daily for 6–12 mo

Disseminated, mild to

moderate severity

Itraconazole, 200 mg thrice daily for 3 d, then once or

twice daily for 6–12 mo

Same as initial

Disseminated, moderately

severe to severe

Lipid AmB, 3–5 mg/kg daily OR AmB-d, 0.7–1.0 mg/kg

daily for 1–2 wk until improvement noted


then 200 mg twice daily for at least 12 mo

Central nervous system L-AmB, 5 mg/kg daily for 4–6 wk Possible options: Fluconazole, 800 mg

dailyItraconazole, 200 mg once or twice

dailyVoriconazole, 200–400 mg twice

daily for at least 12 mo and until resolution

of CSF abnormalities

Immunocompromised

patients

L-AmB, 3-5 mg/kg daily OR AmB-d, 0.7–1.0 mg/kg daily

for 1–2 wk until improvement noted


then 200 mg twice daily for 12 mo. Life-long

suppression with itraconazole, 200 mg daily

if immunosuppression cannot be reversed

Definition of abbreviations: AmB-d 5 amphotericin B deoxycholate; CSF 5 cerebrospinal fluid; L-AmB 5 liposomal amphotericin B.


nazole levels should be monitored. Itraconazole levels shouldbe determined after approximately 2 weeks when steady statehas been reached. A serum level greater than 1.0 mg/ml isrecommended (48).

Fluconazole is not as effective as itraconazole for blastomy-cosis, and is not recommended (51). However, if the patient isunable to tolerate itraconazole, fluconazole can be used, but thedosage should be 800 mg daily. The guidelines acknowledgeanecdotal reports that have shown the effectiveness of vorico-nazole for the treatment of blastomycosis (48, 52–54). Interest-ingly, most of these reports showed benefit when this agent wasused to treat patients who had central nervous system infection.There is no experience to date for the use of posaconazole forblastomycosis, but this agent has good in vitro activity against B.dermatitidis.

Central Nervous System Infection

For patients with central nervous system blastomycosis, a lipidformulation of amphotericin B at a dosage of 5 mg/kg daily isrecommended for 4 to 6 weeks, followed by therapy with an azolefor a total of a least a year of antifungal therapy. The guidelinesoffer several options for azole step-down therapy, based entirelyon anecdotal data (48). Interestingly, there is more experiencewith voriconazole, which is not FDA-approved for the treatmentof blastomycosis, than with itraconazole or fluconazole. Althoughitraconazole has excellent activity against B. dermatitidis, cere-brospinal fluid (CSF) levels are very low; fluconazole achievesexcellent CSF levels, but has only modest activity against B.dermatitidis. Voriconazole achieves good CSF concentrations andalso has excellent activity against the organism. Depending onthe response to therapy and the immune status of the patient withcentral nervous system blastomycosis, azole therapy may have tobe continued for life to prevent relapse of the infection (48).

Length of Therapy

The length of therapy for pulmonary or disseminated forms ofblastomycosis depends on the severity of the infection and theimmune status of the host. Pulmonary blastomycosis and dissem-inated infection in patients who have mild-to-moderate illness isusually treated for a total of 6 to 12 months (48). Patients withdisseminated infection who are severely ill and those who haveosteoarticular infection should receive a total of 12 months ofantifungal therapy. Although skin lesions often begin to resolvewithin the first few months of therapy, treatment should continuefor 6 to 12 months to achieve a mycologic cure. For immunosup-pressed patients, treatment with itraconazole, 200 mg daily, isrecommended for life-long suppressive therapy if the immuno-suppression cannot be corrected.

Conflict of Interest Statement: J.A.S. received grant support from Covance/Merck($100,001 or more). C.A.K. received lecture fees from Pfizer ($3,000) and Astellas($6,000), and received grant support from Merck (z$150,000/yr) and Astellas(z$80,000/yr). She receives royalties from Up to Date ($20,000) and CurrentMedicine ($7,000).

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