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Blastomycosis Robert W. Bradsher
From the Division of Infectious Diseases, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
Unlike many fungal infections that are opportunistic, blastomycosis usually occurs in healthy hosts and has an epidemiology similar to those of the other endemic mycoses, histoplasmosis and coccidioidomycosis. In contrast to blastomycosis, histoplasmosis was once considered to be a rare but uniformly fatal infection [ I ]. However, with specific skin testing, it was discovered that, within areas in which Histoplasma species are endemic, many persons without clinical histories of disease had been infected with the fungus [2]. Blastomycosis can be compared to histoplasmosis in its early history in that more and more patients with subclinical infection are being discovered. Cases of patients with acute blastomycosis who recovered without antifungal therapy have been reported; the majority of these cases are associated with point-source epidemics, such as those at Big Fork, Minnesota, and Eagle River, Wisconsin [3, 4]. In that latter epidemic of blastomycosis, only nine of the 44 patients with infection were treated with an antifungal agent [4]. None of the other 35 untreated patients have experienced relapses or had progressive infections. In addition, Edson and Keys [5] reported a number of cases of patients who underwent surgical resection of a solitary pulmonary nodule due to Blastomyces dermatitidis. As long as no other manifestation of disease was present, surgical therapy alone was sufficient for cure. Despite these cases, the incidence of blastomycosis depends on the reporting of clinically diagnosed cases of infec-
Reprints or correspondence: Dr. Robert W. Bradsher, Division of Infectious Diseases, Department of Medicine, University of Arkansas for Medical Sciences, Slot 639, 4301 West Markham Street, Little Rock, Arkansas 72205. Clinical Infectious Diseases 1992;14(Suppl 1):S82-90 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1403-0011$02.00
tion because there are no simple and reliable markers of previous infection, such as the histoplasmin skin test for histoplasmosis. However, there are clear-cut reports of subclinical infection with B. dermatitidis. In the Eagle River epidemic, not all patients with immune markers of infection (positive serological reactions or positive results with antigen-induced lymphocyte transformation) had signs and symptoms characteristic of blastomycosis [4]. During experiments of specific immunity with cells from patients who were treated for blastomycosis [6, 7], two control subjects with no histories of blastomycosis had evidence of immunity. Cells from these two control subjects displayed lymphocyte responses to a Blastomyces antigen and macrophage inhibition of intracellular growth of the fungus, results that are similar to those of experiments using cells from persons with culture-proven infections and that are dissimilar to responses of other control individuals with no history of exposure. Because both control subjects were long-term avid hunters, they could have been exposed to Blastomyces species [7]. This observation prompted studies of other persons whose environmental exposures to patients with clinical blastomycosis were comparable. A cohort of seven forestry co-workers of a patient with blastomycosis was studied [8]. All seven were exposed daily to woods within the area in which Blastomyces species were endemic; each person had laboratory evidence of previous blastomycosis, but nobody had a history of clinical disease. The prevalence of specific immune markers indicating previous infection with this fungus was 60% among fervent hunters from the same area [8]. These studies were performed with persons from overlapping areas in which blastomycosis and histoplasmosis were endemic. Therefore, studies performed by Vaalar et al. [9] used lymphocytes from forestry workers exposed to areas where blastomycosis, but not histoplasmosis, was endemic (northern Minnesota and northern Wisconsin). Thirty percent of the
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Blastomycosis is a rare but important fungal infection that occurs primarily in the south central and midwestern United States. Epidemics of blastomycosis related to a point-source exposure include patients of all ages and both sexes; however, cases of endemic blastomycosis are usually in young to middle-aged adults and are reported more for men than for women. Pneumonia is the most common manifestation of blastomycosis, and the lungs are almost always the organ initially infected. Skin, bone, prostate, and central nervous system are the next most frequently infected organs in descending order. Amphotericin B is curative, but because of its toxic effects, oral agents have been investigated as therapy for blastomycosis. Ketoconazole should replace amphotericin B as therapy for blastomycosis that is not life threatening. Itraconazole is an experimental agent that is perhaps even more effective than ketoconazole. The therapeutic usefulness of fluconazole for blastomycosis remains unproven. For patients with lifethreatening or central nervous system blastomycosis, amphotericin B remains the treatment of choice.
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develop tests for differential exoantigen analysis of mycelial forms in cultures. The tissue phase of the fungus varies in size from 5 to 15 p.m and in the number of organisms found. Although atypical forms may be noted, most are round and have a double wall, which actually consists of the interior and exterior components of the thick cell surface. The yeast may be found inside or outside of macrophages in the response of pyogranulomatous tissue. Unlike Candida or Aspergillus species, colonization with Blastomyces species does not occur; therefore, detection of the fungus by culture or histologic examination secures a diagnosis of infection. An infection with B. dermatitidis starts with inhalation of spores into the lungs followed by clearing of the organism by bronchopulmonary phagocytes. Alveolar macrophages have been shown by Sugar and Picard [18] to kill conidia, an occurrence that may account for why some persons are not infected even though they have the same potential degree of exposure during an epidemic as infected persons. As the fungus undergoes transition to the yeast phase, it grows in the lungs and can also spread to other organs by the bloodstream. With the development of immunity, inflammatory reactions occur initially as a suppurative response consisting of polymorphonuclear leukocytes and with subsequent influx of monocyte-derived macrophages. This response of pyogranulomatous tissue is distinctive of blastomycosis, although necrosis or fibrosis may also be found. Typically, granuloma of blastomycosis does not caseate, as found in patients with tuberculosis. In the skin lesions of this infection, the histologic changes may prompt an erroneous diagnosis of squamous cell carcinoma or keratoacanthoma [19]. Fungal stains would allow the correct diagnosis, but a misdiagnosis is usually discovered when a second distant site of infection is found. Despite spontaneous resolution of pneumonia in many cases, endogenous reactivation may occur at either pulmonary or extrapulmonary sites with or without previous therapy [20].
Pathophysiology B. dermatitidis is a round, budding, thick-walled yeast cell
with a daughter cell forming a single bud that has a broad base. Like H. capsulatum, this fungus is dimorphic, which means that it exists as mycelial forms in nature and as yeast forms in tissue. A dimorphic fungus grows in cultures as mycelia at 25°C and as yeast at 37°C. The physiological changes causing this transition from mycelia to yeast have been described by Medoff et al. [16] as resulting from heatrelated insults with resultant partial uncoupling of oxidative phosphorylation. The perfect or sexual stage of the fungus is Ajellomyces dermatitidis, and the imperfect or conidial stage is B. dermatitidis. B. dermatitidis grows as a fluffy white mold on fungal media at room temperature and as a brown, wrinkled, folded yeast at 37°C. Early mycelial forms of H. capsulatum and B. dermatitidis in culture may be difficult to differentiate; this fact prompted Kaufman and co-workers [17] to
Clinical Manifestations
Constitutional symptoms observed in patients with blastomycosis include weight loss, fever, malaise, fatigue, and other nonspecific complaints, but these symptoms offer little .diagnostic help. The typical patient is a man between 25 and 50 years of age who has a large number of occupations or recreations that expose him to outdoor areas. In an epidemic, children and women are as likely to be infected. Apart from an outbreak, blastomycosis is rarely diagnosed in children. The male-to-female ratio in large series of cases of endemic blastomycosis have been reported (range, 4:1-15:1). Diagnosis'in women may be significantly delayed because of their lack of exposure histories. In one series [21] of 46 patients in Arkansas who were treated with ketoconazole over a 2-year period, 26 were men and 20 were women. Among patients with pulmonary disease, 14 were men and 14 were women;
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workers had in vitro markers of immunity as evidence of subclinical infection, with no question of cross-reactions due to Histoplasma capsulatum [9]. Blastomycosis appears to have patterns of subclinical infection comparable to those of the other, more extensively studied endemic mycoses, histoplasmosis and coccidioidomycosis. Cases of endemic or sporadic blastomycosis account for the majority of cases, but as mentioned above, a few epidemics of infection from point sources have also been summarized by Sarosi and Davies [10]. A total of nine well-described epidemics in North Carolina, Minnesota, Illinois, Wisconsin, and Virginia have yielded valuable information regarding the biology of this infection. The best hypothesis for pathogenesis has been that blastomycosis results from inhalation of spores from the soil. Unfortunately, B. dermatitidis has been very difficult to isolate from soil, in contrast to the ease of recovering H. capsulatum from soil. Denton and DiSalvo [11] recovered B. dermatitidis from soil and rotted wood in Georgia on three occasions. Sarosi and Serstock [12] isolated the yeast phase of B. dermatitidis from bird droppings, and Bakerspigel and co-workers [13] recovered the fungus from a dirt floor in Canada. Many other investigators of areas for which good clues from epidemiological information to the location of the common-source exposure exist have been unsuccessful in recovering the organism from soil. Klein et al. documented the isolation of B. dermatitidis from soil for the first time in association with epidemics in two separate reports [4, 14]. The isolations were from wet earth containing animal droppings, thereby proving that the fungus exists in microfoci in soil. In the epidemics, the isolation of the fungus was also noted to be associated with bodies of water. Whether water is the primary factor or simply an explanation for greater exposure potential because of recreational activities in areas with wildlife or water has yet to be determined [15].
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in contrast, among patients with extrapulmonary infections, 12 were men but only six were women. Pulmonary Features
ing pulmonary infiltrates. In the series of patients in Arkansas [21], two were asymptomatic, 16 had a clinical picture of chronic pneumonia, and eight initially had acute pneumonia. Skin Involvement
Cutaneous lesions are the next most common manifestation of blastomycosis. The skin lesions are of two major types, verrucous and ulcerative. The verrucous form has a raised, sharp, irregular border with crusting above an abscess in the subcutaneous tissue. These lesions show histologic evidence of papillomatosis, downward proliferation of the epidermis with intraepidermal abscesses, and inflammatory cells in the dermis [26]. The hyperplasia and acanthosis may suggest other diagnoses unless fungi are sought with specific histologic stains, such as Grocott-Gomori methenaminesilver nitrate stain. Ulcers due to blastomycosis have histologic changes similar to those of the verrucous form. The borders are heaped up, and the base usually contains exudate. Although many ulcers of blastomycosis originate from subcutaneous pustular lesions that drain, some patients do not have appreciable inflammation, and their ulcers will have clean bases. On biopsy, microabscesses should be present, even in those patients with little inflammation. Organ Involvement
Osteomyelitis due to B. dermatitidis infection is reported in up to 25% of extrapulmonary cases and may be the reason that the patient seeks medical attention. Granuloma, suppuration, or necrosis in the bone may be found on histologic examination. Essentially every bone has been involved, but the vertebrae, pelvis, sacrum, skull, ribs, and long bones are the most commonly affected [27]. The radiographic appearance of blastomycosis is not specific and cannot be discriminated from that of other fungal, bacterial, or neoplastic diseases. Debridement may be required for cure, although most bone lesions resolve with antifungal therapy alone. The genitourinary system follows the lungs, skin, and bone in frequency of involvement, and because men are more likely infected, prostatitis and epididymo-orchitis are reported most commonly [28]. Analysis of urine collected after prostatic massage will improve the detection of genitourinary involvement. Typically, as with skin or bone infection, B. dermatitidis will cause simultaneous complications in the lungs as well as in the prostate or testicle; therefore, chest radiography should be performed in every case of infection with this fungus. Endometrial infection acquired by sexual' contact with a man with cutaneous blastomycosis and tubo-ovarian abscess following hematogenous dissemination are examples of female genital tract infection, a less frequently diagnosed complication of blastomycosis. Manifestations of blastomycosis that involve the nervous
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The most common presentation of clinical blastomycosis is a pulmonary infiltrate, the majority of which are either alveolar or mass-like infiltrates. In one report [22] of 17 patients whose radiographs revealed abnormalities, 16 had radiographically evident infiltrates. Among the 46 patients in Arkansas [21], chest radiographs revealed masses and alveolar infiltrates for 32% and 48%, respectively. The lobar location of the infiltrate of blastomycosis is not helpful diagnostically, although upper lobe locations have been reported slightly more commonly. Miliary or reticulonodular patterns on radiographs are the next most frequent. Kinasewitz and associates [23] described 11 of 26 patients with blastomycosis who had major pleural disease, a condition previously reported commonly by some authors but considered by other investigators to be distinctly unusual in association with this infection. Although 26% of patients from one series [21] had pleural disease, only two had massive effusions, and only one required drainage via a chest tube. It is of interest that this patient developed a local cutaneous infection at the chest tube site similar to the infection of a patient with a complication of transthoracic needle aspiration described by Carter et al. [24]. Although cavitary disease may occur, it is not found commonly as in patients with chronic pulmonary histoplasmosis or tuberculosis. Because of the mass lesions on chest roentenograms, many patients with blastomycosis are initially thought to have lung cancer. In summary, none of the radiographic patterns are diagnostic for this fungal infection. The different types of clinical presentations of pulmonary blastomycosis include acute pneumonia, chronic pneumonia, and no pulmonary symptoms at all [21]. Patients with acute pneumonia resemble those with bacterial pneumonia with fever, chills, and a cough productive of purulent sputum; a significant number of these patients also have hemoptysis. The patients do not respond to antibiotics, but for some with either epidemic or endemic disease, spontaneous resolution of acute pneumonia occurs, thereby making it appear that the antibiotics have worked. Some patients with this acute process have developed erythema nodosum during the resolution phase of blastomycosis [25]. The symptoms that accompany chronic pneumonia due to blastomycosis usually last 2 to 6 months and include weight loss, night sweats, fever, cough with sputum production, and chest pain. Patients with these symptoms resemble those with other chronic pulmonary illnesses, and a misdiagnosis of more common medical problems such as malignancy or tuberculosis may occur. Blastomycosis may be discovered in patients who deny having pulmonary complaints, even after extensive questioning, by routine radiography demonstrat-
CID 1992;14 (Suppl 1)
CID 1992;14 (Suppl 1)
Blastomycosis
tient with hyperprolactinemia with galactorrhea and amenorrhea [34] have been reported. Although blastomycosis may cause infections in immunocompromised patients, other fungal infections such as disseminated histoplasmosis or cryptococcal meningitis are much more likely to be opportunistic than blastomycosis. Immunosuppressed patients usually develop infection following exposure in the environment or through subsequent reactivation, just like immunocompetent patients. Unlike similar fungi, B. dermatitidis has been reported as a significant pathogen of only a small number of patients with human immunodeficiency virus [35]. Diagnosis The diagnosis of blastomycosis is made by identification of the fungus in tissue or exudate followed by culture. Unlike some organisms, B. dermatitidis is easy to detect in both smears and cultures, the results of which are reliable for a firm diagnosis. Cultures were positive for the fungus in each case in our previous report [21], and for every patient who had exudate, sputum, or tissue examined, the fungus was identified on microscopy. In addition to examinations of sputum by wet preparations with potassium hydroxide, cytological preparations can be used for a dependable diagnosis. Pathologists should be aware of the appearance of the fungus after Papanicolaou's staining [36] since the clinical picture of chronic pneumonia due to blastomycosis may resemble that of carcinoma of the lung, thus prompting cytological examinations of sputum. In areas with a low frequency of this infection, many cases will be diagnosed only after invasive procedures. With newer microbiological techniques, perhaps more cases of blastomycosis will be identified from yeastphase cultures of blood or other specimens, as Musial et al. [37] have recently reported. It is fortunate that diagnosis by smear or culture is relatively easy because other diagnostic techniques used for infections are not reliable for blastomycosis. Clinically available tests include complement fixation (CF), immunodiffusion (ID), and skin tests with blastomycin for delayedtype hypersensitivity. With blastomycosis, these assays have been useful as tools for epidemiological assessments but not for clinical diagnosis. Cross-reactivity to antigens of various fungi, particularly B. dermatitidis and H. eapsulatum, is severely limiting to the specificity of the assays [38]. For example, persons with blastomycosis are just as apt to demonstrate complement-fixing antibodies to histoplasmin as to blastomycin [10]. None of the patients in one series had titers of complement-fixing antibodies to blastomycin >1:8 dilution [21]. The poor sensitivity of the CF test prompted the development of ID testing, which resulted in sensitivity rates of up to 80% in initial reports. When the sera of patients with localized blastomycosis were tested, the results reported by Klein
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system occur in 5% to 10% of cases of disseminated disease and include meningitis or, more commonly, epidural or cranial abscesses [29]. A computed tomogram should direct the surgeon to the cranial abscesses at biopsy, but meningitis may be more difficult to diagnose. Evaluation of CSF usually is not diagnostic, and culture of ventricular fluid may be required for isolation of the fungus. In one series [30], analysis of CSF obtained by lumbar puncture yielded the diagnosis in only two of 22 cases, whereas cultures of ventricular fluid specimens were positive for fungus in six of seven cases. Along with osteomyelitis, neurological manifestations of blastomycosis present the greatest challenge for successful therapy. Lesions of blastomycosis may occur in virtually any organ. Widely disseminated or miliary blastomycosis may present as adult respiratory distress syndrome (ARDS). One patient described by Evans et al. [31] had an ulcer seen at the canna of trachea on bronchoscopy, thereby prompting the speculation that a subcranial lymph node ruptured into the trachea and enough organisms were spilled into the lungs to cause ARDS. The majority of patients with the pattern of diffuse infiltrates, noncardiac pulmonary edema, and refractory hypoxemia die very quickly; three patients in one series died of ARDS despite intensive medical and antifungal therapy [21]. Abscesses are most common in the subcutaneous tissue but, as already noted, may be found in the brain, skeletal system, prostate, or other areas as lesions in the myocardium, pericardium, orbit, sinuses, pituitary or adrenal glands, or other organs [27]. The reticuloendothelial system has been involved, with reports of several cases of lymph node or hepatic involvement, and a few cases of splenic abscesses have been documented [32]. Surgical drainage of splenic abscesses is required, just as it is for the majority of large abscesses secondary to blastomycosis. Lesions in the mouth and oropharyngeal area occur but are not found with the same frequency as lesions seen in patients with disseminated histoplasmosis. One exception is the larynx. Witorsch and Utz [27] refuted the hypothesis that the larynx might become infected primarily rather than by hematogenous dissemination from a pulmonary focus. Laryngeal biopsy reveals histologic features similar to those in the skin. The hyperplasia, acanthosis, and fungating appearance of the larynx may be confused with squamous cell carcinoma. Fixation of the vocal cords secondary to fibrosis has led, in some cases, to radiation therapy or total laryngectomy because of an incorrect diagnosis of neoplasm rather than blastomycosis. Specific endocrine abnormalities may appear in patients with blastomycosis [27]. Adrenal insufficiency from gland destruction, infection of the thyroid glands, hypercalcemia (as seen with other granulomatous diseases), and abnormal menses secondary to blastomycosis have been reported. A single case of diabetes insipidus [33] and one case of a pa-
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Therapy
The first consideration in regard to treatment of the patient with blastomycosis is whether to use an antifungal agent. The severity of the clinical presentation of the patient and the toxicity of the antifungal agent are the major determinants of whether to observe the infection or to use the agent. Relapse of the initial infection either with or without treatment has been reported; therefore, the patient must be carefully followed for a prolonged period if therapy is not given [19, 20]. Because resolution of the infection without therapy [20] may occur in patients with an epidemic focus of infection or from an area where blastomycosis is endemic, observation of pneumonia for 1 to 2 weeks may be considered. If the patient's condition deteriorates or progresses, antifungal therapy should be started. Occasionally the diagnosis of blas-
tomycosis has not been considered for patients with pneumonia until cultures of respiratory secretions (sputum or bronchoscopy washings or brushings) yield the organism. Observation alone may also be indicated for patients whose conditions have already improved while the culture was incubating. As previously noted, surgical resection of a solitary pulmonary nodule may cure the infection without further therapy [5]. The presence of pleural disease during the course of illness mandates antifungal treatment. Likewise, all other forms of extrapulmonary blastomycosis should also be treated with systemic therapy. Amphotericin B
Before antifungal therapy was available, a case-fatality rate among untreated patients with blastomycosis of 78% was documented [47]. In more recent reports, 21% and 28% of untreated patients died of fungal infections [48, 49]. Following its introduction in 1956, amphotericin B has been shown to be effective in the treatment of blastomycosis. In five large series of patients with this fungal infection, intravenous amphotericin B in a dose of at least 1.0 g resulted in cure without relapse in 16 of 19, 21 of 27, 32 of 35, 13 of 15, and 37 of 41 patients [27, 50-53]. A total cumulative dose of 2 g has been associated with cure rates of up to 97%. The mechanism of action of amphotericin B is the interaction of the agent with components of the surface of the cell, thereby altering the integrity of the fungal cell membrane [54]. Unfortunately, this high degree of antimycotic activity is associated with significant toxic effects. In a group of patients with blastomycosis described by Abernathy [55], almost three-fourths (71%) experienced a decline in renal function; a number of other toxic effects, including anemia (53%), anorexia and nausea (53%), fever (49%), hypokalemia (37%), and thrombophlebitis (19%), were also reported. Interruption of therapy during some point in the course was required in 41% of patients, and termination of therapy with amphotericin B before reaching the desired total dose was mandatory because of toxic effects in 14% of the patients [55]. Similarly, all 21 courses of amphotericin B treatment of patients with blastomycosis reported by Witorsch and Utz [27] were complicated by both azotemia and anemia. Because amphotericin B and dehydration are synergistically nephrotoxic, salt loading has been recommended for protection of renal function [56]. Relapse of blastomycosis following amphotericin B therapy occurs only rarely and appears to be dose dependent [10, 19]. In one large retrospective series, relapse occurred in only two of 30 patients who received >1.5 g of the drug, whereas five of 19 patients who received a smaller dose experienced a relapse [51]. Most of the cases of relapse described by Witorsch and Utz [27] occurred shortly after completion of amphotericin B therapy. However, patients have experienced relapse of disease as long as 9 years following treatment. As
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et al. [39] of enzyme immunoassay (EIA) techniques using a yeast-phase antigen (antigen A) were better than those of ID tests. However, similar results of ID and EIA were obtained when the sera from patients with disseminated disease were tested. In the largest outbreak of blastomycosis reported, Klein et al. [40] described antibody detection by EIA, ID, and CF techniques of 77%, 28%, and 9%, respectively. Although cases in which positive reactions occur have been documented, Lambert and George [41] also detected falsepositive results with a similar EIA technique using specimens from persons in areas in which histoplasmosis and blastomycosis were endemic. Therefore, as noted by Sarosi et al. [42], serodiagnosis of blastomycosis is a problem owing to potential low rates of sensitivity and specificity. Klein and Jones [43] have isolated a surface protein of B. dermatitidis that may be useful in the detection of antibody in patients. Confirmation of sensitivity and specificity will enhance the likelihood that this protein may be used clinically as an antigen in the future. Skin testing with blastomycin is, unfortunately, no better as a diagnostic procedure. This mycelial-phase antigen does not provide sufficient specificity or sensitivity for reliable assessment of patients and is no longer available clinically. It may be useful epidemiologically; in the Eagle River outbreak, 15 of 48 patients tested had a positive skin reaction [4]. Unlike the detection of long-lasting immunity with in vitro lymphocyte reactivity to a yeast-phase antigen in patients with blastomycosis [44], reactions to skin tests with blastomycin rapidly diminish and become negative on repeated testing over time [45]. In summary, none of the screening tests are totally reliable for the diagnosis of blastomycosis. Until antigen testing is available for B. dermatitidis, as has been described for H. capsulatum by Wheat and colleagues [46], the diagnosis of blastomycosis will depend on visualization of the fungus on smear, in tissue, or in culture.
CID 1992;14 (Suppl 1)
CID 1992;14 (Suppl I)
Blastomycosis
Ketoconazole
Ketoconazole is an imidazole antifungal agent with in vitro activity against B. dermatitidis similar to that of amphotericin B [58]. The drug works by disrupting the cell membranes following interactions with cytochrome P-450 enzymes; this leads to reduced concentrations of ergosterol, the major sterol of the membrane of the fungus [55, 58]. Ketoconazole is absorbed from the gastrointestinal tract and has been generally well tolerated in clinical studies of patients with other fungal infections. The drug has been used to treat blastomycosis in canines [59, 60], and moderate effectiveness has been shown in a murine model of B. dermatitidis infection [61]. The major advantages of the drug are that it is absorbed from the gastrointestinal tract and is generally well tolerated. Adverse effects of ketoconazole include those that are severe and those that are less of a problem. One severe toxic effect is hepatocellular damage, which appears to be a very rare occurrence [62]; therefore, liver transaminase levels should be monitored during ketoconazole therapy. At higher dosages of the drug, hormonal abnormalities, such as gynecomastia, dysfunctional uterine bleeding, and oligospermia, have been described [21, 58, 63]. More common, but less severe, adverse effects include nausea and vomiting (increased incidence when the drug is taken without a meal) as well as dizziness, pruritus, and headache [21]. The absorption of ketoconazole requires an acidic gastric content; therefore, antacids or H2 blocking agents, such as cimetidine or ranitidine, are contraindicated while the patient is taking ketoconazole. Other agents, such as rifampin, oral contraceptives, cyclosporine, phenobarbital, and phenytoin, may interfere with ketoconazole therapy [55]. With a lower potential of toxicity than amphotericin B, ketoconazole has been viewed with considerable enthusiasm for the treatment of blastomycosis. The results of the initial trial of ketoconazole for blastomycosis performed by the National Institutes of Health (NIH) Mycoses Study Group [64] were not very optimistic. Of 16 patients with blastomycosis,
seven were cured, four were considered to have treatment failures, and five experienced relapse of infection. However, the adequacy of the dose of ketoconazole and the duration of therapy were questioned. Ten of the 25 patients who experienced relapses of various fungal infections received a maximal dose of 200 mg of ketoconazole per day. Some patients received the drug for only 1 month before failure of treatment was declared. After that report, scattered case reports of patients with blastomycosis who were treated with ketoconazole [65-70], two prospective trials of ketoconazole [21, 71], and one retrospective review of ketoconazole treatment of blastomycosis [72] were reported. The results of these reports on the therapeutic usefulness of ketoconazole (400-800 mg/d for at least 6 months) were more promising than those of the initial reports. The results of a second trial of ketoconazole for blastomycosis performed by the NIH Mycoses Study Group [71] were much more successful than those of the initial report. Of the 80 patients enrolled in the study, 89% were cured, as long as treatment with 400 or 800 mg of ketoconazole per day was given for at least 6 months. Relapse occurred 2, 7, 18, and 24 months following therapy. In another trial [21], 35 of 44 patients treated with ketoconazole (400 mg given as a single daily dose with breakfast) were cured without experiencing a relapse. Six patients experienced relapses following therapy, but three of these six were protocol inadherent and received
Blastomycosis Robert W. Bradsher
From the Division of Infectious Diseases, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
Unlike many fungal infections that are opportunistic, blastomycosis usually occurs in healthy hosts and has an epidemiology similar to those of the other endemic mycoses, histoplasmosis and coccidioidomycosis. In contrast to blastomycosis, histoplasmosis was once considered to be a rare but uniformly fatal infection [ I ]. However, with specific skin testing, it was discovered that, within areas in which Histoplasma species are endemic, many persons without clinical histories of disease had been infected with the fungus [2]. Blastomycosis can be compared to histoplasmosis in its early history in that more and more patients with subclinical infection are being discovered. Cases of patients with acute blastomycosis who recovered without antifungal therapy have been reported; the majority of these cases are associated with point-source epidemics, such as those at Big Fork, Minnesota, and Eagle River, Wisconsin [3, 4]. In that latter epidemic of blastomycosis, only nine of the 44 patients with infection were treated with an antifungal agent [4]. None of the other 35 untreated patients have experienced relapses or had progressive infections. In addition, Edson and Keys [5] reported a number of cases of patients who underwent surgical resection of a solitary pulmonary nodule due to Blastomyces dermatitidis. As long as no other manifestation of disease was present, surgical therapy alone was sufficient for cure. Despite these cases, the incidence of blastomycosis depends on the reporting of clinically diagnosed cases of infec-
Reprints or correspondence: Dr. Robert W. Bradsher, Division of Infectious Diseases, Department of Medicine, University of Arkansas for Medical Sciences, Slot 639, 4301 West Markham Street, Little Rock, Arkansas 72205. Clinical Infectious Diseases 1992;14(Suppl 1):S82-90 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1403-0011$02.00
tion because there are no simple and reliable markers of previous infection, such as the histoplasmin skin test for histoplasmosis. However, there are clear-cut reports of subclinical infection with B. dermatitidis. In the Eagle River epidemic, not all patients with immune markers of infection (positive serological reactions or positive results with antigen-induced lymphocyte transformation) had signs and symptoms characteristic of blastomycosis [4]. During experiments of specific immunity with cells from patients who were treated for blastomycosis [6, 7], two control subjects with no histories of blastomycosis had evidence of immunity. Cells from these two control subjects displayed lymphocyte responses to a Blastomyces antigen and macrophage inhibition of intracellular growth of the fungus, results that are similar to those of experiments using cells from persons with culture-proven infections and that are dissimilar to responses of other control individuals with no history of exposure. Because both control subjects were long-term avid hunters, they could have been exposed to Blastomyces species [7]. This observation prompted studies of other persons whose environmental exposures to patients with clinical blastomycosis were comparable. A cohort of seven forestry co-workers of a patient with blastomycosis was studied [8]. All seven were exposed daily to woods within the area in which Blastomyces species were endemic; each person had laboratory evidence of previous blastomycosis, but nobody had a history of clinical disease. The prevalence of specific immune markers indicating previous infection with this fungus was 60% among fervent hunters from the same area [8]. These studies were performed with persons from overlapping areas in which blastomycosis and histoplasmosis were endemic. Therefore, studies performed by Vaalar et al. [9] used lymphocytes from forestry workers exposed to areas where blastomycosis, but not histoplasmosis, was endemic (northern Minnesota and northern Wisconsin). Thirty percent of the
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Blastomycosis is a rare but important fungal infection that occurs primarily in the south central and midwestern United States. Epidemics of blastomycosis related to a point-source exposure include patients of all ages and both sexes; however, cases of endemic blastomycosis are usually in young to middle-aged adults and are reported more for men than for women. Pneumonia is the most common manifestation of blastomycosis, and the lungs are almost always the organ initially infected. Skin, bone, prostate, and central nervous system are the next most frequently infected organs in descending order. Amphotericin B is curative, but because of its toxic effects, oral agents have been investigated as therapy for blastomycosis. Ketoconazole should replace amphotericin B as therapy for blastomycosis that is not life threatening. Itraconazole is an experimental agent that is perhaps even more effective than ketoconazole. The therapeutic usefulness of fluconazole for blastomycosis remains unproven. For patients with lifethreatening or central nervous system blastomycosis, amphotericin B remains the treatment of choice.
CID 1992;14 (Suppl I)
Blastomycosis
develop tests for differential exoantigen analysis of mycelial forms in cultures. The tissue phase of the fungus varies in size from 5 to 15 p.m and in the number of organisms found. Although atypical forms may be noted, most are round and have a double wall, which actually consists of the interior and exterior components of the thick cell surface. The yeast may be found inside or outside of macrophages in the response of pyogranulomatous tissue. Unlike Candida or Aspergillus species, colonization with Blastomyces species does not occur; therefore, detection of the fungus by culture or histologic examination secures a diagnosis of infection. An infection with B. dermatitidis starts with inhalation of spores into the lungs followed by clearing of the organism by bronchopulmonary phagocytes. Alveolar macrophages have been shown by Sugar and Picard [18] to kill conidia, an occurrence that may account for why some persons are not infected even though they have the same potential degree of exposure during an epidemic as infected persons. As the fungus undergoes transition to the yeast phase, it grows in the lungs and can also spread to other organs by the bloodstream. With the development of immunity, inflammatory reactions occur initially as a suppurative response consisting of polymorphonuclear leukocytes and with subsequent influx of monocyte-derived macrophages. This response of pyogranulomatous tissue is distinctive of blastomycosis, although necrosis or fibrosis may also be found. Typically, granuloma of blastomycosis does not caseate, as found in patients with tuberculosis. In the skin lesions of this infection, the histologic changes may prompt an erroneous diagnosis of squamous cell carcinoma or keratoacanthoma [19]. Fungal stains would allow the correct diagnosis, but a misdiagnosis is usually discovered when a second distant site of infection is found. Despite spontaneous resolution of pneumonia in many cases, endogenous reactivation may occur at either pulmonary or extrapulmonary sites with or without previous therapy [20].
Pathophysiology B. dermatitidis is a round, budding, thick-walled yeast cell
with a daughter cell forming a single bud that has a broad base. Like H. capsulatum, this fungus is dimorphic, which means that it exists as mycelial forms in nature and as yeast forms in tissue. A dimorphic fungus grows in cultures as mycelia at 25°C and as yeast at 37°C. The physiological changes causing this transition from mycelia to yeast have been described by Medoff et al. [16] as resulting from heatrelated insults with resultant partial uncoupling of oxidative phosphorylation. The perfect or sexual stage of the fungus is Ajellomyces dermatitidis, and the imperfect or conidial stage is B. dermatitidis. B. dermatitidis grows as a fluffy white mold on fungal media at room temperature and as a brown, wrinkled, folded yeast at 37°C. Early mycelial forms of H. capsulatum and B. dermatitidis in culture may be difficult to differentiate; this fact prompted Kaufman and co-workers [17] to
Clinical Manifestations
Constitutional symptoms observed in patients with blastomycosis include weight loss, fever, malaise, fatigue, and other nonspecific complaints, but these symptoms offer little .diagnostic help. The typical patient is a man between 25 and 50 years of age who has a large number of occupations or recreations that expose him to outdoor areas. In an epidemic, children and women are as likely to be infected. Apart from an outbreak, blastomycosis is rarely diagnosed in children. The male-to-female ratio in large series of cases of endemic blastomycosis have been reported (range, 4:1-15:1). Diagnosis'in women may be significantly delayed because of their lack of exposure histories. In one series [21] of 46 patients in Arkansas who were treated with ketoconazole over a 2-year period, 26 were men and 20 were women. Among patients with pulmonary disease, 14 were men and 14 were women;
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workers had in vitro markers of immunity as evidence of subclinical infection, with no question of cross-reactions due to Histoplasma capsulatum [9]. Blastomycosis appears to have patterns of subclinical infection comparable to those of the other, more extensively studied endemic mycoses, histoplasmosis and coccidioidomycosis. Cases of endemic or sporadic blastomycosis account for the majority of cases, but as mentioned above, a few epidemics of infection from point sources have also been summarized by Sarosi and Davies [10]. A total of nine well-described epidemics in North Carolina, Minnesota, Illinois, Wisconsin, and Virginia have yielded valuable information regarding the biology of this infection. The best hypothesis for pathogenesis has been that blastomycosis results from inhalation of spores from the soil. Unfortunately, B. dermatitidis has been very difficult to isolate from soil, in contrast to the ease of recovering H. capsulatum from soil. Denton and DiSalvo [11] recovered B. dermatitidis from soil and rotted wood in Georgia on three occasions. Sarosi and Serstock [12] isolated the yeast phase of B. dermatitidis from bird droppings, and Bakerspigel and co-workers [13] recovered the fungus from a dirt floor in Canada. Many other investigators of areas for which good clues from epidemiological information to the location of the common-source exposure exist have been unsuccessful in recovering the organism from soil. Klein et al. documented the isolation of B. dermatitidis from soil for the first time in association with epidemics in two separate reports [4, 14]. The isolations were from wet earth containing animal droppings, thereby proving that the fungus exists in microfoci in soil. In the epidemics, the isolation of the fungus was also noted to be associated with bodies of water. Whether water is the primary factor or simply an explanation for greater exposure potential because of recreational activities in areas with wildlife or water has yet to be determined [15].
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in contrast, among patients with extrapulmonary infections, 12 were men but only six were women. Pulmonary Features
ing pulmonary infiltrates. In the series of patients in Arkansas [21], two were asymptomatic, 16 had a clinical picture of chronic pneumonia, and eight initially had acute pneumonia. Skin Involvement
Cutaneous lesions are the next most common manifestation of blastomycosis. The skin lesions are of two major types, verrucous and ulcerative. The verrucous form has a raised, sharp, irregular border with crusting above an abscess in the subcutaneous tissue. These lesions show histologic evidence of papillomatosis, downward proliferation of the epidermis with intraepidermal abscesses, and inflammatory cells in the dermis [26]. The hyperplasia and acanthosis may suggest other diagnoses unless fungi are sought with specific histologic stains, such as Grocott-Gomori methenaminesilver nitrate stain. Ulcers due to blastomycosis have histologic changes similar to those of the verrucous form. The borders are heaped up, and the base usually contains exudate. Although many ulcers of blastomycosis originate from subcutaneous pustular lesions that drain, some patients do not have appreciable inflammation, and their ulcers will have clean bases. On biopsy, microabscesses should be present, even in those patients with little inflammation. Organ Involvement
Osteomyelitis due to B. dermatitidis infection is reported in up to 25% of extrapulmonary cases and may be the reason that the patient seeks medical attention. Granuloma, suppuration, or necrosis in the bone may be found on histologic examination. Essentially every bone has been involved, but the vertebrae, pelvis, sacrum, skull, ribs, and long bones are the most commonly affected [27]. The radiographic appearance of blastomycosis is not specific and cannot be discriminated from that of other fungal, bacterial, or neoplastic diseases. Debridement may be required for cure, although most bone lesions resolve with antifungal therapy alone. The genitourinary system follows the lungs, skin, and bone in frequency of involvement, and because men are more likely infected, prostatitis and epididymo-orchitis are reported most commonly [28]. Analysis of urine collected after prostatic massage will improve the detection of genitourinary involvement. Typically, as with skin or bone infection, B. dermatitidis will cause simultaneous complications in the lungs as well as in the prostate or testicle; therefore, chest radiography should be performed in every case of infection with this fungus. Endometrial infection acquired by sexual' contact with a man with cutaneous blastomycosis and tubo-ovarian abscess following hematogenous dissemination are examples of female genital tract infection, a less frequently diagnosed complication of blastomycosis. Manifestations of blastomycosis that involve the nervous
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The most common presentation of clinical blastomycosis is a pulmonary infiltrate, the majority of which are either alveolar or mass-like infiltrates. In one report [22] of 17 patients whose radiographs revealed abnormalities, 16 had radiographically evident infiltrates. Among the 46 patients in Arkansas [21], chest radiographs revealed masses and alveolar infiltrates for 32% and 48%, respectively. The lobar location of the infiltrate of blastomycosis is not helpful diagnostically, although upper lobe locations have been reported slightly more commonly. Miliary or reticulonodular patterns on radiographs are the next most frequent. Kinasewitz and associates [23] described 11 of 26 patients with blastomycosis who had major pleural disease, a condition previously reported commonly by some authors but considered by other investigators to be distinctly unusual in association with this infection. Although 26% of patients from one series [21] had pleural disease, only two had massive effusions, and only one required drainage via a chest tube. It is of interest that this patient developed a local cutaneous infection at the chest tube site similar to the infection of a patient with a complication of transthoracic needle aspiration described by Carter et al. [24]. Although cavitary disease may occur, it is not found commonly as in patients with chronic pulmonary histoplasmosis or tuberculosis. Because of the mass lesions on chest roentenograms, many patients with blastomycosis are initially thought to have lung cancer. In summary, none of the radiographic patterns are diagnostic for this fungal infection. The different types of clinical presentations of pulmonary blastomycosis include acute pneumonia, chronic pneumonia, and no pulmonary symptoms at all [21]. Patients with acute pneumonia resemble those with bacterial pneumonia with fever, chills, and a cough productive of purulent sputum; a significant number of these patients also have hemoptysis. The patients do not respond to antibiotics, but for some with either epidemic or endemic disease, spontaneous resolution of acute pneumonia occurs, thereby making it appear that the antibiotics have worked. Some patients with this acute process have developed erythema nodosum during the resolution phase of blastomycosis [25]. The symptoms that accompany chronic pneumonia due to blastomycosis usually last 2 to 6 months and include weight loss, night sweats, fever, cough with sputum production, and chest pain. Patients with these symptoms resemble those with other chronic pulmonary illnesses, and a misdiagnosis of more common medical problems such as malignancy or tuberculosis may occur. Blastomycosis may be discovered in patients who deny having pulmonary complaints, even after extensive questioning, by routine radiography demonstrat-
CID 1992;14 (Suppl 1)
CID 1992;14 (Suppl 1)
Blastomycosis
tient with hyperprolactinemia with galactorrhea and amenorrhea [34] have been reported. Although blastomycosis may cause infections in immunocompromised patients, other fungal infections such as disseminated histoplasmosis or cryptococcal meningitis are much more likely to be opportunistic than blastomycosis. Immunosuppressed patients usually develop infection following exposure in the environment or through subsequent reactivation, just like immunocompetent patients. Unlike similar fungi, B. dermatitidis has been reported as a significant pathogen of only a small number of patients with human immunodeficiency virus [35]. Diagnosis The diagnosis of blastomycosis is made by identification of the fungus in tissue or exudate followed by culture. Unlike some organisms, B. dermatitidis is easy to detect in both smears and cultures, the results of which are reliable for a firm diagnosis. Cultures were positive for the fungus in each case in our previous report [21], and for every patient who had exudate, sputum, or tissue examined, the fungus was identified on microscopy. In addition to examinations of sputum by wet preparations with potassium hydroxide, cytological preparations can be used for a dependable diagnosis. Pathologists should be aware of the appearance of the fungus after Papanicolaou's staining [36] since the clinical picture of chronic pneumonia due to blastomycosis may resemble that of carcinoma of the lung, thus prompting cytological examinations of sputum. In areas with a low frequency of this infection, many cases will be diagnosed only after invasive procedures. With newer microbiological techniques, perhaps more cases of blastomycosis will be identified from yeastphase cultures of blood or other specimens, as Musial et al. [37] have recently reported. It is fortunate that diagnosis by smear or culture is relatively easy because other diagnostic techniques used for infections are not reliable for blastomycosis. Clinically available tests include complement fixation (CF), immunodiffusion (ID), and skin tests with blastomycin for delayedtype hypersensitivity. With blastomycosis, these assays have been useful as tools for epidemiological assessments but not for clinical diagnosis. Cross-reactivity to antigens of various fungi, particularly B. dermatitidis and H. eapsulatum, is severely limiting to the specificity of the assays [38]. For example, persons with blastomycosis are just as apt to demonstrate complement-fixing antibodies to histoplasmin as to blastomycin [10]. None of the patients in one series had titers of complement-fixing antibodies to blastomycin >1:8 dilution [21]. The poor sensitivity of the CF test prompted the development of ID testing, which resulted in sensitivity rates of up to 80% in initial reports. When the sera of patients with localized blastomycosis were tested, the results reported by Klein
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system occur in 5% to 10% of cases of disseminated disease and include meningitis or, more commonly, epidural or cranial abscesses [29]. A computed tomogram should direct the surgeon to the cranial abscesses at biopsy, but meningitis may be more difficult to diagnose. Evaluation of CSF usually is not diagnostic, and culture of ventricular fluid may be required for isolation of the fungus. In one series [30], analysis of CSF obtained by lumbar puncture yielded the diagnosis in only two of 22 cases, whereas cultures of ventricular fluid specimens were positive for fungus in six of seven cases. Along with osteomyelitis, neurological manifestations of blastomycosis present the greatest challenge for successful therapy. Lesions of blastomycosis may occur in virtually any organ. Widely disseminated or miliary blastomycosis may present as adult respiratory distress syndrome (ARDS). One patient described by Evans et al. [31] had an ulcer seen at the canna of trachea on bronchoscopy, thereby prompting the speculation that a subcranial lymph node ruptured into the trachea and enough organisms were spilled into the lungs to cause ARDS. The majority of patients with the pattern of diffuse infiltrates, noncardiac pulmonary edema, and refractory hypoxemia die very quickly; three patients in one series died of ARDS despite intensive medical and antifungal therapy [21]. Abscesses are most common in the subcutaneous tissue but, as already noted, may be found in the brain, skeletal system, prostate, or other areas as lesions in the myocardium, pericardium, orbit, sinuses, pituitary or adrenal glands, or other organs [27]. The reticuloendothelial system has been involved, with reports of several cases of lymph node or hepatic involvement, and a few cases of splenic abscesses have been documented [32]. Surgical drainage of splenic abscesses is required, just as it is for the majority of large abscesses secondary to blastomycosis. Lesions in the mouth and oropharyngeal area occur but are not found with the same frequency as lesions seen in patients with disseminated histoplasmosis. One exception is the larynx. Witorsch and Utz [27] refuted the hypothesis that the larynx might become infected primarily rather than by hematogenous dissemination from a pulmonary focus. Laryngeal biopsy reveals histologic features similar to those in the skin. The hyperplasia, acanthosis, and fungating appearance of the larynx may be confused with squamous cell carcinoma. Fixation of the vocal cords secondary to fibrosis has led, in some cases, to radiation therapy or total laryngectomy because of an incorrect diagnosis of neoplasm rather than blastomycosis. Specific endocrine abnormalities may appear in patients with blastomycosis [27]. Adrenal insufficiency from gland destruction, infection of the thyroid glands, hypercalcemia (as seen with other granulomatous diseases), and abnormal menses secondary to blastomycosis have been reported. A single case of diabetes insipidus [33] and one case of a pa-
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Therapy
The first consideration in regard to treatment of the patient with blastomycosis is whether to use an antifungal agent. The severity of the clinical presentation of the patient and the toxicity of the antifungal agent are the major determinants of whether to observe the infection or to use the agent. Relapse of the initial infection either with or without treatment has been reported; therefore, the patient must be carefully followed for a prolonged period if therapy is not given [19, 20]. Because resolution of the infection without therapy [20] may occur in patients with an epidemic focus of infection or from an area where blastomycosis is endemic, observation of pneumonia for 1 to 2 weeks may be considered. If the patient's condition deteriorates or progresses, antifungal therapy should be started. Occasionally the diagnosis of blas-
tomycosis has not been considered for patients with pneumonia until cultures of respiratory secretions (sputum or bronchoscopy washings or brushings) yield the organism. Observation alone may also be indicated for patients whose conditions have already improved while the culture was incubating. As previously noted, surgical resection of a solitary pulmonary nodule may cure the infection without further therapy [5]. The presence of pleural disease during the course of illness mandates antifungal treatment. Likewise, all other forms of extrapulmonary blastomycosis should also be treated with systemic therapy. Amphotericin B
Before antifungal therapy was available, a case-fatality rate among untreated patients with blastomycosis of 78% was documented [47]. In more recent reports, 21% and 28% of untreated patients died of fungal infections [48, 49]. Following its introduction in 1956, amphotericin B has been shown to be effective in the treatment of blastomycosis. In five large series of patients with this fungal infection, intravenous amphotericin B in a dose of at least 1.0 g resulted in cure without relapse in 16 of 19, 21 of 27, 32 of 35, 13 of 15, and 37 of 41 patients [27, 50-53]. A total cumulative dose of 2 g has been associated with cure rates of up to 97%. The mechanism of action of amphotericin B is the interaction of the agent with components of the surface of the cell, thereby altering the integrity of the fungal cell membrane [54]. Unfortunately, this high degree of antimycotic activity is associated with significant toxic effects. In a group of patients with blastomycosis described by Abernathy [55], almost three-fourths (71%) experienced a decline in renal function; a number of other toxic effects, including anemia (53%), anorexia and nausea (53%), fever (49%), hypokalemia (37%), and thrombophlebitis (19%), were also reported. Interruption of therapy during some point in the course was required in 41% of patients, and termination of therapy with amphotericin B before reaching the desired total dose was mandatory because of toxic effects in 14% of the patients [55]. Similarly, all 21 courses of amphotericin B treatment of patients with blastomycosis reported by Witorsch and Utz [27] were complicated by both azotemia and anemia. Because amphotericin B and dehydration are synergistically nephrotoxic, salt loading has been recommended for protection of renal function [56]. Relapse of blastomycosis following amphotericin B therapy occurs only rarely and appears to be dose dependent [10, 19]. In one large retrospective series, relapse occurred in only two of 30 patients who received >1.5 g of the drug, whereas five of 19 patients who received a smaller dose experienced a relapse [51]. Most of the cases of relapse described by Witorsch and Utz [27] occurred shortly after completion of amphotericin B therapy. However, patients have experienced relapse of disease as long as 9 years following treatment. As
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et al. [39] of enzyme immunoassay (EIA) techniques using a yeast-phase antigen (antigen A) were better than those of ID tests. However, similar results of ID and EIA were obtained when the sera from patients with disseminated disease were tested. In the largest outbreak of blastomycosis reported, Klein et al. [40] described antibody detection by EIA, ID, and CF techniques of 77%, 28%, and 9%, respectively. Although cases in which positive reactions occur have been documented, Lambert and George [41] also detected falsepositive results with a similar EIA technique using specimens from persons in areas in which histoplasmosis and blastomycosis were endemic. Therefore, as noted by Sarosi et al. [42], serodiagnosis of blastomycosis is a problem owing to potential low rates of sensitivity and specificity. Klein and Jones [43] have isolated a surface protein of B. dermatitidis that may be useful in the detection of antibody in patients. Confirmation of sensitivity and specificity will enhance the likelihood that this protein may be used clinically as an antigen in the future. Skin testing with blastomycin is, unfortunately, no better as a diagnostic procedure. This mycelial-phase antigen does not provide sufficient specificity or sensitivity for reliable assessment of patients and is no longer available clinically. It may be useful epidemiologically; in the Eagle River outbreak, 15 of 48 patients tested had a positive skin reaction [4]. Unlike the detection of long-lasting immunity with in vitro lymphocyte reactivity to a yeast-phase antigen in patients with blastomycosis [44], reactions to skin tests with blastomycin rapidly diminish and become negative on repeated testing over time [45]. In summary, none of the screening tests are totally reliable for the diagnosis of blastomycosis. Until antigen testing is available for B. dermatitidis, as has been described for H. capsulatum by Wheat and colleagues [46], the diagnosis of blastomycosis will depend on visualization of the fungus on smear, in tissue, or in culture.
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Blastomycosis
Ketoconazole
Ketoconazole is an imidazole antifungal agent with in vitro activity against B. dermatitidis similar to that of amphotericin B [58]. The drug works by disrupting the cell membranes following interactions with cytochrome P-450 enzymes; this leads to reduced concentrations of ergosterol, the major sterol of the membrane of the fungus [55, 58]. Ketoconazole is absorbed from the gastrointestinal tract and has been generally well tolerated in clinical studies of patients with other fungal infections. The drug has been used to treat blastomycosis in canines [59, 60], and moderate effectiveness has been shown in a murine model of B. dermatitidis infection [61]. The major advantages of the drug are that it is absorbed from the gastrointestinal tract and is generally well tolerated. Adverse effects of ketoconazole include those that are severe and those that are less of a problem. One severe toxic effect is hepatocellular damage, which appears to be a very rare occurrence [62]; therefore, liver transaminase levels should be monitored during ketoconazole therapy. At higher dosages of the drug, hormonal abnormalities, such as gynecomastia, dysfunctional uterine bleeding, and oligospermia, have been described [21, 58, 63]. More common, but less severe, adverse effects include nausea and vomiting (increased incidence when the drug is taken without a meal) as well as dizziness, pruritus, and headache [21]. The absorption of ketoconazole requires an acidic gastric content; therefore, antacids or H2 blocking agents, such as cimetidine or ranitidine, are contraindicated while the patient is taking ketoconazole. Other agents, such as rifampin, oral contraceptives, cyclosporine, phenobarbital, and phenytoin, may interfere with ketoconazole therapy [55]. With a lower potential of toxicity than amphotericin B, ketoconazole has been viewed with considerable enthusiasm for the treatment of blastomycosis. The results of the initial trial of ketoconazole for blastomycosis performed by the National Institutes of Health (NIH) Mycoses Study Group [64] were not very optimistic. Of 16 patients with blastomycosis,
seven were cured, four were considered to have treatment failures, and five experienced relapse of infection. However, the adequacy of the dose of ketoconazole and the duration of therapy were questioned. Ten of the 25 patients who experienced relapses of various fungal infections received a maximal dose of 200 mg of ketoconazole per day. Some patients received the drug for only 1 month before failure of treatment was declared. After that report, scattered case reports of patients with blastomycosis who were treated with ketoconazole [65-70], two prospective trials of ketoconazole [21, 71], and one retrospective review of ketoconazole treatment of blastomycosis [72] were reported. The results of these reports on the therapeutic usefulness of ketoconazole (400-800 mg/d for at least 6 months) were more promising than those of the initial reports. The results of a second trial of ketoconazole for blastomycosis performed by the NIH Mycoses Study Group [71] were much more successful than those of the initial report. Of the 80 patients enrolled in the study, 89% were cured, as long as treatment with 400 or 800 mg of ketoconazole per day was given for at least 6 months. Relapse occurred 2, 7, 18, and 24 months following therapy. In another trial [21], 35 of 44 patients treated with ketoconazole (400 mg given as a single daily dose with breakfast) were cured without experiencing a relapse. Six patients experienced relapses following therapy, but three of these six were protocol inadherent and received
