Pulmonary Blastomycosis Research Articles

Efficacy of voriconazole in treatment of murine pulmonary blastomycosis.

We evaluated the efficacy of voriconazole, a new broad-spectrum triazole antifungal compound, in the treatment of murine pulmonary blastomycosis. Since mice metabolize voriconazole rapidly, we took advantage of our previous observation that administration of grapefruit juice to mice resulted in suitable serum voriconazole concentrations so that treatment studies with mice could be done (A. M. Sugar and X.-P. Liu, Med. Mycol. 38:209-121, 2000). Our results show that voriconazole prolonged survival in a dose-dependent fashion and that the fungal burden in the lungs was decreased by voriconazole administered at 40 mg/kg of body weight/day. Voriconazole should be studied in humans with blastomycosis.

Investigation of anti-WI-1 adhesin antibody-mediated protection in experimental pulmonary blastomycosis.

Infection with Blastomyces dermatitidis elicits strong antibody responses to the surface adhesin WI-1. The antibodies are directed chiefly against the adhesive domain, a 25-amino-acid repeat. Tandem-repeat-specific monoclonal antibodies (mAbs) were studied for their opsonic activity in vitro and their capacity to adoptively transfer protection in murine experimental blastomycosis. mAbs to WI-1 enhanced binding and entry of B. dermatitidis yeasts into J774. 16 cells but did not enhance killing or growth inhibition of the yeast. Passive transfer of 8 mAbs to WI-1 into 3 different inbred strains of mice also did not improve the course of experimental infection and sometimes worsened it. mu-deficient mice were more resistant to experimental blastomycosis than were intact littermates, and passive transfer of the mAbs into these mice did not protect them against experimental infection. Thus, antibody to WI-1 does not appear to improve the outcome of murine blastomycosis and may enhance the infection.

Blastomycosis granuloma involving the cranial vena cava associated with chylothorax and cranial vena caval syndrome in a dog

A four-year-old, sexually intact, male dachshund was diagnosed with pulmonary blastomycosis. Itraconazole was administered for 60 days, and the dog was considered to be disease-free at three- and 12-month reevaluations. Two years following discontinuation of itraconazole, the dog developed a granuloma of the cranial vena cava resulting in chylothorax and cranial vena caval obstruction. To the authors' knowledge, this is the first case of a blastomycotic granuloma involving the vena cava reported in the dog. Blastomycosis should be considered as a differential diagnosis for both chylothorax and cranial vena caval syndrome in the dog.

Pulmonary function following blastomycosis in childhood.

In order to determine the pulmonary outcome following blastomycosis during childhood, we compiled a case series of hospitalized patients from a retrospective review with later recall for pulmonary function testing, coupled with prospective measurements of pulmonary function in three patients, at a tertiary care children's hospital. A convenience sample of five of 17 patients hospitalized with pulmonary blastomycosis, whose mean age at the time of diagnosis was 10.6 +/- 5.5 years, was recalled at a mean of 4.5 +/- 3.5 years after diagnosis. Three patients more recently hospitalized underwent serial pulmonary function testing (PFT) prospectively from as soon after the acute infection as their condition permitted. All but two patients had normal PFT when last seen. The two patients with persistent pulmonary sequelae were among those followed up prospectively and had more severe clinical and radiographic pictures at the outset. Pulmonary function in children who suffered from pulmonary blastomycosis is normal in most patients at follow-up years later. Severe radiographic disease and slow recovery over months portend long-term sequelae.

55-Year-Old Man With a Lung Lesion and Hemidysesthesia

55-Year-Old Man With a Lung Lesion and Hemidysesthesia

55-Year-Old Man With a Lung Lesion and Hemidysesthesia

55-Year-Old Man With a Lung Lesion and Hemidysesthesia

Clinical presentation, radiographic findings, and diagnostic methods of pulmonary blastomycosis: a review of 100 consecutive cases.

We sought to determine the relationship among radiographic findings, clinical presentation, and diagnostic testing of pulmonary blastomycosis. We reviewed the medical records of 100 consecutive patients with pulmonary blastomycosis. Air-space infiltrates were the usual radiographic finding of pulmonary blastomycosis. Mass-like infiltrates were associated more with chronic than acute presentations. Air-space and mass-like infiltrate were predominately involved in the upper lobes. Sputum analysis made the initial diagnosis of blastomycosis most often. Acute and chronic presentations were not different between immunosuppressed patients and the remainder of the patients. In addition, infiltrates on chest radiographs in immunosuppressed patients were similar to the other patients. In an endemic area, pulmonary blastomycosis should be considered for any pulmonary infiltrate, especially in the upper lobes. Sputum analysis in most cases aids in the diagnosis, but bronchoscopy and/or tissue biopsy should be considered if the suspicion of blastomycosis is high and sputum analysis is inconclusive, negative, or not possible. Follow-up with chest radiographs after antifungal therapy is reasonable until complete resolution or fibrotic changes in patients with pulmonary blastomycosis.

Immunogenicity and protective efficacy of the WI-1 adhesin of Blastomyces dermatitidis.

People infected with Blastomyces dermatitidis develop strong immunity to the yeast surface adhesin WI-1, including antibody responses to the adhesive domain, a 25-amino-acid repeat, and cellular responses to the N terminus. We studied the immunogenicity of WI-1 and the ability of anti-WI-1 immune responses to protect against lethal pulmonary infection in mice. WI-1 immunization, given in Freund's adjuvant subcutaneously in two doses 2 weeks apart, evoked delayed hypersensitivity responses in a concentration-dependent manner. Immunized mice also had anti-WI-1 antibody responses, with titers reaching an endpoint dilution of approximately 1:800,000. Anti-WI-1 immunoglobulin G (IgG) antibody subclasses were IgG1 > IgG2b > IgG2a > IgG3, indicating a mixed T helper 1 and T helper 2 immune response. In protection experiments, WI-1 immunization significantly prolonged the survival of C57BL/6 and BALB/c mice compared to controls following intranasal administration of a lethal dose of B. dermatitidis yeasts (Kaplan-Meier survival curve P values of 0.027 to 0.0002) and also protected a proportion of the animals from death due to progressive pulmonary blastomycosis. Taken together, our results suggest that administration of WI-1 raises antibody and cell-mediated immune responses, which enhance resistance against pulmonary infection with B. dermatitidis. Mechanisms of vaccine-induced resistance require further investigation.

Pulmonary Blastomycosis in a Cardiac Transplant Recipient

Pulmonary Blastomycosis in a Cardiac Transplant Recipient

Blastomycosis in Northeast Tennessee

To study the epidemiologic and clinical features of blastomycosis in northeast Tennessee. Retrospective review of blastomycosis cases in the region from 1980 through 1995. Hospitals located in the Tri-Cities region of northeast Tennessee. Seventy-two patients with confirmed blastomycosis infection. None. During the 1980 to 1995 study period, we documented 72 cases of blastomycosis. The mean age was 52 years (range, 13 to 86 years), most were male (69.4%), and nine were immunocompromised. A possible environmental exposure was noted for 28 patients. Pulmonary involvement represented the most common site of infection (61 cases), but multiorgan involvement was common (17 cases). Most patients with pulmonary blastomycosis (66%) presented with a chronic illness, and radiologic findings usually revealed local consolidation or a mass-like lesion. Nine patients developed ARDS with an associated mortality rate of 89%, compared with a 10% mortality for non-ARDS pulmonary cases. Antifungal treatment regimens varied widely, with amphotericin B often used for sicker patients. An epidemiologic evaluation revealed that the mean yearly incidence rate for blastomycosis quadrupled between 1980 and 1987 (0.31 cases/ 100,000 population) and 1988 to 1995 (1.23 cases/100,000 population) (p=0.00001). Most new blastomycosis cases in the 1988 to 1995 period occurred in three counties in the region where significant new construction projects have been underway. Blastomycosis is endemic in northeast Tennessee and the number of cases is increasing, coinciding with major new construction in the region. Clinicians in the area must be alert to this condition.

Efficacy of nikkomycin Z against experimental pulmonary blastomycosis.

Nikkomycin Z is a chitin synthetase inhibitor. In vitro, nikkomycin Z had good activity against Blastomyces dermatitidis, with an MIC of 0.78 microg/ml and a minimal fungicidal concentration of 3.1 microg/ml. The efficacies of various treatment durations (3, 5, or 10 days) and doses (200, 400, or 1,000 mg/kg of body weight) of nikkomycin Z given twice daily were compared with those of itraconazole at 200 mg/kg given twice daily and amphotericin B at 6.25 mg/kg in a murine model of pulmonary blastomycosis. All treatments prolonged survival compared with untreated controls (P < 0.05 to 0.01); 100% survival was achieved with 5 or 10 days of any nikkomycin Z dose or with amphotericin B. Amphotericin B and nikkomycin Z, but not itraconazole, reduced infection compared with controls. Amphotericin B and the 10-day regimens of all nikkomycin Z doses were equivalent and superior to itraconazole or nikkomycin Z for < or = 5 days at any dose (P < 0.05 to 0.01). Increased duration and/or dosage improved the efficacy of nikkomycin Z, with 10 days of each dose curing 50 to 90% of the animals. Only a 1,000-mg/kg/day dose of nikkomycin Z was curative when treatment lasted less than 10 days. In contrast, itraconazole cured no mice, while amphotericin B cured all mice. Based on the total amount of drug given, amphotericin B was estimated to be 32 times as active as nikkomycin Z and nikkomycin Z was estimated to be 3 times as active as itraconazole. Overall, nikkomycin Z given orally was well tolerated, had good activity against blastomycosis, and could result in biological cure, thus producing results equivalent to those of parenteral amphotericin B.

Identification ofBlastomyces dermatitidisin the stool of a dog with acute pulmonary blastomycosis

We report the identification of Blastomyces dermatitidis by microscopic examination of a direct faecal smear from a dog with pulmonary blastomycosis. A simultaneously obtained faecal culture grew Blastomyces dermatitidis. The fungus was also cultured from a transtracheal sample from this same dog. This report suggests that yeast-phase cells of B. dermatitidis may be recovered in the stool of dogs with pulmonary blastomycosis following transit through the gastrointestinal tract of swallowed infected sputum. Implications regarding the ecology of Blastomyces dermatitidis are discussed.

Blastomycosis-induced respiratory failure: The successful application of continuous positive airway pressure

A patient diagnosed with pulmonary blastomycosis was seen initially by her primary care physician for severe pain in her right elbow and was treated with steroid therapy and analgesics. She also had been treated for chronic cough and congestion for approximately 2 months before admission. She showed no improvement at home. She was hospitalized for right epicondylitis, and progressively worsening restrictive pulmonary symptoms developed, including hypoxemia and dyspnea. She was transferred to the intensive care unit and treated with mask continuous positive airway pressure (CPAP) and intravenous amphotericin B. Despite worsening hypoxemia, successful management of oxygenation was achieved with CPAP, averting the need for intubation and mechanical ventilation. This case demonstrates the usefulness of CPAP in infectious disorders that create restrictive lung impairment.

Pulmonary blastomycosis in children: findings on chest radiographs.

The purpose of this study was to identify characteristic radiographic findings in children with pulmonary blastomycosis. We reviewed the charts and radiographs of 18 children with culture-proven acute pulmonary blastomycosis. The 10 boys and eight girls were from 1 to 16 years old. Sixteen were Native Canadian Indians, and two were white. All available chest radiographs, including those obtained in follow-up after treatment was terminated, were reviewed by a pediatric radiologist. Consolidation was classified by location and extent, and other abnormalities were noted. Initial chest radiographs showed consolidation in 16 patients. Seven patients had single lobe involvement, most commonly of the left lower lobe. Nine patients had multiple lobe involvement. The left lower lobe was most commonly involved in these cases, but the middle lobe was most severely affected. The upper lobes were involved only in children with multiple lobe disease and were only mildly affected. Cavitation developed in two patients, followed by bronchogenic spread of the disease. Pleural effusions were seen in three patients; two also had rib lesions. Hilar adenopathy developed in two children. Five patients had radiographs available, which had been obtained more than a year after onset, and three of these were abnormal. The most common radiologic finding in children with pulmonary blastomycosis is pulmonary consolidation in one or several lobes, which may undergo cavitation. Lymphadenopathy and pleural effusions are uncommon. Chronic abnormalities may develop.

Treatment of murine pulmonary blastomycosis with SCH 51048, a broad-spectrum triazole antifungal agent.

The in vitro and in vivo activities of a new broad-spectrum triazole derivative, SCH 51048, against Blastomyces dermatitidis were evaluated. As determined by using the new National Committee for Clinical Laboratory Standards proposed standard for susceptibility testing of yeasts, SCH 51048 was the most active of the four agents tested in vitro against 13 strains of B. dermatitidis. In a well-described murine model of acute pulmonary blastomycosis, SCH 51048 was comparable to amphotericin B and at least 30 times more active than itraconazole. On the basis of these experiments, clinical evaluation of SCH 51048 for the use in treatment of human blastomycosis should proceed.

Delayed Treatment of Pulmonary Blastomycosis Causing Vertebral Osteomyelitis, Paraspinal Abscess, and Spinal Cord Compression

A 36-year-old woman with gallbladder disease had an incidental finding of asymptomatic cavitary lung infection with Blastomyces dermatitidis. No treatment was given initially, and 2 months later she presented with vertebral osteomyelitis, paraspinal abscess, and spinal cord compression due to dissemination of the fungus. The patient recovered following surgical debridement and treatment with 1 g of amphotericin B, followed by itraconazole 400 mg QD for 6 months. In spite of previous reports of the self limiting nature of primary pulmonary blastomycosis in the normal host, antifungal therapy may be needed in cases that do not resolve spontaneously within a short period of time, or if transient immunosuppression may be anticipated as may occur following surgery or after acquisition of other infections.

IL-4, IgE, and Interferon-γ Production in Pulmonary Blastomycosis: Comparison in Mice Untreated, Immunized, or Treated with an Antifungal (SCH 39304)

The purpose of this study was to determine if there is a correlation between production of certain lymphokines in progressive blastomycosis in untreated mice, resistance to infection in immunized mice, and cure in antifungal triazole (SCH 39304)-treated mice. Infection was measured by colony-forming units of Blastomyces dermatitidis in lungs. Serum level of IgE was used as a marker for in vivo IL-4 activity. Serum IgE levels rose in untreated mice from 6 μg/ml at 3 weeks to 24 μg/ml by the fourth week as their infection progressed. This corresponded to a peak in vitro production of IL-4 (147 pg/ml) by antigen-stimulated spleen cells at Week 4. By contrast, there was an inverse relationship between serum IgE- and antigen-stimulated production of IFN-γ in vitro, e,g., 80 U/ml at the third week and 4 U/ml at Week 4. In mice undergoing cure with SCH 39304, serum IgE decreased from 12 μg/ml at the third week to 2 μg/ml at Week 4. This correlated with a drop in IL-4 and an increase in IFN-γ production in in vitro assays. As cure proceeded over the next 4 weeks, IgE and IFN-γ measurements were near background levels. In immunized mice a low-grade chronic blastomycosis emerged after 3 weeks of infection. Chronic infection was associated with inverse cycles of elevated IgE in serum and IFN-γ production as assayed in vitro. IL-4 production cycled directly with increased IgE levels in serum. Although spleen cells from untreated mice produced IFN-γ and IL-4 when stimulated with antigen, they did not mount significant proliferative responses. By contrast, spleen cells and lymph node cells from immunized and SCH 39304-treated mice made good proliferative responses to antigen and this correlated with resistance and clearing of the infection, respectively. These data indicate that in pulmonary blastomycosis, serum IgE levels correlate directly with IL-4 and inversely with IFN-γ production. Clearing of the infection by the antifungal agent SCH 39304 reduces lymphokine production to background levels but sensitizes lymphocytes for proliferative responses to antigen.

Reactivation and dissemination of blastomycosis complicating hodgkin's disease: A case report and review of the literature

Patients presenting with Hodgkin's disease (HD) may show lung involvement characterized by contiguous spread from ipsilateral hilar lymph nodes. Lung consolidation or noncontiguous pulmonary involvement makes an alternative diagnosis more likely. This report describes a patient with HD in whom concurrent pulmonary blastomycosis was recognized only after chemotherapy had started and dissemination had occurred. Although Blastomyces dermatitidis may behave as an opportunist pathogen, there are no previous reports of blastomycosis in patients with HD. Undiagnosed active opportunistic infection at the time of diagnosis of HD may complicate staging as well as treatment. Biopsy of lung lesions with stain and culture for opportunistic pathogens should be considered in patients with newly diagnosed HD disease and atypical patterns of lung involvement.

Activities of the triazole D0870 in vitro and against murine blastomycosis

The novel triazole D0870 was tested for in vitro activity, as well as in vivo in a murine model of pulmonary blastomycosis. In vitro, D0870 had inhibitory and fungicidal activity against Blastomyces dermatitidis (MIC = 0.048 microgram/ml; minimal fungicidal concentration = 0.097 microgram/ml). In vivo, D0870 was approximately 100-fold more active than fluconazole on the basis of milligrams per kilogram of body weight given once daily (QD) against blastomycosis. D0870 doses of both 1 or 10 mg/kg given QD and 10 or 100 mg/kg given every other day prolonged survival (P < 0.001) over fluconazole (100 mg/kg given QD). A D0870 dosage of 1 mg/kg QD was equivalent to fluconazole given at 100 mg/kg in reduction of lung burdens of B. dermatitidis, and D0870 administered at 10 mg/kg QD and 10 or 100 mg/kg every other day caused greater reduction (P < 0.001). However, D0870 at 100 mg/kg given QD was lethally toxic, whereas fluconazole at 100 mg/kg was not. These results indicate that D0870 is an effective therapy for murine blastomycosis and should be further tested.

Pulmonary blastomycosis.

Pulmonary blastomycosis has a number of chest radiographic manifestations that may closely resemble those of tuberculosis, histoplasmosis, and other fungal diseases. Radiographic presentations of disease include airspace consolidation, nodular opacities, air bronchograms, masslike lesions, and military disease. Because the geographic distribution of blastomycosis overlaps that of histoplasmosis, distinguishing one from the other on the basis of the radiographic features may be difficult. In blastomycosis, the paucity of calcifications, lymphadenopathy, and cavitation is striking. The article reviews the clinical and radiologic features of blastomycosis and provides illustrative cases to enhance understanding of this disease.