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Pulmonology > Infectious Lung Diseases
Blastomycosis
Article Last Updated: Jul 27, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Basil Varkey, MD, FCCP, Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care, Froedtert Memorial Lutheran Hospital, Medical College of Wisconsin
Basil Varkey is a member of the following medical societies: American Association of Physicians of Indian Origin, American College of Chest Physicians, American Federation for Clinical Research, American Thoracic Society, and Royal College of Physicians
Coauthor(s):
Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle
Editors: Michael Peterson, MD, Chief of Medicine, Vice-Chair of Medicine, University of California at San Francisco; Endowed Professor of Medicine, University of California at San Francisco-Fresno; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Robert S Crausman, MD, MMS, Chief Administrative Officer, Rhode Island Board of Medical Licensure and Discipline, Rhode Island Department of Health; Associate Professor, Department of Medicine, Brown University School of Medicine; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA
Author and Editor Disclosure
Synonyms and related keywords:
blastomycosis, Gilchrist disease, Gilchrist's disease, fungal infection, fungus infection, Blastomyces dermatitidis, B dermatitidis, pulmonary infection, adult respiratory syndrome, ARDS, antifungal treatment
Background
In 1894, Gilchrist first described blastomycosis in the United States. Blastomycosis is a granulomatous fungal infection caused by Blastomyces dermatitidis. Serological studies that use enzyme-linked immunoassay indicate that different genotypes of B dermatitidis exist.
Blastomycosis is a common infection among dogs in endemic areas. It may serve as an indicator of human disease because of the shared environment. Blastomycosis is reported in other animals, including the horse, cow, cat, bat, and lion.
Pathophysiology
Infection occurs by inhalation of aerosolized conidial forms of the fungus from its natural soil habitat. Once inhaled in the lungs, the conidia transform at body temperature to the yeast phase (thermal dimorphism). This transformation provides a survival advantage to the infecting fungus as the thick cell wall of the yeasts provides resistance to phagocytosis and induces expression of an immune-modulating virulence factor (BAD-1) on the cell surface. Then, the yeast forms multiply and may disseminate through the blood and lymphatics to other organs. The evoked pyogranulomatous inflammatory response has an initial influx of neutrophils, followed by macrophage and granuloma formation.
Pulmonary infection may be asymptomatic in nearly 50% of patients. In others, the median incubation period, from inhalation of the fungus to manifestations of symptoms, is 45 days (range 21-106 d). Pulmonary symptoms of varying severity are common, and they most often occur without any symptoms of dissemination to other organs. Extrapulmonary dissemination more often occurs in patients with chronic pulmonary illness and in those who are immunocompromised.
The skin is the most common site of extrapulmonary blastomycosis and is involved in about 20-40% of the cases. Other areas affected, in order of frequency, are the bones (10-25%), prostate and other genitourinary organs (5-15%), and the meninges and brain (~5%). In rare instances, any organ can be affected, including the breast, eye, larynx, trachea, and ear. Reactivation of blastomycosis may occur after a pulmonary infection that resolved with, or without, treatment. An extrapulmonary site only rarely is a site of reactivation (eg, skin, bone, brain).
Frequency
United States
Most cases of blastomycosis occur in the United States. It is endemic in the central and southeastern parts of the country (eg, near the Mississippi River, Ohio River, Great Lakes). True incidence and prevalence are unknown, because there are no reliable markers. Based on confirmed cases, the annual incidence is less than 1 case per 100,000 people in Mississippi, Kentucky, Arkansas, and Wisconsin. Within the endemic areas (eg, Vilas County, Wisconsin), infection by hyperendemic foci is reported at an annual incidence rate of 40 per 100,000.
International
Blastomycosis is distributed throughout the world. Most reported cases outside of the United States are from Canada (Ontario, Manitoba) and the African continent.
Mortality/Morbidity
Retrospective reports in the 1960s indicate a mortality rate of 42% in untreated blastomycosis and 5% in treated cases. Reports in the 1990s indicate a mortality rate of 0-2% in treated cases among immunocompetent patients. In contrast, the mortality rate in immunocompromised patients is 29% and in the subgroup of patients with AIDS is 40%. The reported mortality rate of patients presenting as adult respiratory syndrome (ARDS) is 68%. Complications generally do not occur in immunocompetent patients, and patients can expect a full recovery.
Race
No known racial predilection exists.
Sex
Blastomycosis was thought to occur more often in males than females; however, analysis of outbreak cases from a common source and recent reports do not indicate a significant sex difference. A recent report from Wisconsin revealed that 55 of the 120 cases of blastomycosis were in women (nearly 1:1 male-to-female ratio).
Age
The mean age at diagnosis is approximately 45 years. Most patients are aged 30-69 years; however, persons of any age can acquire the disease. Blastomycosis also occurs in infants and the very elderly.
History
- Most symptoms conform to one of the following specific patterns:
- A flulike illness with fever, chills, myalgia, headache, and a nonproductive cough may occur, which resolves within days. Because of the brief and self-limited nature of these symptoms, blastomycosis may go undiagnosed except in the setting of a known outbreak.
- The patient may present with an acute illness resembling bacterial pneumonia, with symptoms of high fever, chills, a productive cough, and pleuritic chest pain. Sputum is mucopurulent or purulent.
- Chronic illness may occur and simulate tuberculosis or lung cancer, with symptoms of low-grade fever, a productive cough, night sweats, and weight loss. Sputum is mucopurulent or purulent, and hemoptysis may be present.
- The patient may present with a fast, progressive, and severe disease that manifests as ARDS, with fever, shortness of breath, tachypnea, hypoxemia, and diffuse pulmonary infiltrates.
- Skin lesions, although usually asymptomatic, may be the presenting complaint.
- Bone lytic lesions cause bone or joint pain.
- Prostatitis may be asymptomatic or may cause pain on urinating.
- Laryngeal involvement causes hoarseness.
Physical
The physical examination may not reveal any abnormal findings. In the pneumonic form, findings may be present that are associated with pneumonic consolidation (eg, dullness on percussion, bronchial breath sounds, egophony, rales). Decreased or absent breath sounds suggest pleural effusion. Occasionally, erythema nodosum may be observed in association with pulmonary blastomycosis.
- Skin lesions are more common on the face, neck, and extremities. Early in the disease course, the lesions are sharply demarcated papules. Later, they expand to form ulcerated lesions with small pustules at the margins. Central healing and scar formation occur as the lesions grow larger. Some are verrucous, with raised irregular borders; multiple lesions may appear simultaneously or in sequence.
- Lesions begin as papules or pustules or as subcutaneous nodules. Within a few weeks to months, the primary lesions evolve into ulcers, with indurated dusky or violaceous granulomatous or verrucous borders, or into vegetating plaques. Typically, the border is arciform or serpiginous, contains numerous tiny pustules or microabscesses covered with crust, and rises abruptly from the normal surrounding skin. Over a period of months to years, the lesions enlarge, eventually involving a substantial portion of the face, for example, and produce severe disfigurement. As the lesions enlarge, they heal centrally, with atrophic scar studded with telangiectasia.
- Although the vast majority of patients with cutaneous blastomycosis acquire it by dissemination from a pulmonary focus, a few well-documented cases of primary cutaneous (inoculation) blastomycosis have been described in laboratory workers. The skin lesions are described as "chancriform" and are accompanied by nodular lymphangitis.
- Bone involvement rarely leads to a draining abscess. The involved joint may be tender and swollen.
Actinomycosis
Aspergillosis
Brain Abscess
Cryptococcosis
Histoplasmosis
Lung Cancer, Non-Small Cell
Lung Cancer, Oat Cell (Small Cell)
Metastatic Cancer, Unknown Primary Site
Mycobacterium Avium-Intracellulare
Mycobacterium Kansasii
Pneumonia, Bacterial
Pneumonia, Viral
Sporotrichosis
Tuberculosis
Other Problems to be Considered
Skin
Squamous cell carcinoma
Pyoderma gangrenosum
Keratoacanthoma
Tuberculosis verrucosa cutis
Halogenoderma
Lupus vulgaris
Blastomycosislike pyoderma
Chromoblastomycosis
Bone and joints
Metastatic carcinoma
Bacterial osteomyelitis
Brain
Brain neoplasm
Lab Studies
- A leucocyte and differential count may show leucocytosis with a left shift, particularly in cases with a pneumonic presentation; however, the test has low sensitivity and specificity.
- Pulse oximetry is appropriate in detecting hypoxemia in cases that present as pneumonia.
- Arterial blood gases are indicated in the presence of tachypnea, pulmonary infiltrates, and hypoxemia by pulse oximetry.
- Sputum microscopy is a simple and inexpensive test that has a high diagnostic yield of more than 75% in patients with a pneumonic presentation. Place a small sample of freshly expectorated sputum on a slide and digest it with drops of potassium hydroxide. Cover it with a cover slip and examine it under a microscope. Yeasts, 8-20 micrometers in size, with single, broad-based buds, double refractile walls, and multiple nuclei are extremely characteristic of B dermatitidis. This permits the physician to begin treatment without delay.
- Microscopy of other fluids (eg, pus from skin lesions, draining fistulas, aspirate from an abscess) can be examined in a manner similar to that described for sputum to detect the fungus.
- Microscopic examination of a potassium hydroxide wet mount of pus aspirated or expressed from skin microabscesses, fistulae, or subcutaneous abscesses will reveal characteristic broad-based budding yeast. B dermatitidis also is stained by calcofluor; use of this reagent may improve the sensitivity of microscopic examination of pus.
- Sputum culture: Isolation and identification of the organism in an appropriate laboratory culture medium provides absolute confirmation of the diagnosis; however, it may be time-consuming since culture observation may occur as early as 5 days or as late as 30 days.
- Exoantigen testing and a DNA probe reduce the time for making the final identification from a culture.
Imaging Studies
- Chest radiograph
- Findings vary and lack diagnostic specificity. Alveolar infiltrates (eg, consolidation), masslike densities, and nodules are common patterns in order of frequency.
- Cavitation may be present, and there is no predilection for any lobe.
- Pleural effusion is uncommon, but pleural thickening adjacent to an infiltrate may be observed.
- Hilar or mediastinal lymph node enlargement rarely occurs.
- Chest CT scan
- This test is not needed in all cases.
- The test better defines the character and distribution of the abnormalities observed in a roentgenogram and is helpful in identifying mediastinal abnormalities and loculated pleural effusions.
- A head CT scan is useful in the detection of brain abscesses.
Other Tests
- Skin test is not reliable for diagnosis and is not commercially available.
- Serologic tests
- Complement fixation and immunodiffusion tests lack sensitivity and cannot be used to exclude the diagnosis.
- An enzyme immunoassay (EIA) for antibodies to the A antigen of B dermatitidis is a more sensitive test, and titers of greater than 1:32 strongly support the diagnosis.
- Newer tests that use more specific cell wall antigens, radioimmunoassays (RIAs), and Western blot techniques have improved sensitivity and specificity but are not yet available for widespread clinical use.
Procedures
- Bronchoscopy (with washings, brushings, and a biopsy) is indicated in the following situations:
- Absence of sputum
- Nondiagnostic sputum microscopic examination
- Undiagnosed pulmonary mass density, atelectasis, or consolidation
- Hemoptysis
- Percutaneous needle or surgical biopsy of affected organ, such as skin lesions, subcutaneous nodule, bone, or laryngeal lesion
- Prostatic massage: In cases of blastomycosis of the genitourinary tract, the urine collected after a massage is likely to have a higher diagnostic yield.
- Lumbar puncture: Diagnostic yield of examination of cerebrospinal fluid is low in CNS blastomycosis; however, ventricular fluid specimens have a higher yield.
Histologic Findings
The yeast forms are best visualized with a periodic acid-Schiff (PAS) stain, and they are not easily observed with a hematoxylin and eosin (H&E) stain. The methenamine silver and Papanicolaou are other reliable stains. Demonstration of the yeasts is particularly important in blastomycosis that involves sites with squamous epithelium (eg, skin, larynx, trachea) since the hyperplastic response observed in the tissue may simulate squamous cell carcinoma.
Skin lesions of disseminated blastomycosis are characterized by pseudoepitheliomatous hyperplasia of the epidermis, intraepidermal microabscesses, and a suppurating granulomatous reaction in the dermis.
The hyperplastic epidermis lacks the cytological atypia of squamous cell carcinoma. Intraepidermal abscesses contain abundant neutrophils and organisms; organisms are best visualized with the diastase-digested periodic acid-Schiff staining procedure or with the methenamine silver stain. Yeasts are present extracellularly in the dermis or intracellularly in multinucleated giant cells. Intracellular yeasts are easily identified on routine hematoxylin and eosin-stained sections of skin as punched-out "holes" in cytoplasm of the giant cells. The inflammatory infiltrate is polymorphous, containing lymphocytes, histiocytes, and neutrophils. Tuberculoid granuloma formation is unusual, but if it occurs, it is not accompanied by caseation.
Medical Care
Patients with a subclinical disease (presence of serologic or other markers without symptoms) can be observed but not given antifungal treatment. Some experts advise that patients with resolving symptoms of mild disease limited to the lung also may be managed without antifungal treatment. However, many other experts, including these authors, disagree with this approach.
Patients with cutaneous dissemination must be treated. Spontaneous resolution does not occur, and irreversible scarring results.
Consultations
Since blastomycosis is rarely encountered, it is advisable for primary care physicians to seek consultation from a physician more experienced with this disease. In cases with extrapulmonary involvement, consult a specialist (pulmonologist or infectious disease) for diagnosis and treatment recommendations.
- Consult a pulmonologist or an intensivist for blastomycosis that presents with or develops ARDS.
- Surgical consultation may be needed for a tissue biopsy, but only rarely for adjunctive surgical treatment (eg, evacuation of a joint abscess, pleural empyema). Alert the microbiologist to the possibility of blastomycosis before sending any specimen to the laboratory.
- Consultation with a dermatologist may facilitate making the diagnosis by recognition of typical skin lesions, aspiration or expression of microbiologically diagnostic pus, or skin biopsy.
Choice of medication used to treat blastomycosis should be based on type, extent, and severity of disease; the immune status of the patient; and the toxicity of the drug.
Newer drugs, such as voriconazole, posoconazole, and caspofungin, have not yet undergone extensive human studies. Amphotericin B and itraconazole continue to be the main drugs of choice.
Patients with life-threatening disease, pulmonary (eg, ARDS) or extrapulmonary, should be treated with amphotericin at a high dose of 0.7-1 mg/kg/d to a total dose of 1.5-2 g. However, amphotericin is associated with several toxic effects, most notably renal impairment. Other effects include thrombophlebitis at the injection site, chills, fever, nausea, hypokalemia, and anemia. Liposomal formulations are more expensive but cause less renal impairment.
It is reasonable to consider initial treatment with amphotericin B to a minimum cumulative dose of 500 mg followed by itraconazole 200-400 mg for 6 months. This approach, however, has not yet been validated in large clinical studies.
Itraconazole is the drug of choice in mild-to-moderate pulmonary blastomycosis. The appropriate dose is 200-400 mg/d for 6 months. Itraconazole provides the ease of oral administration, low toxicity, and high efficacy. Other azoles (eg, ketoconazole, fluconazole) at 400-800 mg/d for 6 months may also be considered. If disease progresses while on any azole, change to amphotericin B.
In disseminated (extrapulmonary) disease, treatment decision hinges on CNS involvement. Patients with CNS blastomycosis should be treated with amphotericin B (dose schedule as in life-threatening disease). Azoles are not appropriate drugs for CNS disease with the exception of fluconazole. Fluconazole has good cerebrospinal fluid penetration and the dose recommended is a minimum of 800 mg/d.
Patients with mild-to-moderate disseminated blastomycosis without CNS involvement should be treated with itraconazole 200-400 mg/d for 6 months. Treatment period should be extended to 12 months in patients with bone involvement (osteomyelitis).
Immunocompromised patients should be treated early and aggressively with amphotericin B as in life-threatening disease. After the amphotericin B course, chronic suppressive therapy with itraconazole may be needed in some cases.
Drug Category: Antifungal agents
Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.
| Drug Name | Amphotericin B (AmBisome) |
|---|
| Description | Alters fungal cell membrane permeability by binding with ergosterol, resulting in cell component leakage and death.
Administered IV and must be mixed with dextrose in water. |
|---|
| Adult Dose | 1 mg IV over 2 h, titrate up by 10 mg/d to 40-50 mg/d (0.4-0.6 mg/kg) infused IV over 4-6 h
If clinically stable, dose can be administered qod
Total cumulative dose: 2 g; <1.5 g increases risk of relapse
Critically ill: 0.6 mg/kg IV on first d, may increase dose |
|---|
| Pediatric Dose | 0.25-1.5 mg/kg/d IV qd over 2-6 h; 1-1.5 mg/kg IV qod; total cumulative dose 30 mg/kg |
|---|
| Contraindications | Documented hypersensitivity |
|---|
| Interactions | Antineoplastic agents may enhance potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine |
|---|
| Pregnancy | B - Usually safe but benefits must outweigh the risks.
|
|---|
| Precautions | Infusing saline 500 mL IV before and after administration reduces nephrotoxicity; aspirin/diphenhydramine prior to drug infusion decreases chills and fever; using central vein or changing peripheral IV site reduces occurrence of phlebitis; monitor serum K+ level; discontinue for 2 d if serum creatinine of 3 mg/dL or less; not all pregnant women and newborns suffer complications |
|---|
| Drug Name | Itraconazole (Sporanox) |
|---|
| Description | Synthetic thiazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450-dependent synthesis of ergosterol, a vital component of fungal cell membranes. |
|---|
| Adult Dose | 200 mg PO qd for 6 mo; not to exceed 400 mg/d |
|---|
| Pediatric Dose | Not established; adjust dosage to child's weight |
|---|
| Contraindications | Documented hypersensitivity; concurrent use of simvastatin, lovastatin, midazolam, triazolam |
|---|
| Interactions | Antacids may reduce absorption of itraconazole; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (phenytoin metabolism may be altered) |
|---|
| Pregnancy | C - Safety for use during pregnancy has not been established.
|
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| Precautions | Not indicated for CNS blastomycosis; compliance in completing course of therapy necessary; caution in hepatic insufficiencies |
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Further Inpatient Care
- The need for inpatient and ICU care is based on the acuity and pace of the disease progression as well as the immune status of the patient.
- Admit severely and progressively ill patients to the ICU, including those with ARDS.
- Inpatient care often is needed for workup and treatment of blastomycosis presenting as an undiagnosed pneumonia, for pleural effusion, and for extrapulmonary involvement.
- Perform initial treatment of amphotericin B in an inpatient setting, preferably.
Further Outpatient Care
- Complete treatment in an outpatient setting.
- Consider giving amphotericin B through an indwelling central venous line in an observation room with a trained staff.
Medical/Legal Pitfalls
- Failure to diagnose and failure to diagnose in a timely manner are 2 major areas with medicolegal implications. Blastomycosis is a disease that can be mistaken for more common diseases listed in the Differential Diagnosis section.
- Consider this diagnosis in any patient with pneumonia that is not resolving. Blastomycosis may present as a community-acquired pneumonia.
- In endemic areas, consider blastomycosis as a cause of ARDS.
- Be cognizant of the extrapulmonary manifestations in general and the propensity of blastomycosis to mimic carcinoma.
- Abuodeh RO, Chester EM, Scalarone GM. Comparative serological evaluation of 10 Blastomyces dermatitidis yeast phase lysate antigens from different sources. Mycoses. Apr 2004;47(3-4):143-9.
- Chapman SW, Bradsher RW, Campbell GD, et al. Practice guidelines for the management of patients with blastomycosis. Infectious Diseases Society of America. Clin Infect Dis. Apr 2000;30(4):679-83. [Medline].
- Davies SF, Sarosi GA. Epidemiological and clinical features of pulmonary blastomycosis. Semin Respir Infect. Sep 1997;12(3):206-18. [Medline].
- Klein BS, Vergeront JM, Weeks RJ, et al. Isolation of Blastomyces dermatitidis in soil associated with a large outbreak of blastomycosis in Wisconsin. N Engl J Med. Feb 27 1986;314(9):529-34. [Medline].
- Meyer KC, McManus EJ, Maki DG. Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome. N Engl J Med. Oct 21 1993;329(17):1231-6. [Medline].
- Rooney PJ, Sullivan TD, Klein BS. Selective expression of the virulence factor BAD1 upon morphogenesis to the pathogenic yeast form of Blastomyces dermatitidis: evidence for transcriptional regulation by a conserved mechanism. Mol Microbiol. Feb 2001;39(4):875-89.
- Varkey B. Blastomycosis in children. Semin Respir Infect. Sep 1997;12(3):235-42. [Medline].
Blastomycosis excerpt Article Last Updated: Jul 27, 2006
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