Blastomycosis – MD Nexus

Epidemiology

First case reported in 1894 in Baltimore, MD
Canine Blastomycosis: increase in veterinary-reported cases should trigger monitoring for human cases

Endemic Areas

Central US (starting near North Dakota-Minnesota border), south-central US, and southeastern US (limited to South Carolina, but not into Florida)
- This area overlaps most of the endemic area for Histoplasmosis (however, Histo does not extend as far north)

Outbreaks

(often occur close to recreational waterways)

1972 Big Fork, Minnesota Outbreak (in Blasto endemic area, but not in Histo endemic area): 16/21 had positive Blast skin test (only 5 remained positive 3 years later), but only 1/21 had positive Histo skin test
1984 Eagle River, Wisconsin Outbreak (in Blasto endemic area, but not in Histo endemic area): beaver lodge was source of outbreak

Risk Factors

[[Anti-TNF Therapy]]
- Case reports: 2 cases
  [Ruderman EM, Markenson JA. Granulomatous infections and tumor necrosis factor-antagonist therapies. Abstract (# THU0209) presented at: Proceedings of the Annual European Congress of Rheumatology European League Against Rheumatism; June 18-21, 2003; Lisbon, Portugal]
Residence Near Water in a Highly Endemic Area:
Recent Excavation:
AIDS: Blasto is much less common than Histo or Cocci in these patients (probably due to lesser chance of exposure while immunosuppressed)
T-Cell Deficiency (Transplants/Immunocompromised): Blasto is much less common than Histo or Cocci in these patients (probably due to lesser chance of exposure while immunosuppressed)

Etiology

Blastomyces dermititidis infection
- Blastomyces is a soil-dwelling fungus
- Organism: large organism (8-20 µm) with thick double-refractile cell wall/single-budding with broad base of attachment ( broad-based buds )/multiple nuclei
- 10% KOH exam is easiest technique to identify large 8-20 µm organism
- Other fungal stains (PAS, calcofluor white, silver stain): more sensitive, especially when used in combination
- PAP Stain: also sensitive (In one study, sputum were 78% positive by PAP, compared to 37% positive by KOH + PAS) -Multiple sputum samples increases yield
- Notify lab of suspected Blasto, as organisms can be overlooked if inspection is focused on malignancy

Physiology

Infection: via inhalation of airborne 2-5 µm spores (rare cases have direct skin inoculation)
Incubation Period (data from Eagle River outbreak): 45 days (range 21-106 days)
Temporal Phases of Infection:
- Initial neutrophilic inflammatory response:
- Conversion to parasitic yeast form:
- Macrophage response (neutrophils remain): this response may be variable
  - Giant cells and epithelioid granulomas
  - In some cases, granulomas may be non-caseating (resembling sarcoidosis)
  - In some cases, granulomas are absent (neutrophilic inflammation resembles a bacterial infection)
- Confinement to Lungs/Hilar Nodes or Dissemination (mostly disseminates to skin and bones)
  - Lesser probability of dissemination to the prostate, oropharynx. larynx, liver, adrenals, and meninges

Pathology

Large organism (8-20 µm) with thick double-refractile cell wall/single-budding with broad base of attachment (”broad-based buds”)/multiple nuclei
10% KOH exam: easiest technique to identify organism
Other fungal stains (PAS, calcofluor white, silver stain): more sensitive, especially when used in combination
Pap Stain: also sensitive (In one study, sputum were 78% positive by PAP, compared to 37% positive by KOH + PAS)
Multiple sputum samples increases yield
- Notify lab of suspected Blasto, as organisms can be overlooked if inspection is focused on malignancy
Cutaneous Lesions (and Oropharyngeal/Laryngeal Involvement): markedly hyperplastic stratified squamous epithelium
- Microabscesses within downgrowths of rete pegs
- May superficially resemble carcinoma (uniform benign appearance of cells and presence of organisms with special stains helps make diagnosis)

Diagnosis

Sputum GS/Cult+Sens (or aspirated pus): 10% KOH exam is easiest technique to identify large 8-20 µm organism
-Thick double-refractile cell wall
- Single-budding with broad base of attachment ( broad-based buds )
- Multiple nuclei
- Other fungal stains (PAS, calcofluor white, silver stain): more sensitive, especially when used in combination
- PAP Stain: also sensitive (In one study, sputum were 78% positive by PAP, compared to 37% positive by KOH + PAS) -Multiple sputum samples increases yield
- Notify lab of suspected Blasto, as organisms can be overlooked if inspection is focused on malignancy
FOB: may be used
- In one study, FOB was diagnostic in 92% of cases (when culture results were included in the analysis)
  - 64% of cases had BAL/all had bronchial washings
- Cell blocks of BAL fluid with stains (as above) increase the diagnostic yield
- Endobronchial Bx/TBB: H+E stains do not detect organism (silver stains have better sensitivity than PAS stains)
- Fungal Culture: identification is not difficult (but due to growth times, from 5 days-weeks, this is slower)
  - Exoantigen testing: may identify organism, as soon as good growth is established
Pleural Fluid: exudate
- Cell Count/Diff: lymphocyte-predominant usually (although PMN-predominant in some cases)
- Culture: positive
- Cholesterol: elevated >55-60 mg/dL (seen in all exudates)
- Pleural: serum cholesterol ratio: elevated (seen in all exudates)
Pleural Bx: non-caseating granulomas (must rule out TB pleuritis)
- Silver stains: may be positive for Blasto (seen as “double-refractile” walled organism)
- Culture: positive
Blasto Skin Test: no commercially available test
CXR/Chest CT Patterns: no characteristic pattern
- Single or Multiple Round Lung Nodular Densities: may cavitate (and close with treatment)
- Segmental/Lobar Consolidation:
- Diffuse Nodular/Interstitial/Alveolar Infiltrates: may resemble ARDS
- Mass-Like Perihilar Infiltrates (especially on the right side, posterior to hilum, in superior segment of lower lobe): may resemble a neoplasm
- Hilar Adenopathy: less common than in Histo
- Pleural Effusion (10% of cases):
- Pleural Thickening (40% of cases):
- Lack of Calcification (unlike in Histo)
Serologic Tests: positive results from any of these may heighten suspicion of disease, but diagnosis needs to be confirmed by visualization or culture
- Complement Fixation:
- ELISA: highest sensitivity, lowest specificity serologic test
- Immunodiffusion:
CBC:
- Leukocytosis with left shift: common in acute, abrupt onset cases

Clinical Presentations

Asymptomatic Infection: may occur in many cases (demonstrated by outbreak studies using skin testing data)
Acute Pneumonia-Like Ilness
- Abrupt onset-type is common in outbreaks (slower onset-type is common in sporadic cases)
- Acute Blastomycosis resembles a bacterial pneumonia (in contrast to Acute Histoplasmosis, which resembles influenza)
- Clinical Features
  - Cough with Mucopurulent Sputum: characteristic
  - Pleuritic Chest Pain: may occur
  - Fever/Chills: common
  - Weight Loss: more common in sporadic (gradual onset) cases
  - Crackles/Signs of Focal Consolidation: may be absent
- Pleural Effusions (see [[Pleural Effusion-Exudate]]): 10% of cases
Cutaneous Blastomycosis
- May occur in absence of pulmonary symptoms (with normal CXR) in some cases
- May occur up to 3 years after the initial pulmonary symptoms
- May occur in crops or may appear every few days
- Variable Appearance of Skin Lesions: single or multiple
  - SQ Nodules:
  - Papules:
  - Ulcers:
  - Abscesses:
  - Irregular Borders with Crusted Surface (1-10 cm): most characteristic skin lesion
Disseminated Blastomycosis: in patients with T-cell defects (transplants, immunocompromised, AIDS):
- Skin Involvement (20%):
- Osteomyelitis (15%):
- CNS Involvement (3%):
- GU Tract Involvement:
Blastomycosis in Pregnancy
- Blastomycosis is uncommon in pregnancy
- Blastomycosis can transplacentally infect the fetus (which may be fatal to the fetus)

Treatment

Mild-Moderate Blasto (Pulmonary, Disseminated)

Itraconazole 400 mg/day x 6-12 mo
IV Itraconazole is available (limit use to 2 wks to avoid cyclodextrin nephrotoxicity/avoid with CrCl <30 ml/min)
Alternative: Fluconazole 400-800 mg/day x 6-12 mo (less active against Blasto than Itraconazole, but has better CNS penetration)
Subset of Patients with Abrupt Onset (Outbreak-Type), Pulmonary-Limited Blasto Who are Not Severely Ill and are Getting Better Already: this subset may not require any treatment at all and only 1/39 patients had relapse in 20 year folllow-up
- However, given the availability of less toxic treatments (other than Ampho), it is recommended that all ill “abrupt onset-type” patients be treated
- All “slower onset-type” (sporadic-type) cases should be treated to prevent progression of disease
Special Cases:
- Treatment of Subset of Patients with Abrupt Onset (Outbreak-Type), Pulmonary-Limited Blasto Who are Not Severely Ill and are Getting Better Already: this subset may not require any treatment at all and only 1/39 patients had relapse in 20 year folllow-up
  - However, given the availability of less toxic treatments (other than Ampho), it is recommended that all ill abrupt onset-type patients be treated
  - All slower onset-type (sporadic-type) cases should be treated to prevent progression of disease
- Treatment of Blasto in Pregnancy: azoles are category C (fetal risk cannot be ruled out) and Ampho is a safer alternative

Severe Blasto (Pulmonary, CNS, Pleural, Disseminated, Immunocompromised host)

Ampho 0.7-1 mg/kg until stabilized, then Itraconazole 400 mg/day x 6-12 mo
IV Itraconazole is available (limit use to 2 wks to avoid cyclodextrin nephrotoxicity/avoid with CrCl <30 ml/min)
Alternative: Ampho 0.7-1 mg/kg (to total dose of 2 g)
AIDS: infection is severe, cure is not likely, and lifelong maintenance is required after initial response
Meningeal Blasto: liposomal Ampho may achieve higher brain concentrations
Special Cases:
- Treatment of Blasto in AIDS: infection is severe, cure is not likely, and lifelong maintenance is required after initial response
- Treatment of Meningeal Blasto: liposomal Ampho may achieve higher brain concentrations (confirmed in animal studies), so use of it in combo with Fluconazole (which has better CNS penetration than Itraconazole) may be the preferred regimen
  - Intracisternal Ampho: only anecdotal data (has been used in combo with systemic therapy)
- Treatment of Blasto in Pregnancy: azoles are category C (fetal risk cannot be ruled out) and Ampho is a safer alternative
Voriconazole: has not been studied

References

Ruderman EM, Markenson JA. Granulomatous infections and tumor necrosis factor-antagonist therapies. Abstract (# THU0209) presented at: Proceedings of the Annual European Congress of Rheumatology European League Against Rheumatism; June 18-21, 2003; Lisbon, Portugal