Histoplasmosis

Microbiology and Dimorphic Pathogenesis

Thermal Dimorphism

• Environmental form (25°C): the fungus grows as a mold, producing large, finely spiked, sunflower-like spores (tuberculate macroconidia, 8–15 µm) and small spores (microconidia, 2–4 µm).
• Tissue form (37°C): inside the human body it switches to a small oval yeast just 2–4 µm across, with narrow-based budding.

How It Enters and Spreads Inside Macrophages

• Inhalation of microconidia: the small airborne spores travel deep into the alveoli of the lungs.
• Intracellular parasitism: alveolar macrophages engulf the fungus, but H. capsulatum is not killed. Instead it alters the phagolysosome (raising its pH) and multiplies rapidly within the macrophage cytoplasm.
• Systemic spread: infected macrophages travel through the lymph and blood to organs of the reticuloendothelial system, namely the spleen, liver, bone marrow and lymph nodes, as well as the skin and mucous membranes.

Clinical Forms Affecting the Skin and Mucous Membranes

Acute and Chronic Pulmonary Histoplasmosis:

• Acute: flu-like symptoms (fever, chills, dry cough, chest pain), usually self-limiting in people with normal immunity.
• Chronic cavitary: cavities in the upper lungs, coughing up blood and weight loss, easily mistaken for pulmonary tuberculosis.

Progressive Disseminated Histoplasmosis (PDH): occurs mainly in immunocompromised patients. Features include prolonged fever, wasting, an enlarged liver and spleen, widespread lymph node enlargement, bone marrow failure (low counts in all three blood cell lines) and acute adrenal insufficiency.

Skin and Mucosal Manifestations:

• Mucosal ulcers (seen in 30%–50% of PDH cases): on the tongue, palate, gums, lips or larynx. They are painful ulcers with hard, raised edges and an infiltrated, granular base, and are easily misdiagnosed as oral squamous cell carcinoma.
• Varied skin lesions:
  • Umbilicated papules with central necrosis that resemble molluscum contagiosum.
  • Warty plaques, firm infiltrated red plaques or subcutaneous nodules.
  • Secondary immune reactions: erythema nodosum or erythema multiforme during acute pulmonary infection.

Our Diagnostic Workup at Haute-Derma

Cytology and Direct Smears:

• Material is scraped from the base of a mucosal ulcer or aspirated from a lymph node or bone marrow and smeared onto a slide.
• Giemsa or Wright stain: macrophages packed with small round or oval yeasts (2–4 µm) with dark purple nuclei, each surrounded by a clear space (a pseudo-halo caused by cytoplasmic shrinkage during fixation).

Skin or Mucosal Biopsy:

• H&E stain: granulomatous inflammation rich in macrophages, with Langhans giant cells and caseous necrosis (in people with good immunity), or dense sheets of fungus-laden macrophages without granuloma formation (in severely immunocompromised patients).
• Special stains: GMS (Grocott's methenamine silver) and PAS: highlight the walls of the tiny yeasts, black or magenta, crowded inside the macrophage cytoplasm.

Antigen and Serology Tests:

• Histoplasma antigen EIA (urine/serum): the fastest and most sensitive test (sensitivity above 90% in progressive disseminated disease). A falling urine antigen level is an important marker of response to treatment.

Culture (Biosafety Level 3 Warning):

• Tissue is cultured on BHI (brain heart infusion) and SDA media at 25°C and 37°C.
• SAFETY NOTE: the mold form grown at 25°C releases huge numbers of microconidia that can float in the air. Whenever Histoplasma is suspected, cultures must be handled in a Class II/III biosafety cabinet to protect laboratory staff from airborne infection.

Treatment at Haute-Derma

Treatment of Severe and Progressive Disseminated Disease (PDH)

• Induction phase (1–2 weeks):
  • Liposomal amphotericin B (L-AmB): 3.0–5.0 mg/kg/day by slow intravenous infusion.
  • Electrolytes (potassium, magnesium) and kidney function (creatinine) are monitored closely every day.
• Consolidation and maintenance phase (at least 12 months):
  • Once the fever has settled, the patient is clinically stable and blood counts are improving, treatment switches to:
  • Itraconazole (capsules or oral solution): a loading dose of 200 mg three times daily for the first 3 days, then 200 mg twice daily.
  • A trough plasma itraconazole level must be checked after 2 weeks of treatment (target above 1.0 µg/mL) to make sure the drug is being adequately absorbed.

Treatment of Mild to Moderate Disease (Localized Skin/Mucosal Lesions)

• Itraconazole alone:
  • Dose: 200 mg three times daily for the first 3 days, then 200 mg twice daily for at least 6–12 months.
  • Take it right after a full meal or with an acidic drink to maximize absorption.

Secondary Prophylaxis (Long-Term Suppression)

For people with HIV/AIDS and a CD4 count below 150 cells/µL, or with immunosuppression that cannot be reversed: itraconazole 200 mg/day is continued for life, or until the CD4 count has stayed above 150 cells/µL for more than 6 months with an undetectable HIV viral load.