Histoplasmosis

Abstract

Granulomatous infection caused by the dimorphic fungus, Histoplasma capsulatum var. capsulatum. Worldwide distribution with prevalence in the Mississippi and Ohio River Valleys in the United States.

Overview

• Granulomatous infection caused by the dimorphic fungus, Histoplasma capsulatum var. capsulatum

• Worldwide distribution with prevalence in the Mississippi and Ohio River Valleys in the United States

• Found in soil and vegetal detritus contaminated by bird and bat droppings with acquisition via aerosol inhalation or less commonly via direct innoculation

• Risk factors include immunocompromised host and occupations with exposure to high risk environments

• Immunocompromised individuals are more likely to develop disseminated disease to various extrapulmonary locations (e.g. liver, spleen, lymph nodes, bone marrow, skin, CNS, adrenal glands)

  • Fever, malaise, loss of appetite and fatigue are common nonspecific presenting symptoms

  • Cutaneous involvement is uncommon (~5% of cases, may be higher in severely immunosuppressed hosts) but is a helpful diagnostic clue when present

Clinical Presentation

• In the majority of cases the infection is asymptomatic or mild with a self-limited course

• Characterized by three different forms––namely pulmonary, primary cutaneous, and disseminated disease, the latter of which is severe

• Primary cutaneous histoplasmosis due to direct inoculation is uncommon and presents as an isolated ulcer with regional lymphadenopathy that self-resolves

• Secondary cutaneous histoplasmosis seen in disseminated disease is due to hematogenous spread and is characterized by diverse skin morphology including papules, plaques, nodules, umbilicated papules, acneiform, abscess, cellulitis, pyoderma gangrenosum-like lesions or painful mucocutaneous ulcers (Fig. 40.1)

  • Areas of involvement include the face, extremities, trunk, and mucosa (especially oral)

• Depending on organ involvement in disseminated disease symptomatology will vary but may include: petechiae, easy bruising, fatigue, weakness (thrombocytopenia and anemia from bone marrow involvement), hepatomegaly, splenomegaly, lymphadenopathy, altered mental status, photophobia, headache (CNS involvement)

Histopathology

• A varying degree of inflammation is seen characterized by a granulomatous, lymphocytic and/or a mononuclear infiltrate (Fig. 40.2)

• Yeast forms are 2–4 microns in size, often elongated, may demonstrate narrow budding, can have a peripheral rim of clearing

• Organisms are often parasitized by macrophages

• Yeast forms are highlighted by periodic acid-Schiff (PAS), Gomori-Grocott, or silver methenamine (GMS) stains

Differential Diagnosis

In all cases, travel history and exposure history is essential in narrowing the diagnosis; pathologic findings are often diagnostic and biopsy should be considered if any of these entities are suspected.

• Blastomycosis : may see larger lesions with a raised, crusted border with or without ulceration

• Coccidioidomycosis : there may be clinical overlap, but pathology is different and diagnostic

• Cryptococcosis : may have varied clinical presentations and can overlap with histoplasmosis skin findings; biopsy, culture, and serologic testing are helpful

• Paracoccidioidomycosis : lesions may be larger crusted nodules, but biopsy is diagnostic

• Leishmaniasis : bite-site crusted ulcers, which may be grouped, and frequently involve the ear can be helpful; be cautious with pathology as both leish and histo can look similar

• Tuberculosis : can be varied depending on if primary cutaneous involvement or a tuberculid response; pathologic findings are diagnostic

Fig. 40.1

Cutaneous histoplasmosis: Necrotic verrucous violaceous plaque on the forehead.

Fig. 40.2

Cutaneous histoplasmosis: (a) On low power, there is epidermal ulceration with underlying neutrophilic and granulomatous inflammatory infiltrate (H&E, 4×). (b) On higher power, neutrophils surround histiocytes and multinucleated giant cells that have parasitized small yeast forms (H&E, 40×). (c) PAS stain highlights the yeast forms that have been parasitized by macrophages.

Work-Up

• A thorough history and physical exam should be obtained including evaluation of mucosal sites (oral and perianal)

• Histopathologic evaluation of a punch biopsy from a representative skin lesion should be performed

• Culture is considered the gold standard with an incubation time of 3–6 weeks

• Antigen testing of urine, serum, bronchial lavage or CSF is sensitive for acute disseminated and pulmonary histoplamsosis, but there is cross-reactivity with Paracoccidioides and Blastomyces

• Hypercalcemia has been described, which may be nonspecific (present in many granulomatous diseases)

• Evaluation for disseminated disease should be targeted based on potential organs of involvement

  • CBC: leukopenia, thrombocytopenia, anemia (bone marrow/spleen involvement)

  • Peripheral blood smear review to visualize the organism (Wright’s stain)

  • CMP: abnormal AST, ALT, bilirubin

  • Chest x-ray: typically will show diffuse interstitial or reticulonodular pulmonary infiltrates

  • Abdominal CT (assess for enlarged liver, spleen, lymph node)

  • Brain CT/MRI, lumbar puncture (CNS involvement)

  • Endoscopy: Visualize GI lesions

Treatment

• Treatment choice is based on disease severity and underlying comorbidities

• Amphotericin B is the agent of choice for induction therapy for severe disease

• Itraconazole is preferred for mild to moderate disease and is commonly used for maintenance therapy

• If conventional treatment fails additional options include voriconazole or posaconazole

• Patients with HIV/AIDS may require additional management and infectious disease experts should be consulted