Histoplasma/Histoplasmosis

Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. The fungus exists as a mold at low temperatures and as yeast at high temperatures. H. capsulatum is the most common endemic fungal infection in the US and is most prevalent in the midwestern and central states along the Ohio and Mississippi River valleys. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Diagnosis is via different modalities, with the visualization and/or growth of the causative organism made using direct microscopy, histopathology, or culture studies. Management is dependent on disease severity. The antifungal medications that are used include amphotericin B and itraconazole.

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General Characteristics of Histoplasma

Features

  • Morphology: thermally dimorphic fungus
    • Ambient (low) temperature: mold form
    • Body (high) temperature: yeast form
  • Characteristics:
    • Obligate aerobe
    • Mold form:
      • Septate mycelium: thin and branching
      • Produce microconidia and tuberculate macroconidia
    • Yeast form:
      • Reproduce by budding
      • Slightly oval
      • 2–4 µm in diameter
      • Found exclusively in macrophages

Clinically relevant species

  • H. capsulatum var. capsulatum
  • H. capsulatum var. duboisii: exists primarily in Africa

Forms of disease

  • Pulmonary histoplasmosis:
    • Asymptomatic
    • Symptomatic
    • Acute diffuse
    • Chronic pulmonary
  • Disseminated histoplasmosis:
    • CNS
    • GI
    • Skin lesions
    • Adrenal glands

Mnemonic

Histoplasmosis is an infection caused by a dimorphic fungus. Remember the following mnemonic to recall how the fungus exists:

  • “Mold in the cold”
  • “Yeast in the heat”

Epidemiology

Frequency

  • Most common fungal infection endemic in the US
  • Incidence in the US: 500,000 new infections annually
  • Geographic prevalence:
    • US: Midwestern and Central US, Ohio and Mississippi River valleys
    • Worldwide:
      • South and Central America
      • Africa
      • India
    • Australia

Morbidity and mortality

  • Outcomes can vary depending on severity, duration, and host immune state.
  • Mild disease: typically good outcomes
  • Mortality of severe disease (despite hospitalization): 
    • 5% in children
    • 8% in adults
  • Chronic pulmonary histoplasmosis is more likely in individuals with underlying lung disease (particularly emphysema).
  • Disseminated histoplasmosis:
    • Immunocompetent adults: 1 per 2,000 cases of histoplasmosis
    • Immunocompromised individuals: 4%–27% mortality in severe cases
Map of United states areas endemic for histoplasmosis

Map of the United States illustrating the areas endemic for histoplasmosis

Image: “Map showing areas endemic for histoplasmosis in the US” by CDC. License: Public Domain

Pathogenesis

Infectious process

  • Habitat:
    • Found in soil contaminated with bird or bat droppings
    • Droppings increase nitrogen content → favorable for sporulation
    • Common sites:
      • Chicken coops
      • Farm buildings
      • Abandoned buildings
      • Caves
  • Transmission:
    • Inhalation via the respiratory tract
    • Deposition in the pulmonary alveoli
    • Exposures are seen in spelunkers and individuals involved in construction or agriculture.
  • Virulence factors:
    • Siderophores: support intracellular yeast growth
    • Melanin:
      • Found in the cell wall
      • Decreases host defense mechanisms
      • Decreases the susceptibility of yeast to antifungal agents
    • Heat shock proteins (HSPs):
      • HSP60: prevents significant activation of phagocytes
      • HSP82: role in yeast development and cellular stress
    • Yeast-phase-specific (YPS)3 gene:
      • Found in cell wall
      • Unknown function
    • Calcium-binding protein optimizes phagolysosomal conditions for yeast growth.
    • α-(1,3)-glucan: antigenic function
  • Pathogenicity and disease process:
    • Microconidia are phagocytized by macrophages.
    • Conversion to yeast form occurs.
    • Yeast multiply in alveolar macrophages.
    • Dividing yeast destroys macrophages and is then ingested by the recruited phagocytes.
    • H. capsulatum survives by capturing iron and modulating pH (to neutral), thereby decreasing the killing effect of phagolysosomes.
    • The cycle continues and allows the infection to spread to the hilar lymph nodes.
    • Macrophages help spread the organism via the lymphatic system.

Host risk factors

  • HIV infection
  • Primary immunodeficiencies
  • Immunosuppressive disorders
  • Transplant recipients
  • Immunosuppressive drugs:
    • Most common fungal infection in patients on TNF-α inhibitors
    • Glucocorticoids
    • Antirejection therapies for solid organ transplants
  • Extremes of age
  • Heavy inoculation exposure

Clinical Presentation

General findings

Clinical presentation varies depending on host immune status and underlying risk factors.

  • Exposure to Histoplasma in endemic regions is extremely common.
  • The majority of infections are asymptomatic or subclinical.

Pulmonary histoplasmosis

  • < 5% of individuals develop symptomatic disease after low-level exposure.
  • Symptomatic pulmonary histoplasmosis:
    • Presents several weeks after exposure
    • Symptoms:
      • Fever
      • Chills
      • Headache
      • Myalgias
      • Anorexia
      • Cough
      • Pleuritic chest pain
    • Examination:
      • Typically unremarkable
      • May exhibit rales or signs of consolidation
    • Chest X-ray: may be normal, or may show focal infiltrates with/without hilar or mediastinal lymph node involvement
  • Acute diffuse pulmonary histoplasmosis
    • Associated with large inoculum
    • Abrupt onset of symptoms
    • Chest X-ray: diffuse pulmonary infiltrates (reticulonodular)
    • ARDS can develop within days.
    • Dyspnea and fatigue may persist for months after treatment.
  • Chronic pulmonary histoplasmosis
    • Underlying lung disease ↑ risk
    • Symptoms:
      • Productive cough
      • Fatigue
      • Fever
      • Sweats
      • Dyspnea
    • Radiography/CT: 
      • Fibrotic apical infiltrates with cavitation
      • Can be confused for tuberculosis
    • Areas of chronic infection have increased predisposition for:
      • Aspergilloma
      • Atypical mycobacteria
      • Chronic or recurrent pneumonia
  • Broncholithiasis
    • Lymph node calcification or pulmonary granuloma calcification can occur years after the initial infection.
    • The calcification may erode into the adjacent bronchi.
    • Patient may report expectoration of:
      • Small stones
      • Gravel
      • Gritty material
    • Symptoms:
      • Chronic cough
      • Purulent sputum
      • Wheezing
      • Hemoptysis
      • Fever
      • Chills
  • Other pulmonary manifestations:
    • Granulomatous mediastinitis
    • Mediastinal fibrosis

Disseminated histoplasmosis

  • Most patients experience asymptomatic dissemination.
  • Can present acutely or years later
    • Acute: 
      • In infants and immunocompromised individuals
      • Can be rapidly fatal
    • Chronic: older patients who are immunocompetent
  • Symptoms:
    • Fever
    • Malaise
    • Weight loss
  • Examination:
    • Hepatosplenomegaly
    • Lymphadenopathy
    • Pallor
    • Petechiae: if pancytopenic
    • Oral ulcerations
    • Skin lesions
  • Severe disease:
    • Sepsis
    • Disseminated intravascular coagulation
    • Renal failure
    • Hepatic failure
    • Acute respiratory distress
  • CNS:
    • 5%–20% of cases
    • Presentation:
      • Meningitis
      • Isolated chronic meningitis
      • Cerebral vasculitis
      • Focal brain lesions
      • Encephalitis
      • Localized spinal cord involvement
  • GI disease:
    • Although 70% of patients have GI involvement, < 10% present clinically.
    • Can occur throughout the GI tract (most common in the ileum and colon)
    • Manifestations:
      • Oral ulcers
      • Colonic perforation
      • Polypoid-like mass
  • Skin:
    • 10%–15% of cases
    • More often in patients with AIDS
    • Lesions:
      • Nodules
      • Papules
      • Plaques
      • Ulcers
      • Pustules
      • Abscesses
      • Dermatitis
  • Adrenal glands:
    • Involvement is common; however, < 10% of individuals have overt insufficiency
    • Can be unilateral or bilateral
    • Perivasculitis → thrombosis → infarction of the adrenal glands
    • Adrenal insufficiency:
      • Electrolyte abnormalities
      • Orthostatic hypotension
      • Hypoglycemia 
  • Others: less common:
    • Cardiopulmonary: endocarditis, pericarditis, pleuritis
    • GI/abdominal: peritonitis, pancreatitis, cholecystitis
    • Skeletal: osteomyelitis, septic arthritis
    • Chorioretinitis
    • Mastitis
    • Thrombotic microangiopathy
    • Hemophagocytic syndrome
    • Hypercalcemia: due to calcitriol produced by macrophages

Diagnosis

Diagnostic approach

  • Diagnosis cannot be made on clinical information alone.
  • The approach will vary depending on presentation and test limitations.
  • Multiple tests including culture, direct microscopy, and histopathology can help in diagnosis.
    • Time consuming (> 14 days)
    • Variable sensitivity
    • Culture is most effective when the fungal burden is high.
  • Histopathology:
    • KOH prep
    • Stains:
      • Methenamine silver (GMS)
      • PAS
    • Biopsy findings:
      • 2–4-µm narrow, budding yeast cells
      • Granulomas
      • Lymphohistiocytic aggregates
      • Diffuse mononuclear cell infiltrates
  • Culture:
    • Medium: Sabouraud’s dextrose agar
    • Growth: 2–6 weeks
    • Sources:
      • Tissue
      • Sputum and/or bronchoalveolar lavage (BAL)
      • Blood
      • Bone marrow
  • Antigen detection:
    • ELISA for antigen testing
    • Allows for rapid diagnosis, particularly in disseminated disease
    • Sensitivity increases with disease severity (most sensitive test in disseminated disease).
    • False positives can occur with other fungal diseases.
    • Sources:
      • Urine
      • Serum
      • BAL
      • CSF
  • Direct microscopy:
    • Wright’s stained smear (blood)
    • Least expensive
    • Can allow for rapid and confirmatory diagnosis
    • Limited by low sensitivity (< 10%)
  • Others:
    • Antibody tests (immunodiffusion test and complement fixation test)
    • PCR

Imaging

  • Chest X-ray and chest CT:
    • Can be normal
    • Findings:
      • Focal infiltrates
      • Hilar and/or mediastinal lymphadenopathy
      • Calcified granulomas
      • Pulmonary nodules
      • Diffuse interstitial or reticulonodular infiltrates
      • Cavitary lesions (rare)
      • Pleural effusions
  • CT (other areas):
    • Head CT:
      • Can be useful to detect cerebral histoplasmosis
      • Should be performed prior to lumbar puncture
    • Abdominal CT:
      • Can demonstrate adrenal involvement, if suspected
      • The findings typically demonstrate adrenal enlargement.
Chest_X-ray_acute_pulmonary_histoplasmosis

Chest X-ray:
Diffuse pulmonary infiltration due to acute pulmonary histoplasmosis caused by Histoplasma capsulatum

Image: “This chest film shows diffuse pulmonary infiltration due to acute pulmonary histoplasmosis caused by H. capsulatum” by CDC/M. Renz. License: Public Domain

Management

Principles

  • Treatment varies depending on disease severity.
  • Most cases are self-limiting and do not require treatment.
  • Individuals with large inoculum exposure and patients who are immunocompromised usually require treatment.
  • Antifungal drugs are the mainstay of treatment.
Table: Treatment of histoplasmosis
ConditionTreatment
Moderate pulmonary disease or symptoms lasting > 4 weeksItraconazole
Moderately severe to severe pulmonary diseaseAmphotericin B + itraconazole
Chronic pulmonary histoplasmosisItraconazole
Mild disseminated histoplasmosis: mild symptoms with single focus (no CNS involvement)Itraconazole
Severe disseminated histoplasmosis without CNS involvementAmphotericin B + itraconazole
CNS involvementAmphotericin B (prolonged) + itraconazole

Acute pulmonary histoplasmosis

  • No treatment for:
    • Asymptomatic individuals
    • Individuals with mild symptoms
  • Prolonged symptoms (> 4 weeks) or moderate pulmonary disease:
    • Itraconazole for 6–12 weeks (loading dose for the 1st 3 days)
    • Monitor response with chest imaging.
    • Monitor for relapse (several years).
  • Moderately severe to severe pulmonary disease:
    • Amphotericin B for 1–2 weeks, followed by itraconazole for 12 weeks
    • Methylprednisone for 1–2 weeks for ARDS

Chronic pulmonary histoplasmosis

  • Treatment is indicated for all patients.
  • Itraconazole for 1 year (loading dose for the 1st 3 days)

Disseminated histoplasmosis

  • If mild clinical symptoms and single focus of disease (without CNS involvement): itraconazole for 1 year (loading dose for the 1st 3 days)
  • All other cases:
    • Amphotericin B for 1–2 weeks (with CNS involvement: 4–6 weeks)
    • Itraconazole for at least 1 year (loading dose for the 1st 3 days)

Suppressive therapy

  • Relapse can occur if immune recovery is not maintained with antiretroviral therapy in patients with AIDS.
  • Itraconazole is effective in preventing up to 95% of cases.
  • For patients with HIV having CD4 counts < 150 cells/µL → long-term itraconazole

Differential Diagnosis

  • Opportunistic fungal infections: a group of infections that occur in patients with weakened immune systems (especially individuals with CD4 counts < 200 cells/μL). Healthy individuals with normal immune systems are typically not affected. The general signs and symptoms can be similar to those of histoplasmosis. Exposure history, microscopy, and culture of sputum or BAL to identify specific organisms can help differentiate fungal infections.
  • Community-acquired pneumonia: the typical symptoms (cough, fever, pleuritic chest pain) are usually of a shorter duration than those seen in histoplasmosis pneumonia. A chest X-ray will typically demonstrate lobar consolidation (typical) or bilateral interstitial infiltrates (atypical). Gram staining of the sputum and culture often reveals neutrophils and bacteria that are not part of the normal flora. Antibiotics are the general mainstay of treatment.
  • Sarcoidosis: an autoimmune disorder that can present with clinical findings similar to those of histoplasmosis. The common findings include diffuse pulmonary infiltrates, mediastinal lymphadenopathy, erythema nodosum, splenomegaly, and non-caseating granulomas. Although ↑ ACE levels are seen in both diseases, the elevation is classically associated with sarcoidosis.
  • Blastomycosis: a pulmonary disease caused by inhaling the spores of Blastomyces. Patients can develop pneumonia or disseminated extrapulmonary disease. Clinically, pulmonary manifestations can be difficult to distinguish from histoplasmosis. Unlike in histoplasmosis, the skin is the most common site of dissemination in blastomycosis. Blastomyces is endemic to the regions of the Great Lakes and the Ohio and Mississippi River valleys. Diagnosis is made by cultures and imaging.
  • TB: an infectious disease caused by bacteria of the Mycobacterium tuberculosis complex. Like histoplasmosis, TB usually infects the lungs but can also spread to other parts of the body. Both TB and histoplasmosis are associated with a period of latency and can present with similar signs and symptoms. Look for a history of exposure to an environment with TB prevalence (healthcare setting, homeless shelters, etc.). A CD4 count of < 300 cells/μL is typically associated with TB. The diagnosis is established with a tuberculin skin test, blood tests, sputum culture, and lung imaging.
  • Coccidioidomycosis: a pulmonary or hematogenously spread fungal disease caused by Coccidioides species. Like histoplasmosis, coccidioidomycosis is acquired through inhalation. The endemic regions for Coccidioides are distinct from Histoplasma and include southern California, Arizona, New Mexico, and West Texas.

References

  1. Baddley, J.W. (2021). Diagnosis and treatment of histoplasmosis in patients with HIV. UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/diagnosis-and-treatment-of-histoplasmosis-in-patients-with-hiv
  2. Guimarães, A.J., Nosanchuk, J.D., Zancopé-Oliveira, R.M. (2006). Diagnosis of histoplasmosis. Braz J Microbiol 37, 1–13.
  3. Kauffman, C.A. (2020). Histoplasmosis: A clinical and laboratory update. Clin Microbiol Rev 20, 115–132.
  4. Kauffman, C.A. (2021). Diagnosis and treatment of pulmonary histoplasmosis. UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/diagnosis-and-treatment-of-pulmonary-histoplasmosis
  5. Kauffman, C.A. (2021). Pathogenesis and clinical features of pulmonary histoplasmosis. UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/pathogenesis-and-clinical-features-of-pulmonary-histoplasmosis
  6. Kauffman, C.A. (2021). Pathogenesis and clinical manifestations of disseminated histoplasmosis. UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/pathogenesis-and-clinical-manifestations-of-disseminated-histoplasmosis
  7. Linder, K.A., Kauffman, C.A. (2019). Histoplasmosis: Epidemiology, diagnosis, and clinical manifestations. Curr Fungal Infect Reports 13, 120–128.
  8. Mihu, M.R., Nosanchuk, J.D. (2012). Histoplasma virulence and host responses. Int J Microbiol 2012, 268123.

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