• Clinical science

Aspergillosis

Abstract

Aspergillosis is the collective term for diseases caused by mold species in the genus Aspergillus. Aspergillus spores are ubiquitous but do not usually cause infection in immunocompetent individuals. Risk factors for Aspergillus infection include immunosuppression (e.g., HIV, hematologic malignancies, transplant recipients) and underlying pulmonary conditions (e.g., cavernous tuberculosis, COPD). Infections may be localized, causing asymptomatic pulmonary aspergilloma, or symptomatic, complicated infiltrates (e.g., with cavitation, fibrosis, or necrosis). In immunocompromised patients, invasive aspergillosis is common, which manifests as severe pneumonia and septicemia with potential involvement of other organs. In patients with pre-existing bronchopulmonary conditions (e.g., asthma, cystic fibrosis), Aspergillus may cause allergic bronchopulmonary aspergillosis (ABPA), which presents with asthmatic symptoms or sinusitis. Elevated serum IgE levels and eosinophilia indicate a fungal infection. Tissue biopsy followed by histopathology and culture are used to confirm the diagnosis. Medical treatment for aspergillosis infection includes voriconazole, caspofungin, or amphotericin B. An aspergilloma, on the other hand, must be surgically removed. ABPA is primarily managed with glucocorticoid therapy. Immunocompromised patients should receive prophylactic posaconazole.

Etiology

References:[1][2]

Clinical features

Allergic bronchopulmonary aspergillosis (ABPA)

Chronic pulmonary aspergillosis

Invasive aspergillosis

  • Lungs: pulmonary aspergillosis
  • Mucous membranes in sinuses
    • Aspergillus sinusitis with invasion of the surrounding tissue
    • Invasion into the orbit → reduction of visual acuity, painful exophthalmos, chemosis
    • Invasion into the skullCNS involvement, venous sinus thrombosis
  • Skin (via direct inoculation):pustules or hemorrhagic papules/plaques, which may evolve into eschars
  • Disseminated infection
    • CNS: Multiple abscess formation with varied neurological manifestations (cramps, focal neurological deficits )
    • Heart: Aspergillus endocarditis

Invasive aspergillosis mostly infects the bronchioles of the lungs, but can also manifest as a disseminated infection (e.g., in skeletal, cutaneous, or neurological tissue)!

References:[1][2][3][4][5][6]

Diagnostics

ABPA

Chronic pulmonary aspergillosis

The following criteria should be fulfilled for each type:

  • Aspergilloma
    • X-ray and CT
      • Monad sign: a peripheral air crescent around a fungus ball in a pre-existing lung cavity
      • Radiological evidence of a mobile fungus ball
        • The mobility of the fungus ball is demonstrated by moving the patient from a supine position to a prone or lateral recumbent position.
      • The upper lobe is mostly affected because of the increased concentration of oxygen
    • Laboratory tests: positive sputum culture or positive Aspergillus IgG serology
  • Aspergillus nodule
    • X-ray and CT: multiple nodules AND
    • Laboratory tests: positive biopsy result or positive Aspergillus IgG serology
  • Cavitary pulmonary aspergillosis
    • X-ray and CT: one or more cavities with or without aspergilloma AND
    • Laboratory tests: positive Aspergillus IgG serology AND
    • At least one typical symptom ≥ 3 months
  • Fibrotic aspergillosis → criteria as in cavitary pulmonary aspergillosis + extensive fibrosis on CT or biopsy
  • Necrotizing aspergillosis → criteria as in invasive aspergillosis

Invasive aspergillosis

  • Initial work-up
    • Chest CT
      • Multiple nodules
      • Halo sign: hemorrhagic ground glass opacities around nodules
      • Sickle-shaped air crescents around the fungal colony
    • Serum assays
      • Positive galactomannan antigen test
      • Positive 1,3-β-D glucan test
    • If CNS infection is suspected: cranial MRI
      • Manifestation of cerebral aspergillosis: abscess formation
        • T1 with contrast agent:
          • Lesions may be single or multiple.
          • Centrally hypointense with hyperdense ring-enhancing lesions
          • Surrounded by hypointense edema
        • T2: Often hypointense with perifocal hyperintense edema
  • Confirmatory test: positive culture and/or histopathological evidence of invasive aspergillosis
    • Specimen collection
      • Bronchoalveolar lavage via bronchoscopy
      • In patients with peripheral nodular lesions on imaging: endobronchial lung biopsy via bronchoscopy or CT-guided percutaneous biopsy
    • Findings
      • PAS or Gomori methenamine silver stain: septate hyphae branching dichotomously at 45°
      • Positive Galactomannan antigen test
      • Evidence of coagulation necrosis

References:[2][4][7][8][9][10]

Differential diagnoses

Differential diagnosis of pulmonary fungal infections
Mycoses Etiology AIDS-defining illness? Clinical features Diagnosis Treatment

Aspergillosis

  • No
Coccidioidomycosis (Valley fever)
  • Yes
  • Chest x-ray: normal or infiltrates/lymphadenopathy/pleural effusion
  • Serology: increased IgM ; increased IgG at 1–3 months
  • KOH/calcofluor staining on smears or silver/PAS-staining on tissue biopsy: dimorphic fungus and spherules filled with endospores
  • Confirmatory: culture
Paracoccidioidomycosis
  • No
  • Infected patients often asymptomatic
  • Acute pneumonia
  • Painful nasal, pharyngeal, and laryngeal mucosal ulcerations
  • Lymphadenopathy (usually cervical)
  • Can disseminate → extrapulmonary manifestations (including verrucous skin lesions)
  • KOH/calcofluor staining on smears or silver/PAS-staining on tissue biopsy: budding yeast with “captain's wheel” appearance
  • Cultures have a low sensitivity
Blastomycosis
  • No
  • Infected patients often asymptomatic
  • Pneumonia with flulike symptoms
  • Can disseminate → extrapulmonary manifestations (verrucous skin lesions, lytic bone lesions, genitourinary involvement , CNS lesions )
  • KOH/calcofluor staining on smears or silver/PAS-staining on tissue biopsy: broad-based dimorphic fungus
  • Confirmatory: culture
Histoplasmosis
  • Pathogen: Histoplasma capsulatum
  • Risk factors: AIDS, exposure to bird or bat droppings especially in Mississippi and Ohio river valleys
  • Yes
  • Infected patients often asymptomatic
  • Acute pneumonia
  • Can disseminate → extrapulmonary manifestations
Cryptococcosis
  • If extrapulmonary manifestations
  • Infected patients often asymptomatic
  • Isolated pneumonia is possible
  • Extrapulmonary: cryptococcal meningoencephalitis or brain abscess: headache, fever, signs of increased intracranial pressure, confusion, absent meningeal signs
Candidiasis
Pneumocystis pneumonia
  • Yes
  • Chest x-ray or CT: Diffuse, bilateral ground-glass opacities
  • Silver stain and immunofluorescence on bronchoalveolar lavage (or lung biopsy if sputum is negative): disc shaped-yeasts
  • Cannot be cultured


References:[11][12][13][14][15][16][17][18][19][20][21]

The differential diagnoses listed here are not exhaustive.

Treatment

ABPA

Pulmonary aspergillosis

Asymptomatic patients without disease progression do not require treatment, but regular follow-up with imaging and Aspergillosis antibody titer tests are nonetheless absolutely necessary.

  • Aspergilloma
    • Definitive treatment: surgical resection (e.g., lobectomy) of the aspergilloma
    • Antifungals (e.g., oral itraconazole or voriconazole) should be used preoperatively and postoperatively (for 4–12 weeks)
    • In the event of massive hemoptysis: bronchial angiography and embolization for temporary stabilization
  • Aspergillus nodule: antimycotic treatment
  • Other chronic pulmonary types
    • Antimycotic treatment is necessary (e.g., oral treatment in mild disease or intravenous voriconazole; posaconazole or amphotericin B in severe disease)
    • In cases of severe disease, surgical resection may be required. Hemoptysis may necessitate surgical embolization.

Invasive aspergillosis

  • Treatment of choice: IV voriconazole
  • Protective measures taken at the clinic/hospital to improve the immune status of the patient
  • HIV-infected patients: HIV antiretroviral therapy should be initiated as soon as possible or adjusted after consulting an HIV specialist

References:[4][5][22][23][24]

Prevention

Prophylactic therapy

Reduction of mold exposure

The following measures reduce the risk of indoor mold exposure according to the CDC guidelines:

  • Protective measures taken during the construction of buildings, both indoors and outdoors:
    • Adequate insulation
    • Sealing of the floor to prevent moisture from the soil from entering and pervading it
    • Protection from driving rain
    • Regular re-roofing
    • Ensuring the floors and roofs are watertight.
    • Adequate dust cover measures need to be incorporated during construction and restoration work so that there is reduced exposure to the mold present in the dust that is normally stirred up.
  • Protective measures taken at home:
    • Use a ventilation hood while cooking, add mold inhibitors to wall paint, use mold killers in bathrooms, ensure regular ventilation (complete opening of the windows for 5–10 min) and adequate heating (especially in winter) in order to keep the humidity as low as possible.
    • Avoid drying laundry indoors, use of humidifiers, and carpets in bathrooms.