Aspergillosis

Overview

Aspergillosis encompasses a spectrum of diseases caused by Aspergillus, a common mold found throughout the environment in soil, decaying vegetation, household dust, and building materials. While most people breathe in Aspergillus spores daily without getting sick, the fungus can cause serious infections in people with weakened immune systems, lung diseases, or allergies. The severity ranges from mild allergic reactions to life-threatening invasive infections that spread throughout the body.

There are several forms of aspergillosis, each affecting the body differently. Allergic bronchopulmonary aspergillosis (ABPA) occurs in people with asthma or cystic fibrosis and causes allergic reactions. Chronic pulmonary aspergillosis develops slowly over months or years, creating cavities in the lungs. Aspergillomas, or "fungus balls," grow in pre-existing lung cavities. The most severe form, invasive aspergillosis, occurs almost exclusively in immunocompromised individuals and can spread from the lungs to other organs, with mortality rates of 30-95% depending on the patient's condition and how quickly treatment begins.

The incidence of aspergillosis has increased significantly over the past decades, paralleling the rise in immunocompromised populations due to organ transplantation, cancer chemotherapy, and advanced HIV/AIDS treatment. Aspergillus fumigatus causes approximately 90% of invasive infections, though other species like A. flavus, A. niger, and A. terreus are also pathogenic. Understanding the different manifestations of aspergillosis is crucial for healthcare providers, as early recognition and appropriate treatment can dramatically improve outcomes, particularly in high-risk populations.

Symptoms

Symptoms of aspergillosis vary dramatically depending on the type of infection and the organs affected. The presentation can range from mild respiratory symptoms to severe systemic illness.

Organ-Specific Symptoms

• Sinus aspergillosis:
  • Facial pain and pressure
  • Nasal congestion and discharge
  • Headaches
  • Reduced sense of smell
  • Black necrotic tissue in severe cases
• Cerebral aspergillosis:
  • Severe headaches
  • Focal neurological deficits
  • Seizures
  • Altered mental status
  • Vision changes
• Cutaneous aspergillosis:
  • Papules or nodules
  • Necrotic skin lesions
  • Black eschars
  • Wound infections

Aspergilloma (Fungus Ball) Symptoms

• Often asymptomatic
• Hemoptysis (most common symptom)
• Chronic cough
• Weight loss
• Fatigue

Causes

Aspergillosis is caused by fungi of the genus Aspergillus, with several species capable of causing human disease. Understanding the causative organisms and transmission is crucial for prevention and treatment.

Causative Organisms

• Aspergillus fumigatus:
  • Most common cause (90% of invasive cases)
  • Highly thermotolerant
  • Small spore size (2-3 μm) allows deep lung penetration
  • Produces various toxins and enzymes
• Aspergillus flavus:
  • Second most common pathogen
  • More common in warmer climates
  • Can produce aflatoxins
  • Higher propensity for sinus infections
• Other species:
  • A. niger (ear infections, aspergillomas)
  • A. terreus (resistant to amphotericin B)
  • A. nidulans (chronic granulomatous disease)
  • A. ustus (emerging pathogen)

Environmental Sources

• Indoor environments:
  • Household dust
  • Air conditioning systems
  • Water-damaged buildings
  • Potted plants and soil
  • Stored grains and hay
• Outdoor environments:
  • Decaying vegetation
  • Compost piles
  • Construction sites
  • Agricultural areas
  • Bird droppings
• Healthcare settings:
  • Hospital construction/renovation
  • Contaminated air handling systems
  • False ceilings
  • Fireproofing materials

Pathogenesis

• Spore inhalation:
  • Primary route of infection
  • Spores reach alveoli
  • Normal immune system clears spores
  • Immunocompromised cannot eliminate
• Germination and invasion:
  • Spores germinate into hyphae
  • Hyphae invade blood vessels
  • Angioinvasion causes thrombosis
  • Tissue necrosis and dissemination
• Host response:
  • Neutrophils primary defense
  • Macrophages kill conidia
  • T-cell immunity important
  • Allergic response in ABPA

Risk Factors

Different forms of aspergillosis have distinct risk factors, though immunosuppression is the most significant for invasive disease:

Risk Factors for Invasive Aspergillosis

• Severe immunosuppression:
  • Prolonged neutropenia (<500 cells/μL for >10 days)
  • Hematopoietic stem cell transplant
  • Solid organ transplant
  • High-dose corticosteroids
  • Chemotherapy for hematologic malignancies
• Primary immunodeficiencies:
  • Chronic granulomatous disease
  • Severe combined immunodeficiency
  • CARD9 deficiency
  • STAT3 mutations
• Critical illness:
  • Severe COVID-19
  • Severe influenza
  • ARDS requiring mechanical ventilation
  • Severe burns
  • Advanced liver disease

Risk Factors for ABPA

• Underlying lung disease:
  • Asthma (1-2% develop ABPA)
  • Cystic fibrosis (7-15% develop ABPA)
  • Bronchiectasis
• Genetic factors:
  • HLA associations
  • CFTR mutations
  • IL-4 receptor polymorphisms

Risk Factors for Chronic Pulmonary Aspergillosis

• Pre-existing lung cavities:
  • Previous tuberculosis
  • Sarcoidosis
  • Bullous emphysema
  • Lung cancer cavities
  • Pneumocystis pneumonia
• Other lung conditions:
  • COPD
  • Non-tuberculous mycobacterial infection
  • Previous lung surgery
  • Radiation therapy
• Systemic factors:
  • Diabetes mellitus
  • Alcoholism
  • Low body weight
  • Male gender

Environmental Risk Factors

• Living near construction sites
• Exposure to water-damaged buildings
• Agricultural work
• Gardening and composting
• Bird keeping
• Marijuana smoking (contaminated sources)

Diagnosis

Diagnosing aspergillosis requires a combination of clinical suspicion, imaging, laboratory tests, and sometimes tissue diagnosis. The approach varies by type of aspergillosis.

Clinical Assessment

• History:
  • Immunosuppression status
  • Underlying lung disease
  • Environmental exposures
  • Symptom timeline
  • Previous fungal infections
• Physical examination:
  • Respiratory findings
  • Fever patterns
  • Skin lesions
  • Neurological signs
  • Sinus involvement

Laboratory Tests

• Galactomannan antigen test:
  • Serum test for invasive aspergillosis
  • Optical density index >0.5 considered positive
  • Can be tested in BAL fluid
  • False positives with beta-lactam antibiotics
• Beta-D-glucan test:
  • Non-specific fungal marker
  • Elevated in various fungal infections
  • Useful for screening
• Aspergillus-specific IgG:
  • Useful for chronic pulmonary aspergillosis
  • Elevated in ABPA
  • Monitoring treatment response
• ABPA-specific tests:
  • Total IgE >1000 IU/mL
  • Aspergillus-specific IgE and IgG
  • Eosinophilia
  • Positive skin test to Aspergillus

Imaging Studies

• Chest CT scan:
  • Halo sign (early invasive aspergillosis)
  • Air crescent sign (recovery phase)
  • Cavities with fungus balls
  • Bronchiectasis in ABPA
  • Tree-in-bud pattern
• Chest X-ray:
  • Initial screening tool
  • May show infiltrates, cavities
  • Less sensitive than CT
• MRI:
  • For cerebral aspergillosis
  • Sinus involvement
  • Spinal involvement

Microbiological Diagnosis

• Direct microscopy:
  • KOH preparation
  • Calcofluor white stain
  • Septate hyphae with acute angle branching
• Culture:
  • Sputum (low sensitivity)
  • Bronchoalveolar lavage
  • Tissue biopsy
  • Growth at 37°C important
• Molecular methods:
  • PCR for Aspergillus DNA
  • Species identification
  • Resistance testing

Tissue Diagnosis

• Bronchoscopy with BAL:
  • Galactomannan in BAL fluid
  • Microscopy and culture
  • Transbronchial biopsy
• CT-guided biopsy:
  • For peripheral lesions
  • When bronchoscopy non-diagnostic
• Surgical biopsy:
  • Definitive diagnosis
  • When other methods fail
  • Therapeutic and diagnostic

Treatment Options

Treatment of aspergillosis depends on the type and severity of infection, immune status, and underlying conditions. Early treatment significantly improves outcomes.

Invasive Aspergillosis Treatment

• First-line therapy:
  • Voriconazole:
    • 6 mg/kg IV q12h x 2 doses, then 4 mg/kg q12h
    • Oral: 200 mg q12h
    • Therapeutic drug monitoring recommended
    • Watch for visual disturbances, liver toxicity
  • Isavuconazole:
    • 372 mg q8h x 6 doses, then 372 mg daily
    • Fewer drug interactions
    • Better tolerated than voriconazole
• Alternative therapy:
  • Liposomal amphotericin B (3-5 mg/kg/day)
  • Posaconazole (delayed-release tablets)
  • Caspofungin or other echinocandins
• Combination therapy:
  • Consider for salvage therapy
  • Voriconazole + echinocandin
  • Limited evidence for routine use

ABPA Treatment

• Corticosteroids:
  • Prednisolone 0.5-0.75 mg/kg/day x 2 weeks
  • Gradual taper over 3-6 months
  • Monitor IgE levels
  • Watch for steroid side effects
• Antifungal therapy:
  • Itraconazole 200 mg twice daily
  • Reduces steroid requirements
  • Continue for 3-6 months
  • Monitor liver function
• Newer therapies:
  • Omalizumab (anti-IgE)
  • Mepolizumab (anti-IL-5)
  • Dupilumab considerations

Chronic Pulmonary Aspergillosis Treatment

• Antifungal therapy:
  • Itraconazole 200 mg twice daily (first-line)
  • Voriconazole for itraconazole failure
  • Posaconazole as salvage therapy
  • Treatment duration: 6-12 months minimum
• Surgical resection:
  • For localized disease
  • Massive hemoptysis
  • Drug-resistant aspergillosis
  • High surgical risk in many patients
• Supportive care:
  • Pulmonary rehabilitation
  • Nutritional support
  • Management of hemoptysis
  • Bronchial artery embolization

Aspergilloma Treatment

• Observation:
  • For asymptomatic patients
  • Regular imaging follow-up
  • Monitor for symptoms
• Medical therapy:
  • Limited efficacy for aspergillomas
  • May prevent progression
  • Consider for poor surgical candidates
• Surgical resection:
  • Definitive treatment
  • For symptomatic disease
  • Recurrent hemoptysis
  • Good pulmonary reserve required

Adjunctive Measures

• Immune reconstitution:
  • Reduce immunosuppression if possible
  • G-CSF for neutropenia
  • Consider granulocyte transfusions
• Surgery indications:
  • Lesions near great vessels
  • Pericardial invasion
  • Massive hemoptysis
  • CNS lesions causing mass effect

Prevention

Prevention strategies focus on reducing exposure to Aspergillus spores and prophylactic treatment for high-risk patients:

Environmental Control

• Hospital measures:
  • HEPA filtration in high-risk units
  • Positive pressure rooms
  • Sealed windows and doors
  • Minimize construction exposure
  • Regular air quality monitoring
• Home environment:
  • Avoid water-damaged areas
  • Remove visible mold
  • Use HEPA filters
  • Avoid gardening/composting
  • Limit exposure to construction

Antifungal Prophylaxis

• High-risk patients:
  • Posaconazole for AML/MDS chemotherapy
  • Voriconazole for lung transplant
  • Consider for allogeneic HSCT
  • Duration based on risk period
• Monitoring during prophylaxis:
  • Regular liver function tests
  • Drug level monitoring
  • Watch for breakthrough infections
  • Resistance surveillance

Patient Education

• Recognize early symptoms
• Avoid high-risk activities
• Wear N95 masks in dusty environments
• Report exposures to healthcare team
• Medication compliance

Screening and Surveillance

• Regular galactomannan testing in neutropenia
• CT imaging for persistent fever
• Pre-emptive therapy strategies
• Post-treatment monitoring

When to See a Doctor

Early recognition and treatment of aspergillosis improve outcomes significantly, especially in immunocompromised patients:

Seek Immediate Medical Attention If:

• Persistent fever during neutropenia
• Coughing up blood (hemoptysis)
• Severe chest pain with breathing
• Sudden shortness of breath
• Confusion or neurological symptoms
• Black discharge from nose
• Vision changes with sinus symptoms

High-Risk Patients Should Contact Doctor For:

• New or worsening cough
• Fever not responding to antibiotics
• Unexplained weight loss
• Night sweats
• Worsening fatigue
• Any respiratory symptoms during immunosuppression

Patients with Lung Disease Should Report:

• Worsening asthma despite treatment
• Brown mucus plugs
• Recurrent respiratory infections
• Progressive breathlessness
• New wheezing patterns

Post-Treatment Monitoring:

• Side effects from antifungal medications
• Visual disturbances on voriconazole
• Skin changes or photosensitivity
• Abnormal liver function tests
• Return of symptoms

Related Conditions

References

1. Patterson TF, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases. 2016;63(4):e1-e60.
2. Cadena J, Thompson GR, Patterson TF. Aspergillosis: Epidemiology, Diagnosis, and Treatment. Infectious Disease Clinics of North America. 2021;35(2):415-434.
3. Agarwal R, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy. 2013;43(8):850-873.
4. Denning DW, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. European Respiratory Journal. 2016;47(1):45-68.
5. Kosmidis C, Denning DW. The clinical spectrum of pulmonary aspergillosis. Thorax. 2015;70(3):270-277.
6. Ullmann AJ, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clinical Microbiology and Infection. 2018;24(Suppl 1):e1-e38.