Allergic Bronchopulmonary Aspergillosis and Allergic Fungal Disease

Allergic fungal disease is a group of hypersensitivity disorders caused by fungal antigens in the airways, mucosa, or lung, without tissue invasion. The prototype is allergic bronchopulmonary aspergillosis, a Th2 mediated hypersensitivity reaction to Aspergillus fumigatus in people with asthma or cystic fibrosis. Related disorders include allergic fungal rhinosinusitis, severe asthma with fungal sensitisation, allergic bronchopulmonary mycosis from other fungi, and hypersensitivity pneumonitis from inhaled fungal and other organic antigens.

Allergic bronchopulmonary aspergillosis affects about 1 to 3 percent of adults with asthma worldwide (an estimated 4 to 5 million people), and about 5 to 15 percent of patients with cystic fibrosis. Rates are higher in tuberculosis endemic regions and in patients referred to chest clinics.

It is frequently missed and treated as poorly controlled asthma or tuberculosis for years. Genetic susceptibility includes HLA-DR2 and HLA-DR5 alleles, interleukin 4 receptor alpha, interleukin 10, surfactant protein A, and CFTR variants.

Inhaled Aspergillus fumigatus conidia germinate in the mucus of the bronchi, and hyphae remain in the airway lumen without invading tissue. Aspergillus proteases and allergens disrupt the epithelium, and in a genetically susceptible person, a Th2 response follows, with interleukins 4, 5, and 13, eosinophils, and production of total IgE and Aspergillus specific IgE and IgG.

Mast cell degranulation causes bronchospasm, eosinophils and mucus plugging cause mucoid impaction, and repeated inflammation leads to central bronchiectasis and fibrosis. Cystic fibrosis airway mucus supports fungal growth.

Another approach grades disease by imaging into serological (no bronchiectasis), with bronchiectasis (central), with high attenuation mucus, and chronic pleuropulmonary fibrosis.

• Poorly controlled asthma with wheeze, cough, and breathlessness, despite adequate inhaled therapy and adherence.
• Expectoration of brown or golden plugs (mucus casts), in about 30 to 50 percent.
• Recurrent chest infiltrates, fever, pleuritic chest pain, and haemoptysis.
• Fatigue and weight loss, and peripheral eosinophilia.
• In cystic fibrosis, deterioration in lung function and new infiltrates that do not respond to antibacterial therapy.
• Many patients have few symptoms, and the diagnosis is made by screening asthma patients with skin tests or serology.

Consensus criteria (International Society for Human and Animal Mycology) require a predisposing condition (asthma or cystic fibrosis), and the following:

Additional tests:

• Aspergillus fumigatus specific IgG.
• Recombinant allergens (Asp f 1, Asp f 2, Asp f 3, Asp f 4, Asp f 6) that increase specificity for ABPA compared with sensitisation alone.
• Sputum culture and microscopy for eosinophils and hyphae.
• Skin prick testing, and spirometry.

Screening of asthma: skin prick testing or specific IgE for Aspergillus fumigatus in all patients with difficult to control asthma, and measurement of total IgE where sensitisation is found. A normal total IgE (under 500 IU per mL) in a steroid naive patient excludes the disease in most cases.

The aims are to suppress the immune response (corticosteroids), reduce fungal burden (antifungals), control asthma, prevent progression to fibrosis, and detect exacerbations.

Corticosteroids

Response is judged by clinical improvement within 2 to 6 weeks, clearing of infiltrates within 4 to 8 weeks, and a fall in total IgE of 35 percent or more by 6 weeks. Measure IgE every 6 to 8 weeks for the first year and then every 3 to 4 months.

Remission is a sustained symptom and radiological response with IgE at least 50 percent below baseline for 6 months off treatment.

Corticosteroid side effects require attention: bone protection (calcium, vitamin D, and a bisphosphonate where long term), glucose, blood pressure, adrenal suppression, mood, infection, and Pneumocystis prophylaxis in selected patients.

Antifungal therapy

Antifungals alone are less effective than steroids in acute disease, and they do not replace them in the first episode of ABPA.

Biologics

• Omalizumab (anti IgE) 150 to 600 mg subcutaneously every 2 to 4 weeks (dose by body weight and total IgE) reduces exacerbations and steroid requirements, with limited randomised evidence. Total IgE measurements become unreliable (free IgE is needed) during therapy.
• Dupilumab, mepolizumab, benralizumab, and tezepelumab have been used in steroid dependent or refractory disease, with case series evidence.

Maintenance and follow up

Treatment of asthma (inhaled corticosteroid with long acting bronchodilator, add on therapy) and of bronchiectasis (airway clearance), avoidance of heavy fungal exposure where possible, regular IgE and imaging follow up, and spirometry. A patient in remission is monitored every 3 to 6 months for the first years, and relapses occur in 20 to 50 percent. Long term complications include bronchiectasis, fibrosis, respiratory failure, and pulmonary hypertension.

Allergic fungal rhinosinusitis is a non invasive hypersensitivity reaction to fungal antigens in the sinuses of atopic, immunocompetent people, with thick eosinophilic mucin and polyposis. Causes include dematiaceous fungi (Bipolaris, Curvularia, Exserohilum, and Alternaria) and Aspergillus species, and it is common in warm and humid regions, including India, the Middle East, and the southern United States.

• Diagnostic criteria:
  • type I hypersensitivity (skin tests or specific IgE)
  • nasal polyposis
  • characteristic computed tomography (heterogeneous hyperdense material with "double density" signs, expansion and thinning of sinus walls, and erosion in some)
  • eosinophilic mucin with fungal hyphae on stain (Grocott methenamine silver) without tissue invasion
  • fungal growth in culture in many cases
• Clinical features: chronic nasal obstruction, rhinorrhoea with thick brown or green mucus, anosmia, headache, facial pressure, proptosis, and, in some, eyelid or facial deformity in young people. Total IgE is often raised.
• Treatment:
  • functional endoscopic sinus surgery with removal of mucin and polyps
  • perioperative and postoperative corticosteroids (oral prednisolone 0.5 mg per kg daily tapered over 2 to 8 weeks, or longer in recurrent disease)
  • intranasal corticosteroid sprays and saline or budesonide irrigations
  • antihistamines
  • in recurrent or refractory disease, itraconazole 200 mg daily for 3 to 6 months (limited and mixed evidence), immunotherapy (limited), and biologics (omalizumab, dupilumab)
• Recurrence: frequent, and long term follow up with endoscopy is needed.