Allergic Bronchopulmonary Aspergillosis: Management Ritesh Agarwal, MD, DM Professor of Pulmonary Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India

Intended aims of this module To be aware of the different stages of allergic bronchopulmonary aspergillosis (ABPA) To be familiar with the management goals and treatment approaches for patients with ABPA To gain an understanding of the roles of glucocorticoids, antifungals and other adjunctive management options in ABPA

Introduction ABPA occurs in persons with asthma and those with cystic fibrosis ABPA may occur in conjunction with allergic fungal sinusitis (symptoms including chronic sinusitis with purulent sinus drainage) Patients often manifest with uncontrolled asthma, expectoration of mucus plugs, and haemoptysis Recurrent pulmonary infiltrates ( fever) unresponsive to antibacterial therapy suggests ABPA in patients with asthma and cystic fibrosis Patients with asthma and ABPA may have poorly controlled disease and difficulty tapering off oral corticosteroids Agarwal et al. Clin Exp Allergy. 2013; 43:850-873. Agarwal et al. Expert Rev Respir Med. 2016;10:1317-1334.

Diagnostic criteria for ABPA Predisposing conditions Bronchial asthma, cystic fibrosis Obligatory criteria (both should be present) Elevated A. fumigatus-specific IgE (>0.35 kUA/L) Elevated total IgE levels (>1000 IU/mL) Other criteria (at least two of three) Elevated A. fumigatus-specific IgG (>27 mgA/L) Radiographic pulmonary opacities consistent with ABPA Eosinophil count >500 cells/µL (may be historical) Agarwal et al. Clin Exp Allergy. 2013; 43:850-873. Agarwal et al. Expert Rev Respir Med. 2016;10:1317-1334.

Stages of ABPA Stage Definition Features 1 Acute Never diagnosed to have ABPA in the past; presentation with uncontrolled asthma/constitutional symptoms, and meeting the diagnostic criteria of ABPA 2   Response Clinical and/or radiological improvement AND fall in IgE by ≥25% of baseline at eight weeks 3 Exacerbation Clinical and/or radiological worsening accompanied by an increase in IgE by ≥50% from the ‘new’ baseline 4 Remission Sustained clinicoradiological improvement with IgE levels remaining at or below the ‘new’ baseline (or increase by <50%) for ≥6 months off therapy 5a Treatment-dependent ABPA Two or more relapses within six months of stopping treatment OR deterioration in clinical and/or radiological condition and/or immunological worsening on tapering oral steroids/azoles 5b Glucocorticoid-dependent asthma Systemic corticosteroids required for asthma control while the ABPA activity is controlled (as indicated by IgE levels and thoracic imaging) 6 Advanced ABPA Presence of complications (cor pulmonale and/or chronic type II respiratory failure) along with presence of extensive bronchiectasis Agarwal et al. Clin Exp Allergy. 2013; 43:850-873.

Management goals To optimise control of cystic fibrosis and exacerbation of asthma To avoid steroid dependency To improve airflow through reduction of mucus and obstruction To control bacterial infection (often associated with bronchiectasis) To control severity and exacerbation frequency of ABPA To avoid treatment (steroids and/or antifungal) related adverse events To control emergence of antifungal resistance Moss et al. Eur Respir J. 2014; 43:1487-1500. Denning et al. Clin Transl Allergy. 2014; 4:14. Agarwal et al. Clin Exp Allergy. 2013; 43:850-873.

Management approaches Control of the immune response Control of airway fungal burden Airway hypersensitivity syndrome; IgE mediated Approach Immunosuppression with oral steroids Reduced inflammation Anti-IgE therapy ? More fungus, more airway immune response Approach Antifungal therapy to decrease airway fungal burden Avoiding environmental exposures to fungal organisms Patterson et al. Clin Infect Dis. 2016; 63: e1-e60 Moss et al. Eur Respir J. 2014; 43:1487-1500.

Management: Glucocorticoids Oral glucocorticoids reduce the inflammatory response in acute stage (stage 1) and exacerbations (stage 3) of ABPA Mainstay of ABPA management Inhaled steroids are not effective (can control asthma in some patients). Many short and long-term adverse events Relapse is frequent after discontinuation Greenberger et al. J Allergy Clin Immunol Pract. 2014;2:703-708. Agarwal et al. Chest. 2009;135:805-826

Management: Antifungals Adding oral itraconazole to steroids in patients with recurrent or chronic ABPA may be helpful This may allow more rapid resolution of infiltrates and symptoms, facilitating steroid tapering or lowering the required dose of maintenance corticosteroids Relapse after improvement during antifungal therapy is common; Long-term suppressive therapy may be necessary Therapeutic azole monitoring is recommended to optimise ABPA control and avoid emergence of resistance In CF patients with ABPA, the concomitant use of itraconazole and inhaled steroids may precipitate Cushing’s syndrome Moreira et al. Clin Exp Allergy. 2014; 44:1210-1227. Stevens et al. N Engl J Med. 2000; 342:756-762.

Management: Antifungals Indications for itraconazole in ABPA Recurrent exacerbations Glucocorticoid-dependent ABPA Transformation to CPA Alternative to steroids in acute-stage ABPA in those at-risk for steroid complications Itraconazole solution is preferred in CF patients because of poor absorption of capsules. Patients who fail itraconazole, or are intolerant to itraconazole, may respond to voriconazole, posaconazole, or inhaled amphotericin B Chang et al. Curr Allergy Asthma Rep. 2013;13:152-61. Agarwal et al. Expert Rev Respir Med. 2016;10:1317-1334.

Management: Itraconazole vs. Placebo Higher response in the itraconazole group (46%), compared to the placebo group (19%, P=0.04) The rate of adverse events was similar in the two groups Stevens et al. N Engl J Med. 2000; 342:756-762.

Management: Itraconazole vs. Prednisolone Composite response was significantly higher in the prednisolone group compared with the itraconazole group (100% vs 88%; P = .007) The rate of adverse events was higher in the glucocorticoid arm Prednisolone was more effective in inducing response than itraconazole in acute-stage ABPA Agarwal et al. Chest. 2018:S0012-3692(18)30077-1.

Omalizumab 13 patients with chronic ABPA randomized to 4-month treatment with omalizumab (750 mg monthly) or placebo Exacerbations occurred less frequently Mean FeNO decreased Basophil sensitivity to A. fumigatus decreased significantly after omalizumab but not after placebo Voskamp et al. J Allergy Clin Immunol Pract 2015; 3: 192-199

Management: Surgical care Areas of mucoid impaction in ABPA may have a mass-like appearance and are sometimes resected as an undiagnosed lung mass; however, steroid therapy and oral itraconazole therapy are preferred. Patients who have associated allergic fungal sinusitis benefit from surgical resection of obstructing nasal polyps and inspissated mucus in addition to corticosteroid therapy. Nasal washes with amphotericin or itraconazole have also been employed Allergic fungal sinusitis usually requires endoscopic sinus surgery to improve drainage

Other treatment additions in ABPA Azithromycin Reduces cough and sputum production Nebulized hypertonic saline May help clears sputum in some patients Vaccination Haemophilus influenzae / Pneumococcal vaccines Prevents exacerbation Kellett et al. Respir Med. 2005; 99:27–31.

Stage-wise management of ABPA Stage 1: Acute • Prednisolone 4-16 weeks • Total IgE follow-up every 8 weeks for 1 year Stage 2: Response • Management of underlying CF or Asthma Stage 3: Exacerbation • Same management as Stage 1 • Prednisolone: daily for 2 weeks, then every other day for 8 weeks Total serum IgE should be repeated after the initial 8 weeks of corticosteroid therapy, then every 8 weeks for 1 year Stage 4: Remission • Management of underlying CF or Asthma Stage 5: Corticosteroid-dependent asthma Oral corticosteroids, given indefinitely Stage 6: End-stage fibrosis • Daily oral corticosteroids An antifungal may be considered as a corticosteroid-sparing agent at any stage from 1 to 5 Agarwal et al. Expert Rev Respir Med. 2016;10(12):1317-1334. Virnig & Bush. Curr Opin Pulm Med.2007;13:67-71. Greenberger. J Allergy Clin Immunol. 2002;110:685-692.

Total IgE is a useful test for monitoring treatment response in ABPA Total IgE declines consistently from baseline to 2 months on therapy Aspergillus specific IgE values are variable Total IgE is a useful test in monitoring treatment responses in ABPA while A. fumigatus specific IgE has limited utility. Agarwal et al. Mycoses. 2016;59(1):1-6.

High-attenuated mucus in ABPA High-attenuation mucus (HAM) is a characteristic radiologic finding seen in patients with ABPA HAM impaction in ABPA is associated with initial serologic severity and frequent relapses Central bronchiectasis and HAM are independent predictors of recurrent relapses in ABPA Therapeutic flexible or rigid bronchoscopy may be required to relieve HAM. Agarwal et al. PLoS ONE. 2010; 5(12): e15346.

Summary The treatment of ABPA is directed at the inflammatory component caused by the hypersensitivity reaction to Aspergillus fumigatus Timely diagnosis and treatment can prevent the progression to end-stage ABPA The underlying asthma or cystic fibrosis (CF) should also be aggressively treated Corticosteroids are a cornerstone of therapy for exacerbations of ABPA Antifungal interventions in ABPA improved patient and disease outcomes in both asthma and cystic fibrosis Antifungals are considered an adjunctive but not primary therapy for APBA For patients with corticosteroid-dependent ABPA, addition of itraconazole leads to improvement in the condition without added toxicity

END