Approach
The treatment of allergic bronchopulmonary aspergillosis (ABPA) is directed at the inflammatory component caused by the hypersensitivity reaction to Aspergillus fumigatus, as well as antigen mitigation by reducing the fungal burden in the airways. Timely diagnosis and treatment can prevent progression to end-stage ABPA.[22] Underlying asthma or cystic fibrosis (CF) should be aggressively treated. Environmental control measures should be reviewed to ensure maximal mould spore avoidance. Specific therapy is based on the disease stage, the goals being to prevent progressive loss of lung function and to ameliorate symptoms.
Stage 1: acute
Patients with stage 1 disease are symptomatic with fever, cough, increased sputum production, haemoptysis, or chest pain. Investigations show infiltrates limited to the upper or middle lobe, and a markedly elevated serum IgE.[44]
The mainstay of treatment for ABPA is systemic corticosteroids to suppress the inflammatory response to A fumigatus. Evidence supporting this therapy is mostly from longitudinal case series.[7][45][46] The Infectious Disease Society of America (IDSA) recommends that first-line treatment of acute ABPA should include a combination of a corticosteroid plus antifungal therapy.[26]
Corticosteroids
In one case series, all patients responded to corticosteroids with a significant decline in IgE and resolution of infiltrates on chest imaging.[45] The optimal dose for systemic corticosteroids is not known as there have been no prospective or randomised trials to guide dosing regimens.
Measurement of total serum IgE should be repeated after the initial 6-8 weeks of corticosteroid therapy, then every 8-12 weeks for 1 year.[47] Any rise in serum IgE >100% over baseline suggests an exacerbation. If the total serum IgE level does not drop by >35% over 2 months of therapy, the patient may not be taking the corticosteroid as instructed, or another diagnosis should be considered, such as infection.[48] A chest x-ray or computed tomography (CT) scan of the chest should be repeated after 4-8 weeks of therapy to document clearing of infiltrates.[47]
Antifungal therapy
Azole antifungals (e.g., itraconazole, voriconazole, posaconazole) are effective against A fumigatus.
Itraconazole is used most commonly for the treatment of ABPA due to its better adverse-effect profile, tolerability, and because it is the most well studied. One RCT reported that prednisolone significantly increased the composite response rate, compared with itraconazole, in patients with ABPA (100% vs 88%; P=0.007).[49] Similar results were found for both treatments for percent decline in IgE at 6 weeks and 3 months, number of patients with exacerbations at 1 and 2 years, time to exacerbation, and the improvement of lung function at 6 weeks.[49] However, adverse effects were significantly higher for patients treated with prednisolone.
Evidence suggests that voriconazole or posaconazole are reasonable second-line therapies for ABPA. One retrospective review of adult asthmatic patients who were refractory to or had developed adverse effects to itraconazole treatment with ABPA. Both voriconazole and posaconazole demonstrated similar results for clinical response at 3, 6, and 12 months, and reduction in total IgE at 9 and 12 months.[50] Treatment with voriconazole and posaconazole may also improve asthma control and reduce severity.[50]
Therapeutic drug monitoring is recommended with voriconazole in combination with corticosteroids. Marked adrenal suppression has been seen with concomitant use of systemic corticosteroids and azole antifungals; both agents can cause adrenal suppression in their own right due to metabolism through CYP450.[51][52] In addition, azoles can increase the serum concentration of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, which is important for drug monitoring in CF patients.
If azole antifungals are unavailable or contraindicated, amphotericin-B deoxycholate and its lipid derivatives may be considered for initial therapy.[26] One systematic review concluded that amphotericin-B does not improve exacerbation-free status at 1 year. Although some evidence suggested that amphotericin-B treatment delayed the time to first exacerbation compared with the control arm, this result was not statistically significant.[53]
Stage 2: remission
This stage involves patients who have been successfully treated with oral prednisolone for acute ABPA (with or without antifungal treatment) or an exacerbation. Patients are asymptomatic or have stable asthma >6 months after stopping corticosteroids; no infiltrates are seen on chest imaging; and serum IgE may be elevated or normal.[44]
Treatment in this phase is targeted at the underlying asthma or CF. In patients with asthma, therapy may include inhaled corticosteroids and/or long-acting beta-agonists. In patients with CF, therapy may include corticosteroids and/or long-acting beta-agonists, along with mucus-clearance agents, antibiotics, non-steroidal anti-inflammatory drugs, and supplemental oxygen. Although inhaled corticosteroids are the mainstay of treatment for the airway inflammation of asthma, there is conflicting literature about their long-term impact on ABPA exacerbations, prevention of relapses, and maintenance of lung function.[54][55] Long-term treatment with systemic corticosteroids is not recommended, because it does not prevent new infiltrates.[5]
See Asthma in adults (Management approach), Cystic fibrosis (Management approach)
Stage 3: exacerbation
This may be diagnosed by an increase in total serum IgE >100% of baseline on routine monitoring, or by clinical symptoms of cough, dyspnoea, increased sputum, and fever.[48] Treatment is the same as for acute stage 1 ABPA.
In practice, flares may be asymptomatic and only noted due to the rise in IgE or new infiltrates on chest imaging. Treatment of flares is similar to treatment for the acute phase of ABPA, usually with systemic corticosteroids in combination with antifungal treatment (see stage 1: acute).
Stage 4: corticosteroid-dependent asthma
This stage is diagnosed when the patient cannot be weaned off prednisolone without exacerbation of asthma symptoms or persistence of elevated total serum IgE levels. In such circumstances, alternate treatments such as antifungal therapy (see stage 1) or biologicals may be indicated to help patients wean off corticosteroids.
In practice, off-label use of biological agents as a corticosteroid-sparing therapy may be used for patients with corticosteroid-dependent asthma who cannot taper off oral corticosteroids despite a course of antifungal therapy. Evidence from a retrospective chart review suggests that omalizumab, mepolizumab, dupilumab, or benralizumab may reduce the dose of, or eliminate the need for, corticosteroid treatment.[56]
Biologics may also be used in preference to antifungal therapy as a corticosteroid-sparing therapy for patients in whom antifungal treatment is contraindicated, such as those with liver disease, or those taking other treatments that interact with CYP450 inhibitors.[57][58]
Omalizumab
A monoclonal antibody directed against IgE that prevents IgE binding to receptors on effector cells. It is used for patients with allergic asthma who have asthma exacerbations despite maximal standard therapy. Case reports of its use in ABPA in patients with corticosteroid-dependent cystic fibrosis showed it to be a corticosteroid-sparing therapy with associated clinical improvements.[59][60][61] Trials of omalizumab in patients with asthma and ABPA demonstrated reductions in exacerbations of asthma and oral corticosteroid requirements, but in one study it did not improve spirometry.[62][63] However, there is a lack of evidence for the efficacy and safety of anti-IgE therapy for people with CF and APBA.[64]
Mepolizumab
The addition of mepolizumab, an interleukin (IL)-5 antagonist monoclonal antibody, at conventional doses for patients with severe asthma complicated by ABPA led to a significant decrease in peripheral eosinophil counts, an increase in FEV1, improvement in asthma control scores, and a significant reduction in exacerbations and oral corticosteroid dose.[65] In another small study of nine patients with ABPA, some of whom had failed treatment with antifungal therapy or omalizumab, all patients treated with an IL-5 antagonist had decreased exacerbations compared to the prior year, improved asthma-related quality of life, and reduced oral corticosteroid dose.[66] Reductions in IgE levels and mucus plugging have also been noted with the use of mepolizumab for treatment of ABPA.[67]
Dupilumab
Evidence from one case study demonstrates that dupilumab, an IL-4 antagonist monoclonal antibody, successfully treated patients with ABPA, often those who have failed conventional therapies or other biologics.[68] A multi-centre randomised clinical trial testing the efficacy of dupilumab in ABPA has been completed and results are currently being analysed.[69]
Benralizumab
Evidence from case series suggests that benralizumab, an IL-5 antagonist monoclonal antibody, successfully treats ABPA, and may be more effective than mepolizumab (another IL-5 antagonist) at clearing bronchial mucus plugs.[70][71]
Stage 5: end-stage fibrosis
This occurs when the patient is unable to be weaned off oral corticosteroids and there are obstructive and restrictive lung changes. Clinically, patients are dyspnoeic and appear cyanotic, with fibrotic, bullous, or cavitary lesions on chest imaging. Serum IgE may be normal. In practice, it is unlikely that end-stage fibrosis will respond to any immunomodulation. Patients may benefit from pulmonary rehabilitation, and oxygen supplementation as needed. A referral to a lung transplant centre should be considered.
Environmental control
Patients should be counselled to avoid areas of possible exposure to A fumigatus. Although ubiquitous in the environment, A fumigatus can be seen in particularly high quantities in dead and decaying organic matter such as compost piles. The patient's home should be assessed for damp and water damage, because this can encourage the growth of moulds of all types, including Aspergillus.[47][72] In practice, patients may be advised to keep indoor humidity below 50% as mould grows in humid environments. If mould is present in the home, professional remediation should be considered.
Comorbid conditions
Diagnosis and management of associated allergic rhinitis, sinusitis, and GORD may be of benefit in improving asthma control. GORD evaluation should be considered in patients who have poorly controlled asthma, especially with night-time symptoms. Treatment includes avoiding heavy meals (especially those with high fat content), caffeine, and alcohol; avoiding food and drink within 3 hours of sleep; elevating the head of the bed; and using acid-reducing medications. It should be noted, however, that a randomised controlled trial found treatment with esomeprazole (a proton-pump inhibitor) did not improve asthma control in patients who had poorly controlled asthma with minimal or no symptoms of gastro-oesophageal reflux.[73] See Gastro-oesophageal reflux disease (Management approach).
Rhinitis or sinusitis symptoms or diagnosis should be evaluated in patients who have asthma, because the inter-relationship of the upper and lower airway suggests that therapy for the upper airway will improve asthma control. Treatment of allergic rhinitis includes intranasal corticosteroids, antihistamine therapy, and possibly immunotherapy. Treatment of sinusitis includes intranasal corticosteroids and antibiotics. Evidence is inconclusive regarding the effect on asthma of sinus surgery in patients who have chronic rhinosinusitis.[74]
See Allergic rhinitis (Management approach) and Chronic rhinosinusitis without nasal polyps.
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