Allergic broncho‐pulmonary aspergillosis: Old disease, new frontiers

Allergic bronchopulmonary aspergillosis (ABPA) is a disease of the airways caused by type one hypersensitivity to Aspergillus fumigatus or other Aspergillus spp., occurring almost exclusively in individuals with asthma or cystic fibrosis (CF). The original treatise on ABPA published 70 years ago reported classical manifestations of intermittent pyrexia, brown sputum plugs, aspergillus sensitization, peripheral eosinophilia, migratory radiological opacities and progressive bronchiectasis.1 Recently, the International Society for Human and Animal Mycology (ISHAM) issued a new ABPA consensus guideline, prompting us to review current frontiers in epidemiology, diagnosis and treatment.2 How often do clinicians encounter ABPA? The answer to this is surprisingly complicated. The prevalence of ABPA generally has been estimated at 2.5%–11.3% in asthma patients, and 2%–15% of those with CF.3, 4 However, reported ABPA prevalence varies markedly by region. In India, the prevalence of ABPA among unselected people with asthma in secondary care is the highest in the world, at 16.2%.4 In contrast, at our tertiary asthma and allergy service in Melbourne, Australia, the prevalence of ABPA even among asthma patients with a total IgE >1000 IU/mL was only 15.8%, which suggests a much lower ABPA prevalence among unselected Australian asthma patients.5 How these intriguing regional differences in ABPA prevalence relate to environmental or genetic factors remains unclear, and further investigation may enhance our understanding of disease pathogenesis. It is also relevant to note that underlying asthma prevalence is an order of magnitude higher in Australia (11.2%) than India (0.84%). Therefore, screening recommendations from ISHAM—to perform aspergillus-specific IgE testing in all adults newly diagnosed with asthma—should be interpreted judiciously according to local context, taking into account the background prevalence of asthma and ABPA.2 When to consider an ABPA diagnosis? ISHAM recommends clinicians consider the possibility of ABPA in patients with either; predisposing conditions of asthma, CF, chronic obstructive lung disease and bronchiectasis; or a compatible clinic-radiological presentation, even in those without a predisposing diagnosis.2 Two essential criteria for diagnosis are proposed; positive A. fumigatus specific IgE ≥0.35 kUA/L and total IgE ≥500 IU/mL. Two of the following additional features are also needed; IgG against A. fumigatus, blood eosinophil count ≥500 cells/μL, or typical computer tomography changes of central and proximal cylindrical bronchiectasis with mucus plugging and high attenuation mucus, or fleeting opacities on chest x-ray. Other common radiological features are upper lobe predominance, atelectasis, air trapping, tree-in-bud changes, centrilobular nodules and pleuropulmonary fibrosis.2 Compared to the previous edition, the most significant change in the new diagnostic criteria is the halving of the total IgE threshold for diagnosis, from 1000 to 500 IU/mL, associated with increased diagnostic sensitivity from 91% to 98%, albeit at the expense of specificity.2 Again, precise test characteristics—and consequently, the optimum diagnostic threshold for total IgE—will vary considerably depending on the background prevalence of asthma, ABPA and alternative causes for elevations in total IgE such as atopic dermatitis.6 Are there new treatment approaches? The main goals of ABPA treatment are to reduce allergen exposure and burden, and suppress allergic inflammation to minimize progression of structural lung disease (Figure 1). In people with bronchiectasis and CF, adjunctive measures to improve mucus clearance also reduce the lower airway microbial burden and airway inflammation. Exposure to allergenic fungal spores should be minimized, by avoiding water damaged indoor environments or handling of garden mulch and damp organic matter. Oral antifungals help reduce fungal burden. Observational studies and randomized controlled trials of azoles including Ketaconazole, Itrazonazole, Voriconazole and Posaconazole all show benefit, reducing exacerbations, steroid requirements and total IgE over time.7-9 However, side effects and drug interactions may be significant; Posaconazole seems to be the agent tolerated best. Inhaled Itraconazole and newer antifungal agents are undergoing trials and may be future options. Allergic inflammation has traditionally been suppressed using systemic corticosteroids, with their attendant side effects.10 High dose Prednisolone (initiated at 0.75 mg/kg/day for 6 weeks, continued at 0.5 mg/kg/day for 6 weeks, tapered by 5 mg every 6 weeks and ceased after eight to 10 months) was previously thought necessary to induce remission. More recent randomized trial data show that medium dose Prednisolone (initiated at 0.5 mg/kg/day for 2 weeks, continued at 0.5 mg/kg alternate days for 8 weeks, tapered by 5 mg every 2 weeks and ceased after 3–5 months) achieves comparable remission rates with fewer side effects.11, 12 While corticosteroid therapy is generally effective for initial disease control, approximately 50% of patients relapse after treatment cessation, so it is often combined with antifungal treatment. The availability of monoclonal therapies targeting allergic and eosinophilic inflammation in severe asthma presents a potential avenue for treating ABPA without the toxicities of corticosteroids and antifungals. In a small crossover randomized controlled trial, targeting IgE with Omalizumab reduced ABPA exacerbations and exhaled nitric oxide.13 Australian registry data has shown that Omalizumab reduces exacerbations and oral corticosteroid use in severe asthma with fungal sensitisation, including in patients with ABPA.14 However, in patients on Omalizumab, ABPA activity can no longer be easily assessed using total IgE levels in the circulation, which are confounded by IgE bound to Omalizumab. Case series also suggest benefit with other biologics which target eosinophil accumulation, such as Mepolizumab, Benralizumab and Dupilumab. Trial results are pending following recent completion of a Phase II study of Dupilumab for ABPA.15 Pregnancy with ABPA presents a management dilemma, since azole antifungals are generally avoided, and systemic corticosteroids may provide inadequate disease control or cause unacceptable side effects. Here, the established safety profile of Omalizumab in pregnancy provides an attractive steroid-sparing treatment option.16 Azithromycin and other macrolide antibiotics reduce the frequency of exacerbations in both asthma and bronchiectasis, though their role in ABPA specifically is not defined.17, 18 Patients with bronchiectasis and mucus plugging benefit from airway clearance techniques applied regularly, mucolytics such as hypertonic saline, and where appropriate, bronchoscopic removal of inspissated plugs causing segmental or lobar collapse. In summary, clinicians managing patients with ABPA should acquaint themselves with local disease epidemiology, apply current diagnostic guidelines in clinical context, and await an imminent paradigm shift towards monoclonal biologic therapy based on maturing trial data. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians. Eve Denton has received speaker fees and unrestricted grants from Sanofi, Menarini, Boehringer Ingelheim and AstraZeneca in conjunction to Optimum Patient Care Global Limited. Peter Wark has received grant funding and speaker fees from AstraZeneca, Sanofi/Regeneron and Novartis. Mark Hew has received speaker fees, unrestricted grants and consultancy fees, from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi, Seqirus, Teva, Chiesi and Aravax, all paid to his employer Alfred Health.