|Year : 2020 | Volume
| Issue : 2 | Page : 91-100
Allergic bronchopulmonary aspergillosis: A systematic review of its management with a call to action in Saudi Arabia
Saad Mohammed AlShareef
Department of Medicine, College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia; Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia
|Date of Submission||01-Nov-2019|
|Date of Decision||16-Dec-2019|
|Date of Acceptance||13-Jan-2020|
|Date of Web Publication||02-Apr-2020|
Saad Mohammed AlShareef
Department of Medicine, College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh; Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria
Source of Support: None, Conflict of Interest: None
Allergic bronchopulmonary aspergillosis (ABPA) is a relatively common, but underdiagnosed allergic complication of asthma and cystic fibrosis, occurring in about 13% and 9% of cases, respectively. Significant progress has been made over the last decade in establishing diagnostic criteria and a pragmatic clinical approach to its management with steroids, antifungals, and newer agents, including anti-immunoglobulin E (IgE) monoclonal antibodies. In spite of this, there is very little literature on ABPA in Saudi Arabia, and the few papers that do exist suggest that ABPA may be associated with Aspergillus species other than Aspergillus fumigatus. This is of particular concern since the recommended current diagnostic screening is based on A. fumigatus-specific IgE levels, and other Aspergillus species may have different clinical profiles. This article provides an overview of ABPA for the practicing physician, provides an up-to-date review of randomized controlled trials in ABPA, and highlights urgent research priorities for ABPA in Saudi Arabia.
Keywords: Allergic bronchopulmonary aspergillosis, Aspergillus, asthma, cystic fibrosis
|How to cite this article:|
AlShareef SM. Allergic bronchopulmonary aspergillosis: A systematic review of its management with a call to action in Saudi Arabia. J Nat Sci Med 2020;3:91-100
|How to cite this URL:|
AlShareef SM. Allergic bronchopulmonary aspergillosis: A systematic review of its management with a call to action in Saudi Arabia. J Nat Sci Med [serial online] 2020 [cited 2021 Oct 19];3:91-100. Available from: https://www.jnsmonline.org/text.asp?2020/3/2/91/279649
| Introduction|| |
Pulmonary reactions to the opportunistic fungus Aspergillus fumigatus occur along a spectrum of disease states from chronic aspergillosis (aspergilloma, Aspergillus nodules, and chronic cavitating/chronic fibrosing pulmonary aspergillosis) to invasive (acute, subacute, and chronic) and allergic (allergic bronchopulmonary aspergillosis [ABPA], hypersensitivity pneumonitis, and asthma with fungal sensitization) [Figure 1]. ABPA lies firmly at the allergic end of the spectrum, representing a complex immunological reaction to not only A. fumigatus but also other fungi and yeasts in the airways of patients with preexisting lung pathology, especially asthma and cystic fibrosis (CF).
ABPA was originally described in 1952 as a series of three patients with recurrent wheeze, pulmonary infiltrates, and blood and sputum eosinophilia. ABPA has since challenged clinicians in terms of pathoetiology and risk factors, relationship with other diseases, diagnostic difficulties, clinical features, and management. Many of these issues remain unresolved, hampering the identification and management of this disease which, if left undiagnosed and undertreated, can result in severe pulmonary fibrosis, bronchiectasis, and increasingly severe asthma with loss-of-lung function. Further, the disease is relatively common, so there are significant but unquantified individual and societal costs.
This prompted this review of the pathoetiology, clinical features, diagnostic criteria, and management of ABPA to refresh clinical knowledge about this important but underrecognized condition. The article contains a systematic literature search of randomized clinical trials to present the best available evidence to physicians on the management of ABPA and to establish the current evidence base for therapeutic use. The review reveals that there are almost no studies on ABPA in Saudi Arabia which, as well as suggesting that the disease may be underdiagnosed and poorly appreciated, also reveals that ABPA may be related to Aspergillus species other than Aspergillus flavus, raising questions about the validity and utility of current diagnostic criteria. Key areas for further clinical and basic research to improve outcomes for patients with ABPA in Saudi Arabia are discussed.
| Pathoetiology, Genetics, and Risk Factors|| |
The pathogenesis of ABPA remains incompletely understood but can be regarded in terms of a pathogen–host–immune response triad. Aspergillus is an ubiquitous airborne saprophytic fungus measuring 3–5 μm in diameter and present in the soil, compost, grass, and sewerage plants. Given their size, the spores are readily inhaled into the lower respiratory tract which, when not cleared by intact clearance mechanisms and innate immune defenses, provides the ideal temperature for sporulation in susceptible hosts. Patients with asthma and CF have severely disrupted innate and adaptive immunity, allowing spores to persist.
While the Aspergillus conidia are coated with rod A hydrophobin and melanin, rendering them immunologically inert, growing fungal hyphae synthesize proteins that (i) cause tissue damage and (ii) are recognized by the innate immune system. These proteins include pathogen-associated molecular patterns (PAMPs) such as β-glucan, chitin, galactomannan, and galactosaminogalactan. PAMPs are recognized by epithelial cells and antigen-presenting cells (APCs) such as dendritic cells (DCs) through surface pattern recognition receptors (PRRs) including Toll-like receptors, which when engaged trigger intracellular cascades to activate the APCs to release cytokines and chemokines.
Under “normal” pathogen clearance circumstances, APCs activate CD4 T-cells to a T-helper 1 (Th1) pro-inflammatory phenotype, which helps to clear the fungus. However, in ABPA, the hosts mount a predominantly Th2 response to the fungus through a series of signaling cascades, including reduced interferon-β signaling through the Janus kinase/signal transducers and activators of transcription pathway and consequently reduced CXCL10 expression., A competing hypothesis is that Aspergillus conidia activates an alternative (complement receptor 3) PRR pathway to mount a Th2 response. Regardless of the initiating molecular event, activated epithelial cells and DCs drive the Th2 response via the chemokine CCL17 binding to CCR4 on Th2 cells and Th2 cytokines including IL-4., This response fails to clear the fungus but instead establishes an active chronic inflammatory response, characterized by neutrophils, eosinophils, and B-cells that produce immunoglobulin E (IgE) antibodies, which degranulate mast cells and basophils, ultimately stimulating mucus production and bronchoconstriction and establishing a persistent chronic inflammatory process.
In meta-analyses, 12.9% (95% confidence interval [CI]: 7.9–18.9) of asthmatics and 8.9% (95% CI: 7.4–10.7) of patients with CF can be diagnosed with ABPA, although the wide CIs for ABPA in asthma reflect the variable estimates in the different studies. Given that all individuals with asthma and CF are exposed to Aspergillus but not all of them develop ABPA, it seems likely that there are genetic susceptibility factors. In one study of 164 ABPA patients, 5% were identified as familial, and a number of polymorphisms and mutations in innate immunity genes have been associated with ABPA., Heterozygous mutations in the CF-causing gene CFTR are enriched in ABPA patients as compared to asthmatics or the background population, and some protective and predisposing HLA haplotypes have been identified in CF patients rendering them more or less susceptible to developing ABPA.,
| Clinical Features of Allergic Bronchopulmonary Aspergillosis|| |
ABPA primarily occurs in patients with existing CF or asthma, although cases have been described in association with chronic obstructive pulmonary disease (COPD; in about 1%) and post-tuberculosis (TB) fibrocavitary disease;, the clinical implications of these other disease associations remain uncertain. Classical ABPA presents with recurrent episodes of wheezing and poorly controlled asthma, fever, malaise, fatigue, weight loss, and hemoptysis. 31%–69% of patients also describe coughing brownish mucous plugs. However, patients may exhibit few if any of these symptoms, especially in the context of asthma; in one case series, 19% of patients with ABPA were regarded as having well-controlled asthma. In CF, ABPA is associated with a deteriorating clinical condition with usually nonspecific symptoms but reduced lung function, pneumothorax, hemoptysis, and poor nutritional status. On examination, auscultation is likely to reveal wheezing and rhonchi in asthmatic patients and crepitations in CF patients, although again the features are nonspecific.
Due to this nonspecific presentation, the differential diagnosis is often wide, particularly in asthmatic patients. The differential diagnosis includes severe exacerbation of asthma, asthma with fungal sensitization, pneumonia, chronic pulmonary Aspergillosis, bronchiectasis, chronic eosinophilic pneumonia, COPD, Churg–Strauss syndrome, bronchocentric granulomatosis, TB, and hypersensitivity pneumonitis. It is also perhaps unsurprising that ABPA has historically been seriously underdiagnosed, with diagnostic delays of up to 10 years in some studies. Furthermore, as many as a third of cases have been misdiagnosed as TB in developing countries. It is unknown how prevalent ABPA is in Saudi Arabia or how aware of the condition physicians are.
| Diagnostic Criteria|| |
Recognizing that there are no pathognomonic features for ABPA, there have been two main attempts to establish diagnostic criteria for ABPA. The oldest and most widely used until recently were the Patterson criteria, which has eight major and three minor criteria: major criteria – (i) asthma; (ii) presence of transient pulmonary infiltrates (fleeting shadows); (iii) immediate cutaneous reactivity to A. fumigatus; (iv) elevated total serum IgE; (v) precipitating antibodies against A. fumigatus; (vi) peripheral blood eosinophilia; (vii) elevated serum IgE and IgG to A. fumigatus; and (viii) central/proximal bronchiectasis with normal tapering of distal bronchi; minor criteria – (i) expectoration of golden-brownish sputum plugs; (ii) positive sputum culture for Aspergillus species; and (iii) late (Arthus-type) skin reactivity to A. fumigatus. However, growing clinical experience and a lack of agreement over the number of criteria required for diagnosis prompted the International Society of Human and Animal Mycology (ISHAM) to form the “ABPA in asthmatics” working group, who reported revised diagnostic and classification criteria in 2013. These revised criteria, further refined in 2016, adopted an integrated clinical, radiological, and immunological approach; since as noted above, patients can show minimal symptoms in asthma or significant crossover with CF lung disease in CF and the radiological features are often transient and nonspecific.
The ISHAM group diagnostic criteria for ABPA are summarized in [Table 1]., First, predisposed asthmatic and CF individuals should first undergo screening for sensitization to A. fumigatus. While skin prick or intradermal testing has been used as the screening tool, its suboptimal sensitivity of approximately 90%, lack of standardization, and risk of anaphylaxis disfavor its use. Instead, A. fumigatus-specific IgE titers are recommended as a screening test; the ISHAM working group recommended a cutoff of >0.35 kUA/L, which was subsequently validated and shown to have a sensitivity of 100% and a specificity of 66.2%. Total IgE is less useful as a screening test due to difficulties in establishing reliable cutoff values and interindividual variability in normal IgE levels; however, a total IgE >1000 IU/mL is then used as a diagnostic criterion for ABPA in asthma. According to the ISHAM criteria, both a positive screening test and a total IgE >1000 IU/mL are required to secure the diagnosis.
|Table 1: Updated diagnostic criteria for allergic bronchopulmonary aspergillosis|
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In terms of secondary criteria, while eosinophil counts are a poor screening tool, again due to nonspecificity and wide normal variability, the ISHAM working group suggested a cutoff of >500 cells/μL. Likewise, the presence of A. fumigatus-specific IgG antibodies can help to support the diagnosis, with a sensitivity and specificity of 89% and 100%, respectively, with a cutoff of 27 mgA/L.
Imaging is also useful for supporting the diagnosis, although again there are no pathognomonic features for ABPA. Chest radiography is normal in 50% of ABPA cases; however, when fleeting or “finger-in-glove” opacities due to mucoid impaction are present in asthmatic patients, this is highly suggestive of ABPA. However, high-resolution computed tomography is the preferred modality, revealing not only the bronchiectasis and mucoid impactions characteristic of the disease, but also the distribution of the disease, which is important since central bronchiectasis is a classical ABPA sign., Magnetic resonance imaging is reserved for those patients in whom radiation exposure needs to be limited, such as pregnant women and children.
In addition to diagnostic criteria, the ISHAM working group also developed a nonsequential clinical staging system of ABPA for patients with asthma: Stage 0, asymptomatic; Stage 1, acute with (1a) or without (1b) mucoid impaction; Stage 2, response; Stage 3, exacerbation; Stage 4, remission; Stage 5a, treatment-dependent ABPA; Stage 5b, glucocorticoid-dependent asthma; and Stage 6, advanced ABPA. These stages are useful not only for clinical trial purposes as outcome measures but also practically when considering management decisions; for instance, Stage 5 disease warrants prolonged therapy with additional agents such as itraconazole or omalizumab, an anti-IgE monoclonal antibody.
Although the ISHAM criteria represent a noteworthy development and are a huge step forward in standardizing the diagnosis of ABPA for future clinical and research studies, there remain difficulties in applying the criteria in practice; indeed, only about two-thirds of cases of diagnosed as ABPA met the ISHAM criteria in one retrospective study. Therefore, validation and universal application of ISHAM criteria are still evolving.
| Diagnosis and Impact on Prevalence Estimates: the Saudi Perspective|| |
Although some disagreement still exists in terms of diagnostic criteria for ABPA, particularly around the areas of assay standardization and cut-point validation, these developments in diagnostic criteria over the last few years take the field closer to the consensus clinical guidelines. As well as aiding practical clinical decision-making, robust diagnostic criteria allow improved assessments of disease prevalence and therefore individual and healthcare burden. With respect to the current prevalence estimates, there have been two major meta-analyses of the prevalence of ABPA - one in asthma and one in CF. In asthma, with the caveat of diagnostic variability resulting in significant statistical heterogeneity, ABPA prevalence ranged from 2% to 32%, with a pooled prevalence of 12.9% (95% CIs: 7.9–18.9) and a higher prevalence in industrialized countries (25.6%) than developing countries (12.7%). In CF, the prevalence of ABPA ranged from 2% to 25%, with a pooled prevalence of 8.9% (95% CIs: 7.4–10.7), significantly higher in adults than in children (10.1% vs. 8.9%, P < 0.0001). Again, statistical heterogeneity was high.
These estimates, at least in the case of asthma, are likely to be high given that most of the studies were of tertiary hospital populations enriched for more severe disease. The population prevalence has been more difficult to determine but would be of considerable interest for the purposes of implementing screening, healthcare expenditure planning, and early administration of antifungals to reduce associated morbidity and mortality in Stage 0 disease. In this regard, there have been a few attempts to estimate population-level burden of ABPA. For instance, Agarwal et al. estimated a burden of 0.12–6.09 million ABPA individuals in a population of 1.2 billion in India. Denning et al. estimated a global burden of 4.8 million ABPA patients. There is clearly a need for prospective population and clinical cohort studies to precisely define the prevalence of ABPA using the latest diagnostic criteria.
As across the globe, the prevalence of asthma is increasing in Saudi Arabia; therefore, the prevalence of ABPA in Saudi Arabia is also likely to be increasing and constitute a significant but underdiagnosed healthcare burden. Asthma is a significant disease in Saudi Arabia, with an estimated prevalence of 4%. Despite asthma being relatively common in Saudi Arabia, there is very little literature on ABPA, suggesting that there is relatively low awareness of the condition. Using old diagnostic criteria, Al-Mobeireek et al. estimated a 2.7% (95% CIs: 1.3%–5.4%) period prevalence of ABPM in 264 patients attending a tertiary asthma outpatient clinic. Interestingly, Aspergillus niger was more frequently isolated than A. fumigatus in this study, and women were more likely to be affected than men. The only other two studies on ABPA in Saudi Arabia are a single case report of ABPA mimicking TB and a retrospective review of asthmatics attending a tertiary university hospital in Saudi Arabia: Only ten ABPA cases were identified over a 9-year period, with only one case due to A. fumigatus while the others due to A. flavus, Aspergillus terreus, and A. niger.
Therefore, there is an urgent need for clinical and microbiological ABPA studies in Saudi Arabia, not only to optimally diagnose and manage the local population, but also because these limited data suggest that the new diagnostic criteria – which rely on A. fumigatus-specific IgE titers - may not be readily applicable to this population and might underdiagnose ABPA. Central Arabia is known to have low average humidity that can inhibit the growth of Aspergillus species, with marked geographic variation in skin prick positivity for Aspergillus in the dry central region compared to the more humid coastal region (2% vs. 35%). Different Aspergillus species in different geographic regions may also in part explain findings, like the higher prevalence in industrialized countries than developing countries. Supporting different geographical distributions of Aspergillus, Sehgal et al. reported that 30% of ABPA cases were due to A. flavus in 53 subjects investigated in Northern India, and these patients had a slight different clinical profile, being more likely to have high-attenuation mucus and a trend toward higher occurrence of sinusitis. Although the antigens used in A. fumigatus-specific IgE tests are known to cross-react with other Aspergillus species, given the reliance on this test for screening, it will be important to establish the range of causative organisms in different populations and the sensitivity and specificity of current assays for these organisms of interest, especially if they produce different disease phenotypes. A screening approach using highly A. fumigatus-specific IgE assay might miss cases in which A. fumigatus is not the causative organism, so ISHAM diagnostic guidelines may not be entirely suitable in the Saudi population.
| Management|| |
ABPA must be managed using a two-pronged approach, as summarized in [Figure 2]: (i) controlling the immune response to manage symptoms and prevent the development of immune reaction-mediated complications and (ii) decreasing the burden of organisms to decrease host exposure to the stimulus. Given that asthma and CF are chronic disorders and ABPA superimposes on these conditions as repeated acute exacerbations, therapy is long term and should not only control the underlying asthma or CF but also treat the acute exacerbation, prevent further exacerbations, and prevent progression to bronchiectasis and end-stage lung disease. The heterogeneity in the predisposing condition, severity and frequency of exacerbations, response to therapy, side effects of therapy, and emergence of antifungal resistance mandate that management must be individually tailored to optimize outcomes.
|Figure 2: The two-pronged management strategy for allergic bronchopulmonary aspergillosis|
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The 2016 Infectious Diseases Society of America Practice Guidelines on the management of aspergillosis recommend oral corticosteroids to reduce the inflammatory response in ABPA, with inhaled corticosteroids to control asthma in the relevant population. Itraconazole is recommended as the first-line antifungal in symptomatic patients, CF patients with low forced expiratory volume (FEV1), and ABPA complicated by mucoid impaction, bronchiectasis, or chronic pulmonary aspergillosis. In CF patients, itraconazole solution is preferred to capsules due to poor absorption of the latter. Voriconazole, posaconazole, or inhaled amphotericin B is recommended in itraconazole-resistant or -intolerant patients. Symptomatic relief can be achieved with nebulized hypertonic saline.
Given these relatively vague guidelines, a comprehensive search was conducted for randomized controlled trials (RCTs) on the management of ABPA through the PubMed online database utilizing the following terms: “ABPA” AND “randomized controlled trial.” After obtaining the full-text articles, data were extracted including the study title, year of publication, author, objectives, design, patient population, duration, site, intervention description, and findings pertaining to outcomes of interest. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was used to guide the systematic review. Due to variability in interventions, patient populations, and outcome measures, extracted data were summarized descriptively. Conclusions were drawn based on qualitative synthesis of the findings.
Of 30 English-language papers identified in the original search, eight were RCTs [Figure 3].,,,,,, The studies and their results are summarized in [Table 2]. The main groups of agents studied were corticosteroids, antifungals, and anti-IgE therapy (e.g., omalizumab), the latter being monoclonal antibodies toward IgE that prevents IgE binding to high-affinity FcεRI receptors on the surface of mast cells and basophils and currently used in severe asthma., The results can be summarized as follows: (i) with respect to antifungal use, there is RCT evidence that itraconazole improves responses without additional toxicity while also reducing cellular and biochemical markers of airway and systemic inflammation (sputum eosinophil counts, sputum eosinophil cationic protein, serum IgE, and A. fumigatus-specific IgG), and nebulized amphotericin B plus nebulized budesonide (vs. nebulized budesonide alone) decreases the frequency of exacerbations; (ii) with respect to antifungal versus glucocorticoid use, prednisolone more effectively induced responses than itraconazole in acute-stage (diagnosed for the first time) ABPA, but itraconazole alone was also effective in a considerable number of patients and with fewer side effects; (iii) with respect to glucocorticoid use, medium-dose corticosteroids (oral prednisolone 0.5 mg/kg/day for 2 weeks followed by 0.5 mg/kg on alternate days for 8 weeks, then taper by 5 mg every 2 weeks and discontinue after 3–5 months) are as effective as high-dose glucocorticoids (0.75 mg/kg/day for 6 weeks followed by 0.5 mg/kg/day for 6 weeks, then taper by 5 mg every 6 weeks and discontinue after 8–10 months) both in terms of exacerbation rates and glucocorticoid-dependency, but with fewer side effects; and (iv) omalizumab appears to be effective in patients with ABPA. Two studies had negative results: An early study of nebulized natamycin versus placebo in terms of sparing steroids (no difference between groups); and Vitamin D, low levels of which are associated with poor asthma control and ABPA in patients with CF, did not significantly affect total IgE levels or exacerbations compared to control (prednisolone alone).
|Figure 3: Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart of the search for randomized trials on allergic bronchopulmonary aspergillosis|
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|Table 2: Randomized controlled trials of therapies for allergic bronchopulmonary aspergillosis|
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Despite these data being the best available, the studies were small and several were nonblinded, single institution, and conducted by the same research group. There are, therefore, significant sources of bias in these data. Other clinical trials are ongoing or have not yet reported (clinicaltrials.gov identifiers: NCT02440009, A Randomized Trial of Itraconazole in Acute Stages of ABPA; NCT01621321, Voriconazole versus Oral Steroids in ABPA; NCT02273661 Evaluation of a Therapeutic Strategy Including Nebulized Liposomal Amphotericin B [Ambisome®] in Maintenance Treatment of ABPA [CF Excluded]; NCT03960606, Study in Adult Asthmatic Patients With ABPA). It should also be noted that that there is emerging literature, although not yet tested in randomized trials, on combined anti-IgE and anti-interleukin (IL)-5 therapy for patients with treatment-resistant ABPA.
These and other data and clinical experience suggest that a pragmatic approach to the management of ABPA is:
- All patients should receive oral prednisolone administered at a dose of 0.5 mg/kg/day for 2 weeks followed by 0.5 mg/kg/day on alternate days for 8 weeks, then tapered by 5 mg every 2 weeks to complete a total steroid duration of 3–5 months, with the caveat that a small proportion of patients in this regimen may not respond adequately and thus may require higher doses
- Inhaled steroids should not be used in place of oral steroids but instead reserved for controlling asthma symptoms in ABPA
- Itraconazole can be used for initial therapy of ABPA in asthmatic patients with bronchiectasis or mucoid impaction and CF patients with frequent exacerbations and/or falling FEV1; antifungal trough levels should be measured to ensure adequate absorption and avoid toxicity. However, in other patients, itraconazole can be reserved for exacerbations and glucocorticoid-dependent disease
- Omalizumab can be reserved for patients with recurrent exacerbations or treatment-dependent ABPA
- Nebulized amphotericin B can be reserved for patients in whom alternatives have been exhausted.
Patients should be closely monitored with serum IgE levels, chest X-rays, and lung function testing, aiming for a decrease in IgE of about 25%, since this is associated with clinical, spirometric, and radiological improvements, recognizing that about half of patients experience an exacerbation.
| Conclusions and Future Directions|| |
ABPA remains a clinical challenge although clear progress is being made in terms of diagnosis and management. This concise review of ABPA summarizes the most important aspects of the condition for clinical teams in Saudi Arabia and represents an important step in raising awareness about ABPA in the country. Although the systemic review was limited to management only, the discussion raises a number of general and Saudi Arabia-specific clinical issues and challenges that need to be addressed:
- There are only limited data on ABPA in Saudi Arabia, and the little that does exist suggests that there might be important geographic differences that might impact the diagnosis and clinical presentation
- Therefore, studies that explore the incidence of ABPA due to fungal species other than A. fumigatus in Saudi Arabia, and their association with clinical presentation, course, and severity, are urgently required
- Studies are also required to assess the sensitivity and specificity of current A. fumigatus-specific IgE assays with respect to different Aspergillus species to establish how applicable they are to the Saudi population
- Given that the exact prevalence of ABPA in Saudi Arabia is currently unknown but could constitute a significant healthcare burden, prospective population and clinical cohort studies are required to precisely define the prevalence of ABPA in Saudi Arabia using the latest diagnostic criteria. This will help with healthcare utilization, planning, implementing screening, and policy-making
- Given the nonspecific nature of ABPA presentation, all patients with asthma should routinely be screened for ABPA using A. fumigatus-specific IgE levels or, if other organisms are implicated, relevant screening tests that have sufficient sensitivity for the target population
- New technologies such as deep sequencing should be employed to discover susceptibility factors and diagnostic biomarkers; in this regard, thymus and activation regulated chemokine (TARC [CCL17]) has been shown to have a diagnostic accuracy of 93% in one study, and there is an ongoing prospective cohort study evaluating TARC as a diagnostic biomarker in ABPA (NCT NCT03267394)
- Since current clinical trial data are sparse, Saudi Arabian institutions should partner in multicenter studies to better establish optimal treatment protocols, particularly with respect to newer agents, such as anti-IgE monoclonal antibodies, Vitamin D supplementation, and monoclonal antibodies targeting IL-5 (mepolizumab, reslizumab), which have recently shown benefit in asthma,
- New clinical trials should also specifically examine therapies in patient subgroups, especially CF patients, who are currently underrepresented in the clinical data.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Agarwal R, Sehgal IS, Dhooria S, Aggarwal AN. Developments in the diagnosis and treatment of allergic bronchopulmonary aspergillosis. Expert Rev Respir Med 2016;10:1317-34.
Greenberger PA, Bush RK, Demain JG, Luong A, Slavin RG, Knutsen AP. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol Pract 2014;2:703-8.
Tracy MC, Okorie CU, Foley EA, Moss RB. Allergic bronchopulmonary aspergillosis. J Fungi (Basel) 2016;2. pii: E17.
Hinson KF, Moon AJ, Plummer NS. Broncho-pulmonary aspergillosis: A review and a report of eight new cases. Thorax 1952;7:317-33.
Knutsen AP, Slavin RG. Allergic bronchopulmonary aspergillosis in asthma and cystic fibrosis. Clin Dev Immunol 2011;2011:843763.
Chaudhary N, Datta K, Askin FB, Staab JF, Marr KA. Cystic fibrosis transmembrane conductance regulator regulates epithelial cell response to Aspergillus
and resultant pulmonary inflammation. Am J Respir Crit Care Med 2012;185:301-10.
Aimanianda V, Bayry J, Bozza S, Kniemeyer O, Perruccio K, Elluru SR, et al
. Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature 2009;460:1117-21.
Beauvais A, Fontaine T, Aimanianda V, Latgé JP. Aspergillus
cell wall and biofilm. Mycopathologia 2014;178:371-7.
Bhushan B, Homma T, Norton JE, Sha Q, Siebert J, Gupta DS, et al
. Suppression of epithelial signal transducer and activator of transcription 1 activation by extracts of Aspergillus fumigatus
. Am J Respir Cell Mol Biol 2015;53:87-95.
Homma T, Kato A, Bhushan B, Norton JE, Suh LA, Carter RG, et al
. Role of Aspergillus fumigatus
in triggering protease-activated receptor-2 in airway epithelial cells and skewing the cells toward a T-helper 2 bias. Am J Respir Cell Mol Biol 2016;54:60-70.
Becker KL, Gresnigt MS, Smeekens SP, Jacobs CW, Magis-Escurra C, Jaeger M, et al
. Pattern recognition pathways leading to a Th2 cytokine bias in allergic bronchopulmonary aspergillosis patients. Clin Exp Allergy 2015;45:423-37.
Schuyler M. The Th1/Th2 paradigm in allergic bronchopulmonary aspergillosis. J Lab Clin Med 1998;131:194-6.
Agarwal R, Aggarwal AN, Gupta D, Jindal SK. Aspergillus
hypersensitivity and allergic bronchopulmonary aspergillosis in patients with bronchial asthma: Systematic review and meta-analysis. Int J Tuberc Lung Dis 2009;13:936-44.
Maturu VN, Agarwal R. Prevalence of Aspergillus
sensitization and allergic bronchopulmonary aspergillosis in cystic fibrosis: Systematic review and meta-analysis. Clin Exp Allergy 2015;45:1765-78.
Shah A, Kala J, Sahay S, Panjabi C. Frequency of familial occurrence in 164 patients with allergic bronchopulmonary aspergillosis. Ann Allergy Asthma Immunol 2008;101:363-9.
Overton NL, Brakhage AA, Thywißen A, Denning DW, Bowyer P. Mutations in EEA1 are associated with allergic bronchopulmonary aspergillosis and affect phagocytosis of Aspergillus fumigatus
by human macrophages. PLoS One 2018;13:e0185706.
Vaid M, Kaur S, Sambatakou H, Madan T, Denning DW, Sarma PU. Distinct alleles of mannose-binding lectin (MBL) and surfactant proteins A (SP-A) in patients with chronic cavitary pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. Clin Chem Lab Med 2007;45:183-6.
Agarwal R, Khan A, Aggarwal AN, Gupta D. Link between CFTR mutations and ABPA: A systematic review and meta-analysis. Mycoses 2012;55:357-65.
Corvol H, Blackman SM, Boëlle PY, Gallins PJ, Pace RG, Stonebraker JR, et al
. Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. Nat Commun 2015;6:8382.
Muro M, Mondejar-López P, Moya-Quiles MR, Salgado G, Pastor-Vivero MD, Lopez-Hernandez R, et al
. HLA-DRB1 and HLA-DQB1 genes on susceptibility to and protection from allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Microbiol Immunol 2013;57:193-7.
Agarwal R, Hazarika B, Gupta D, Aggarwal AN, Chakrabarti A, Jindal SK. Aspergillus
hypersensitivity in patients with chronic obstructive pulmonary disease: COPD as a risk factor for ABPA? Med Mycol 2010;48:988-94.
Dhooria S, Kumar P, Saikia B, Aggarwal AN, Gupta D, Behera D, et al
. Prevalence of Aspergillus
sensitisation in pulmonary tuberculosis-related fibrocavitary disease. Int J Tuberc Lung Dis 2014;18:850-5.
Chakrabarti A, Sethi S, Raman DS, Behera D. Eight-year study of allergic bronchopulmonary aspergillosis in an Indian teaching hospital. Mycoses 2002;45:295-9.
Agarwal R, Gupta D, Aggarwal AN, Saxena AK, Chakrabarti A, Jindal SK. Clinical significance of hyperattenuating mucoid impaction in allergic bronchopulmonary aspergillosis: An analysis of 155 patients. Chest 2007;132:1183-90.
Greenberger PA. Clinical aspects of allergic bronchopulmonary aspergillosis. Front Biosci 2003;8:s119-27.
Kirsten D, Nowak D, Rabe KF, Magnussen H. Diagnosis of bronchopulmonary aspergillosis is often made too late. Med Klin (Munich) 1993;88:353-6.
Rosenberg M, Patterson R, Mintzer R, Cooper BJ, Roberts M, Harris KE. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 1977;86:405-14.
Agarwal R, Chakrabarti A, Shah A, Gupta D, Meis JF, Guleria R, et al
. Allergic bronchopulmonary aspergillosis: Review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy 2013;43:850-73.
Agarwal R, Maskey D, Aggarwal AN, Saikia B, Garg M, Gupta D, et al
. Diagnostic performance of various tests and criteria employed in allergic bronchopulmonary aspergillosis: A latent class analysis. PLoS One 2013;8:e61105.
Agarwal R, Dua D, Choudhary H, Aggarwal AN, Sehgal IS, Dhooria S, et al
. Role of Aspergillus fumigatus
-specific IgG in diagnosis and monitoring treatment response in allergic bronchopulmonary aspergillosis. Mycoses 2017;60:33-9.
Agarwal R, Khan A, Garg M, Aggarwal AN, Gupta D. Chest radiographic and computed tomographic manifestations in allergic bronchopulmonary aspergillosis. World J Radiol 2012;4:141-50.
Garg MK, Sharma M, Agarwal R, Aggarwal AN, Gupta P, Sodhi KS, et al
. Allergic bronchopulmonary aspergillosis: AllA radiologist needs to know. Curr Pediatr Rev 2016;12:179-89.
Banka R, Kamath A. Application of the ISHAM criteria for diagnosis of ABPA in a clinical cohort at a university teaching hospital. Eur Respir J 2018;52 Suppl 62:PA1136.
Agarwal R, Denning DW, Chakrabarti A. Estimation of the burden of chronic and allergic pulmonary aspergillosis in India. PLoS One 2014;9:e114745.
Denning DW, Pleuvry A, Cole DC. Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults. Med Mycol 2013;51:361-70.
Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, et al
. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006;368:733-43.
Al Frayh AR, Shakoor Z, Gad El Rab MO, Hasnain SM. Increased prevalence of asthma in Saudi Arabia. Ann Allergy Asthma Immunol 2001;86:292-6.
Moradi-Lakeh M, El Bcheraoui C, Daoud F, Tuffaha M, Kravitz H, Al Saeedi M, et al
. Prevalence of asthma in Saudi adults: Findings from a national household survey, 2013. BMC Pulm Med 2015;15:77.
Al-Mobeireek AF, El-Rab MO, Al-Hedaithy SS, Alasali K, Al-Majed S, Joharjy I. Allergic bronchopulmonary mycosis in patients with asthma: Period prevalence at a university hospital in Saudi Arabia. Respir Med 2001;95:341-7.
Al-Mobeireek A, Alamoudi O. Allergic bronchopulmonary aspergillosis mimicking pulmonary tuberculosis. Saudi Med J 2002;23:476.
Mobeireek A, Gad El-Rab MO, Joharjy I, Al-Sohaibani M, Ashour M. Allergic bronchopulmonary aspergillosis: Disease pattern in Central Arabia. Trop Med Int Health 1998;3:34-40.
Al-Frayh A, Gad-El-Rab MO, Al-Najjar A, Hasnain SM. A comparative study of immediate skin test reactivity to inhalant allergens in asthmatic children of two different regions in Saudi Arabia. Ann Saudi Med 1992;12:468-71.
Sehgal IS, Choudhary H, Dhooria S, Aggarwal AN, Bansal S, Garg M, et al
. Prevalence of sensitization to Aspergillus flavus
in patients with allergic bronchopulmonary aspergillosis. Med Mycol 2019;57:270-6.
Fukutomi Y, Tanimoto H, Yasueda H, Taniguchi M. Serological diagnosis of allergic bronchopulmonary mycosis: Progress and challenges. Allergol Int 2016;65:30-6.
Patterson TF, Thompson GR 3rd
, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al
. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious Diseases Society of America. Clin Infect Dis 2016;63:e1-60.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. J Clin Epidemiol 2009;62:1006-12.
Agarwal R, Aggarwal AN, Dhooria S, Singh Sehgal I, Garg M, Saikia B, et al
. A randomised trial of glucocorticoids in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Eur Respir J 2016;47:490-8.
Agarwal R, Dhooria S, Singh Sehgal I, Aggarwal AN, Garg M, Saikia B, et al
. A randomized trial of itraconazole vs. prednisolone in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Chest 2018;153:656-64.
Currie DC, Lueck C, Milburn HJ, Harvey C, Longbottom JL, Darbyshire JH, et al
. Controlled trial of natamycin in the treatment of allergic bronchopulmonary aspergillosis. Thorax 1990;45:447-50.
Dodamani MH, Muthu V, Thakur R, Pal A, Sehgal IS, Dhooria S, et al
. A randomised trial of vitamin D in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Mycoses 2019;62:320-7.
Ram B, Aggarwal AN, Dhooria S, Sehgal IS, Garg M, Behera D, et al
. A pilot randomized trial of nebulized amphotericin in patients with allergic bronchopulmonary aspergillosis. J Asthma 2016;53:517-24.
Stevens DA, Schwartz HJ, Lee JY, Moskovitz BL, Jerome DC, Catanzaro A, et al
. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N
Engl J Med 2000;342:756-62.
Wark PA, Hensley MJ, Saltos N, Boyle MJ, Toneguzzi RC, Epid GD, et al
. Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: A randomized controlled trial. J Allergy Clin Immunol 2003;111:952-7.
Emiralioglu N, Dogru D, Tugcu GD, Yalcin E, Kiper N, Ozcelik U. Omalizumab treatment for allergic bronchopulmonary aspergillosis in cystic fibrosis. Ann Pharmacother 2016;50:188-93.
Voskamp AL, Gillman A, Symons K, Sandrini A, Rolland JM, O'Hehir RE, et al
. Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol Pract 2015;3:192-9.
Kreindler JL, Steele C, Nguyen N, Chan YR, Pilewski JM, Alcorn JF, et al
. Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus
mounted by CD4+T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis. J Clin Invest 2010;120:3242-54.
Patel J, Ayars AG, Rampur L, Bronson S, Altman MC. Combination anti-IgE and anti-IL5 therapies in patients with severe persistent asthma and allergic bronchopulmonary aspergillosis (ABPA). J Allergy Clin Immunol 2018;141(2):AB234.
Agarwal R, Gupta D, Aggarwal AN, Saxena AK, Saikia B, Chakrabarti A, et al
. Clinical significance of decline in serum IgE levels in allergic bronchopulmonary aspergillosis. Respir Med 2010;104:204-10.
Latzin P, Hartl D, Regamey N, Frey U, Schoeni MH, Casaulta C. Comparison of serum markers for allergic bronchopulmonary aspergillosis in cystic fibrosis. Eur Respir J 2008;31:36-42.
Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al
. Mepolizumab treatment in patients with severe eosinophilic asthma. N
Engl J Med 2014;371:1198-207.
Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al
. Mepolizumab for severe eosinophilic asthma (DREAM): A multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-9.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]