Allergic aspergillosis in asthmatic patients in a tertiary hospital in the Kingdom of Bahrain

Introduction

Aspergillus fumigatus is associated with most Aspergillus-related diseases which can be attributed to unique characteristics such as high dispersibility, minute conidial size, and the ability to sustain such size regardless of the degree of humidity, thus avoiding the mucociliary clearance and accessing the lower airways of the host.[1234]

A. fumigatus antigen sensitization is associated with airflow obstruction as well as severe asthma attacks.[56] Indeed, inhaling allergenic antigens might elicit hyperresponsiveness, but a crucial difference between A. fumigatus antigens and other allergens, say pollen or dust mites, is the ability to germinate and colonize the host.[7]

Among the wide spectrum of diseases caused by A. fumigatus, allergic bronchopulmonary aspergillosis (ABPA) stands as one of the most common; it is often defined as an indolent immunological respiratory disease, with potential progression, involving hyperresponsiveness reactions to persistent Aspergillus species (mostly A. fumigatus) in the airways.[89] Moreover, overlooked ABPA may progress to cause irreversible bronchi damage and lung fibrosis, as well as chronic sputum production, recurrent pneumonias, and ultimately respiratory failure; therefore, early diagnosis of ABPA is advised.[10]

Some disparities surround pinpointing the global incidence of ABPA in asthmatics, one report declared a 6% prevalence, whereas another analytical report concluded a 2.5% prevalence of ABPA in asthma.[1112] In countrywide projections, in New Zealand, ABPA was estimated to be 4.9%, in China was 2.5%, and in India, ABPA prevalence ranged from 6.9% to 22.3%.[61314151617]

Furthermore, among asthmatics, Aspergillus sensitization has been estimated to vary between 5.5% to 38.5% around the globe, according to ISHAM working group.[6131417181920]

Unfortunately, there are no reports in our region regarding Aspergillus sensitization and ABPA prevalence; therefore, the aim of this study is to determine the prevalence of A. fumigatus sensitization and ABPA in the Kingdom of Bahrain.

Methodology

This analytical case–control study was conducted in Al-Salmaniya Medical Complex, Kingdom of Bahrain where the relative humidity averages 47%–83% all year long.[21] Ethical approval was granted by the Research Technical Support Team at the Ministry of Health. All individuals signed a bilingual (Arabic and English) written consent before participating in the study as well as an overall verbal description of the study delivered by the principal investigator. Furthermore, the individuals responded to a questionnaire covering demographic characteristics, hypersensitivity profiles, and family history. Clinical examination of the respiratory system was performed by the corresponding physician at the clinic.

Results

During this analytical case–control study, 172 outpatients were selected, 20 of which were rejected due to sampling or storing errors, leaving 152 eligible participants (119 asthmatics and 33 controls).

Discussion

Substantial evidence illuminates a viable relation between Aspergillus sensitization and worsening asthma severity, in young children to aging adults.[78] Many reasons might amount to that correlation such as the persistent production of thick bronchial secretions in some asthmatics, that accommodates a hospitable growth environment for fungi; another reason might be genetic predisposition, for example, in patients with a defect in surfactant A2.[2526] Among asthmatics, Aspergillus sensitization has been estimated to vary between 5.5% to 38.5% around the globe, according to ISHAM working group.[6131417181920] Comparatively, our findings show that 19 of 119 asthmatic patients exhibited A. fumigatus sensitization, giving a 16% prevalence of A. fumigatus sensitization in asthmatic patients, supported with significant statistical correlation at 95% confidence, P < 0.05. This middle range prevalence seems to be lower than the regionally closest recorded rate by Al-Mobeireek et al.[18] at 23% although the Saudi study in that particular area included smaller sample size at 54 patients. Furthermore, they used skin prick test which lacks accuracy in comparison with Phadia 250 ImmunoCap fluoro-enzyme immunoassay.[2728]

In this study, atopy was reported by 97% of asthmatic individuals (P < 0.05, OR = 13.7, 95% CI = 3.9–47.8); however, lower rates were reported in New Zealand, India, Singapore, Europe, and United States, at 86.8% 75%, 78%, 72%, and 62.1%, respectively.[613202930] Moreover, allergic rhinitis in asthma was reported in a range of 63–85%; our findings suggest a 65% occurrence of allergic rhinitis in asthmatics.[620] It is worth noting that 95% of asthmatics are polysensitized to various allergens.[831] Our findings show that 75.6% of asthmatics were sensitized to pollen grains (P < 0.05, OR = 3.7, 95% CI = 1.6–8.5), and 22.3% reported one or many food allergies (P < 0.05, OR = 8.3, 95% CI = 1.08–64.1). In the literature, sensitization to tree and grass pollen was estimated to be 49% in asthmatics; whereas, food allergies in adult asthmatics was a diminutive 2.5%.[2932] The discrepancies between our results and the reports in the literature can be attributed to many reasons, one of which is that the data used to construct our estimations were reported by the individuals themselves with the occasional support of the medical profile whenever applicable. Another reason is that differences in the population size and characteristics would most likely produce deviations. Furthermore, the dearth of reports in some research topics, like food allergy in asthmatic adults, hindered objective comparisons.

In addition, asthmatic candidates reported experiencing cough (94.1%; P < 0.05, OR = 1.56, 95% CI = 1.04–2.33), wheeze (85.7%; P < 0.05, OR = 5.29, 95% CI = 2.23–12.56), dyspnea (65.5%), sputum production (77.3%), and night distress (44.5%; P < 0.05, OR = 3.29, 95% CI = 1.12–9.72); these rates were similar to the estimates in the studies conducted in Saudi Arabia and India.[1827] Uncharacteristically, hemoptysis was reported in 3 (2.5%) asthmatic individuals that were not diagnosed with aspergillosis or other pulmonary condition; so, further analysis needs to be implemented.

Furthermore, the continuous exposure to Aspergillus antigens will consequently lead to pulmonary aspergillosis (e.g., ABPA and CPA), causing liable severe asthma, lung tissue destruction, respiratory failure, and eventually death.[533] ABPA is a potentially progressive pulmonary disease that is caused by a complex hyperreactivity response to Aspergillus antigens in the lungs.[9] Some disparities surround pinpointing the incidence of ABPA in asthmatics; one report declared a 6% prevalence whereas another analytical report concluded a 2.5% prevalence of ABPA in asthma.[1112] Moreover, countrywide projections provided diverse rates, in New Zealand, ABPA was estimated to be 4.9%; in China, it was 2.5%; and in India, ABPA prevalence ranged from 6.9% to 22.3%.[61314151617] Conjunctively, our findings suggest a 10.1% prevalence of ABPA in asthmatics.

One of the main causes of the disparity in ABPA prevalence is the absence of consensus on the parameters of ABPA diagnostic criteria.[34] Indeed, most of the cases reflect the corresponding specialist opinion, which might be delayed or incomplete; also, candidates at different ABPA stages might not fulfill all the diagnostic parameters, which deems ABPA prevalence as a speculative manner prone to disparity and error.[611]

It has been proposed by Greenberger[10] that ABPA should be considered in any asthmatic patient who shows any of the following signs: bronchiectasis, history of pneumonias, mucous plugs, elevated A. fumigatus-specific antibodies, and increased severity of asthma symptoms; Henceforth, proper case management should be administered. Moreover, oversighting ABPA diagnosis might occur when negative radiographic imaging is obtained, thus awaiting the manifestation of bronchiectasis to secure the diagnosis despite the immunological evidence; this type of clinical mishap overlooks the early stages of ABPA the “Sero-ABPA”; evidently, underdiagnosing the disease and decreasing the reported prevalence.[1035] Therefore, in our study, it was crucial to avoid this mishap, thereupon, accounting the immunological evidence as the quasi-main evidence of ABPA along with symptoms’ manifestation, then supplementing the radiographic evidence whenever possible. Unfortunately, radiographic evidence was not always available because our population consisted of asthmatic outpatients attending the pulmonary clinic and were not managed as aspergillosis patients; incidentally, they were not administered a CT-scan by the corresponding clinician. This measure of patient selection provided benefits like minimizing inclusion bias, although missed some evidence that cannot be determined as positive or negative. Nevertheless, some studies did not require central bronchiectasis to diagnose ABPA in asthmatic patients, relying mostly on immunological evidence, so our characterization of ABPA was not a novel approach but a tested measurement.[3637] All in all, 5 out of 119 (4.2%) asthmatic patients have fulfilled the designated ABPA criteria, whereas additional 7 (5.9%) only missed the radiographic evidence; therefore, the combined prevalence of ABPA in asthmatic patients in Bahrain is 10.1%.

Furthermore, risk factors facilitating the manifestation and development of aspergillosis are many, one of which is bronchiectasis in 73% of ABPA patients; yet, among asthmatics, lower prevalence was recorded at 15.5%, although our findings only reported 5% prevalence (P < 0.05, OR = 0.14, 95% CI = 0.05–0.43).[1537] In addition, tuberculosis and lung cancer are of the most critical risk factors in developing aspergillosis, reaching a prevalence of 81% and 10.3%, respectively; yet, in our asthmatic group, only 2% were affected by each condition.[3839] Interestingly, diabetes affected about 12% of aspergillosis patients, although a higher prevalence was reported in our findings at 23.5% of asthmatics. Viable reason can explain such differences between our findings and other articles, which is that most studies were conducted retrospectively, giving the option to include the most characteristic subject in the manner of the research, contrary to our prospective research.

Despite the lack of consensus in the parameters of ABPA criteria, elevated levels of Aspergillus-specific IgE are unanimously considered an essential part in the diagnosis.[40] In fact, it is currently considered the most sensitive screening tool for ABPA in asthmatics, surpassing skin prick test and sputum cultures, and providing a 100% sensitivity and 77.3% specificity.[2740] Unfortunately, the absence of standardized antigens is a major drawback for this test; generally, the desired results should administer a genuine, species-specific indication of sensitization rather than levels inflated with cross-reactivity.[41]

It is worth noting that most fungal allergens in varied species belong to the same protein families (e.g., MnSOD, thioredoxin, and cyclophilin) and share similarities in the three-dimensional structure and charge distribution; hence, cross-reactivity is eminent while using crude fungal extracts, as it has been the case for many years.[42] Therefore, it is important to rely on an antigen that is confined in a particular species, as well as, lacks homologies in the genome of said species, hence avoiding suspicion of crossreactivity with any similar protein to our designated antigen.[43]

Moreover, few A. fumigatus antigens fulfill these conditions, one of which is Asp f1 that we utilized to measure the levels of specific IgE in the serum, it represents a species-specific protein as well as no recorded homology with any other fungus and among other Aspergillus species.[4243] Furthermore, Asp f1 is an 18 kD A. fumigatus-specific allergen that belongs to the mitogillin family of cytotoxins.[44] It is not generated in the conidia but produced in the mycelium within 12 h of germination; and while exposure to A. fumigatus is common, minute number of people immunologically project its presence, yet it is found in 75%–85% of ABPA patients; therefore, Asp f1 is a viable marker for aspergillosis.[4445] Moreover, Asp f1 induces T-cell proliferation, inhibits protein synthesis, and ultimately contributes to the pathogenesis of aspergillosis, especially during the early stages of the disease.[46] In related Japanese studies,[4047] they stated that Asp f1 showed a good diagnostic performance, and it can effectively characterize ABPA as well as provide genuine indication of A. fumigatus sensitization; also, they estimated a 77% sensitivity and 85% specificity for Asp f1, surpassing many of the available screening tools.

Conclusion and Limitations

In this research, valuable insight was attained on the effect of Aspergillus exposure on asthmatic patients. For the first time in the Kingdom of Bahrain, the prevalence of Aspergillus sensitization and ABPA in asthmatic patients were determined (16% and 10.1%, respectively), by analyzing various immunological markers such as A. fumigatus-specific IgE, with the support of clinical and radiological evidences.

Such findings will hopefully lead to a better management of asthmatic patients and enhance our understanding of Aspergillus epidemiology in the region.

One immense limitation is not utilizing more than one antigen for the serological analysis, we could not mitigate this limitation because of the budget ceiling that forced us to choose between a sizable population or using various antigens, and given that aspergillosis is not very common, we opted to include as many individuals as possible. Furthermore, the lack of regional and global reports left few knowledge blanks about the topic.