Severe Asthma With Fungal Sensitization Research Articles

Clinical Spectrum of Aspergillosis in Children with Severe Asthma: A Retrospective Observational Study

Introduction: Aspergillus species can affect the respiratory system of genetically predisposed asthma patients. Allergic Broncho-Pulmonary Aspergillosis (ABPA) is one of the manifestations of aspergillosis. Most research on ABPA has been conducted in the adult population, with very few studies including paediatric patients. Aim: To examine the clinical spectrum of aspergillosis in severely asthmatic children aged between 2 and 18 years admitted to the Paediatric Intensive Care Unit (PICU). Materials and Methods: This retrospective observational study was conducted from September 2021 to August 2022. Out of 76 children aged between 2 and 18 years who presented with asthma over one year, 24 children fulfilling the inclusion criteria (severe asthma requiring PICU admission) were included in the study by convenient sampling. Children were diagnosed with ABPA and Severe Asthma with Fungal Sensitisation (SAFS) based on the ISHAM (International Society for Human and Animal Mycology) work group criteria (history of asthma, raised Aspergillus-specific and total Immunoglobulin E (IgE), presence of Aspergillus-specific IgG, eosinophilia, and positive radiological findings). Descriptive statistics elaborated in the form of mean and standard deviation. Results: A total of 24 patients with acute severe asthma were admitted to the PICU over one year. Nearly 60% (15/24) of the patients fulfilled the criteria for subgroup A (comprising poorly controlled asthma, eosinophilia, or positive radiological findings). Among them, six (25%) patients had total serum IgE levels > 1000 IU/mL, three (12.5%) had levels between 500- 1000 IU/mL, and six (25%) had levels <500 IU/mL. Among these patients, 60% (9/15) had elevated Aspergillus-specific IgE and IgG levels. As per the ISHAM work group criteria, 6/24 (25%) patients were diagnosed with S-ABPA (Serological ABPA) and 3/24 (12.5%) patients were diagnosed with SAFS. Conclusion: Aspergillus sensitivity is increasingly being detected in asthmatic children, requiring further work-up, especially in patients with poorly controlled asthma.

Aspergillus sensitisation detection using point-of-care lateral flow assay in moderate to severe asthma.

Allergic fungal airway diseases are associated with asthma exacerbations and poor control. However, the early identification of allergic Aspergillus airway diseases can be challenging, especially in resource-poor countries. We aimed to evaluate the clinical utility of the point-of-care Aspergillus IgG-IgM lateral flow assay in diagnosing Aspergillus airway diseases in patients with moderate-severe asthma. Patients with moderate-severe asthma, severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) were recruited. Clinical information was extracted from clinical records. Blood samples were collected for serological tests. Serum samples were evaluated using Aspergillus immunochromatographic test (ICT). A total of 65 patients were recruited into the study, of whom 23.1% had clinical diagnosis of ABPA, 18.5% had SAFS and 58.5% had moderate-to-severe asthma who did not fit ABPA or SAFS criteria. The ICT test gave a sensitivity of 69 [95% confidence interval: 51-88]% and a specificity of 77 [60-88]% in predicting a positive Aspergillus IgG test. The sensitivity and specificity for a positive Aspergillus IgE were 77 [59-88]% and 86 [71-94]%, respectively. The majority (sensitivity: 87 [62-96]%) of patients with ABPA had positive ICT results, with a specificity of 70%. The negative predictive value was high (95 [82-99]%) with a low negative likelihood ratio (< 0.2), making it potentially useful in ruling out ABPA. The ICT assay may be valuable in ruling out ABPA in resource-limited countries where serological investigations are less feasible. The ICT assay may be particularly useful in ruling out ABPA and warrants further validation.

Severe asthma with fungal sensitization is associated with worse small airway dysfunction but similar symptom control

Severe asthma with fungal sensitization is associated with worse small airway dysfunction but similar symptom control

Estimated burden of serious fungal infections in Togo.

Over the years, the focus of infectious diseases in many African countries has been mainly on viral, bacterial and parasitic infections. Serious fungal infections (SFIs) with comparable morbidity rate in these countries remain neglected. To estimate the burden of SFI in Togo and to stimulate efforts for improved attention. Literature was thoroughly searched for epidemiological data on SFI in Togo. Incidence and/or prevalence of SFI was estimated using socio-demographics, health system's information, risk-groups data and SFI rates obtained from national and international studies. About 5.29% of the 7,265,286 Togolese population is estimated to suffer from SFI annually. Among HIV patients, 1,342, 1,650 and 330 may develop cryptococcal meningitis, Pneumocystis pneumonia and disseminated histoplasmosis respectively per year. Oral and oesophageal candidiasis may annually affect 19,800 and 7,535 persons, respectively, living with HIV. Estimated incidence of invasive aspergillosis (IA) was 283 cases. Prevalence of chronic pulmonary aspergillosis (CPA) was estimated at 191 cases. The annual incidence of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) was 4,577 and 6,042 cases, respectively. Tinea capitis and recurrent Candida vaginitis presumably affect 232,271 children and 108,979 women respectively. Candidaemia incidence is estimated at 5 cases per 100, 000 inhabitants and fungal keratitis may affect 981 persons annually. SFIs in Togo are probably more significant than expected. These findings underscore the need to increase awareness among healthcare professionals, enhance diagnostic and therapeutic capacities and intensify epidemiological studies for effective management of fungal infections in Togo.

Comprehensive Gene Expression Signature Using RNA-Seq in Airways of Mouse Model of Severe Asthma with Fungal Sensitization

Introduction: Inhalation of fungal allergens induces airway epithelial damage following airway inflammation and excessive mucus secretion, which can lead to severe asthma with fungal sensitization (SAFS). Comprehensive gene expression analysis in Alternaria-exposed mouse airways, a model of SAFS, has not been conducted. Methods: BALB/c mice received intranasal administration of Alternaria extract or phosphate-buffered saline twice a week for 6 weeks. Lung sections and bronchoalveolar lavage fluid were obtained to assess airway inflammation. RNA-Seq in the central airway was performed, and gene ontology (GO) analysis and gene set enrichment analysis (GSEA) were conducted for pathway analyses. An in vitro experiment using human airway epithelial cell 16HBE14o- was performed to validate the RNA-Seq findings. Results: Eosinophilic airway inflammation with mucus overproduction and airway remodeling was observed in mice exposed to Alternaria. RNA-Seq analysis revealed 403 upregulated and 108 downregulated genes in airways of Alternaria-exposed mice. In GO analysis, the functions of immunoglobulin (Ig) receptor binding, Ig production, inflammatory response, and T-cell activation were upregulated, while those of keratinization and defense response to other organisms were downregulated. GSEA revealed positive enrichment in T-cell receptor complex, immunological synapse, antigen binding, mast cell activation, and Ig receptor binding, and negative enrichment in keratinization and cornification in Alternaria-exposed mice relative to control. Alternaria exposure to 16HBE14o- cells validated the downregulation of epithelial keratinization-related genes, including SPRR1A, SPRR1B, and KRT6B. Conclusion: RNA-Seq analysis showed that Alternaria exposure induced inflammatory response and impaired defense mechanisms in mice airway epithelium, which might be therapeutic targets for SAFS.

Updated estimated incidence and prevalence of serious fungal infections in Trinidad and Tobago

Objective: To estimate the incidence and prevalence of serious fungal infections in Trinidad and Tobago (T&T), with a population of 1 394 973 million. Methods: The medical literature was searched to obtain published data on the incidence and prevalence of fungal infections in the Caribbean. If data were unavailable, estimations were performed using the frequencies of fungal infection in populations at risk. Asthma and pulmonary tuberculosis rates were used to derive the prevalence of allergic bronchopulmonary aspergillosis (ABPA), severe asthma with fungal sensitization (SAFS), and chronic pulmonary aspergillosis (CPA). Results: The estimated annual burden of fungal infections was 46 156 persons (3.3% of the population), including 21 455 women with recurrent vulvovaginal candidiasis, 118 persons with invasive aspergillosis, 3637 adults with ABPA, 4800 with SAFS, and 178 with CPA. Annually, we estimated 70 cases of candidemia and 14 647 cases of tinea capitis in children. Of the 11 000 persons living with HIV/AIDS, it was estimated that there were 40 cases of cryptococcal meningitis, 88 cases of disseminated histoplasmosis, and 124 cases of Pneumocystis pneumonia. Conclusion: There seems to be an extensive burden of fungal infections in T&T. Hence, targeted interventions are required to improve clinical and laboratory diagnosis and a national surveillance system should be implemented.

Evaluation of an Aspergillus IgG/IgM lateral flow assay for serodiagnosis of fungal asthma in Uganda.

BackgroundDiagnosis of fungal allergies in asthma remains problematic in low-and middle-income countries due to non-availability of point-of-care testing. In this study, we aimed to evaluate the performance of an Aspergillus immunochromatographic technology (ICT) IgG/M lateral flow device (LFD) for the serological diagnosis of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitisation (SAFS) among Ugandan adult asthmatics.Methods374 adult (aged ≥18years) asthmatics in the African Severe Asthma Program study, Ugandan site constituted the study population. ABPA and SAFS were diagnosed according to standard criteria. Asthmatics who did not meet the above criteria constituted a control group. The LFD tests were performed and read according to manufacturer’s instructions.ResultsABPA was found in 12/374 (3.2%) and SAFS in 60/374 (16%) participants. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the Aspergillus ICT for the diagnosis of ABPA were 0.0%, 96.4%, 0.0% and 96.7% respectively, and for SAFS 6.7%, 97.1%, 30.8% and 84.5% respectively. False positive and negative rates were 3.5% and 3.2% for ABPA and 2.4% and 14.9% for SAFS, respectively. Patients with a positive LFD significantly had higher median Aspergillus fumigatus-specific IgE levels compared to those with negative LFD (median: 0.06 kUA/l VS 0.03 kUA/L, P = 0.011).ConclusionThe Aspergillus ICT IgG/M LFD had a poor diagnostic performance for the diagnosis of both ABPA and SAFS. Its greatest value may be in distinguishing chronic and allergic aspergillosis in Africa.

New Perspectives in the Diagnosis and Management of Allergic Fungal Airway Disease.

Allergy to airway-colonising, thermotolerant, filamentous fungi represents a distinct eosinophilic endotype of often severe lung disease. This endotype, which particularly affects adult asthma, but also complicates other airway diseases and sometimes occurs de novo, has a heterogeneous presentation ranging from severe eosinophilic asthma to lobar collapse. Its hallmark is lung damage, characterised by fixed airflow obstruction (FAO), bronchiectasis and lung fibrosis. It has a number of monikers including severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis/mycosis (ABPA/M), but these exclusive terms constitute only sub-sets of the condition. In order to capture the full extent of the syndrome we prefer the inclusive term allergic fungal airway disease (AFAD), the criteria for which are IgE sensitisation to relevant fungi in association with airway disease. The primary fungus involved is Aspergillus fumigatus, but a number of other thermotolerant species from several genera have been implicated. The unifying mechanism involves germination of inhaled fungal spores in the lung in the context of IgE sensitisation, leading to a persistent and vigorous eosinophilic inflammatory response in association with release of fungal proteases. Most allergenic fungi, including Alternaria and Cladosporium species, are not thermotolerant and cannot germinate in the airways so only act as aeroallergens and do not cause AFAD. Studies of the airway mycobiome have shown that A. fumigatus colonises the normal as much as the asthmatic airway, suggesting it is the tendency to become IgE-sensitised that is the critical triggering factor for AFAD rather than colonisation per se. Treatment is aimed at preventing exacerbations with glucocorticoids and increasingly by the use of anti-T2 biological therapies. Anti-fungal therapy has a limited place in management, but is an effective treatment for fungal bronchitis which complicates AFAD in about 10% of cases.

Real-World Effectiveness of Anti–IL-5/5R Therapy in Severe Atopic Eosinophilic Asthma with Fungal Sensitization

Severe asthma with fungal sensitization (SAFS) is a complex clinical phenotype associated with poorly controlled type 2 inflammation and significant morbidity from both the disease itself and a high steroid burden. To assess the effectiveness of biologic therapies targeting eosinophilic inflammation in SAFS. We assessed the effectiveness of treatment with mepolizumab or benralizumab in patients with SAFS, and compared outcomes with patients with severe atopic asthma without fungal sensitization and patients with severe nonatopic asthma. Baseline clinical characteristics and clinical outcomes at 48 weeks were evaluated. A subgroup analysis was performed of patients who met the criteria for allergic bronchopulmonary aspergillosis (ABPA) rather than SAFS. A total of 193 patients treated with mepolizumab (n= 63) or benralizumab (n= 130) were included. Patients with SAFS had higher baseline IgE level compared with patients with severe atopic asthma without fungal sensitization and severenonatopic asthma (733 ± 837 IU/mL vs 338 ± 494 and 142 ± 171, respectively; both P < .001). There were no other significant baseline differences in clinical characteristics betweengroups. At 48 weeks, there were significant improvements in 6-item asthma control questionnaire score and exacerbation frequency, and reduction in maintenance oral corticosteroid dose across all groups (all P < .05). No significant between-group differences in outcomes were observed at 48 weeks. Patients with ABPA (n= 9) had a significant reduction in exacerbation frequency (P= .013) with treatment. Treatment with eosinophil-targeting biologics led to improvements in exacerbation frequency, oral corticosteroid requirements, and patient-reported outcomes in patients with SAFS, with a reduction in exacerbations in the subgroup of patients with ABPA. These data highlight the potential clinical utility of targeting eosinophilic inflammation in SAFS and ABPA.

Role of circulating microRNA-132 in allergic bronchopulmonary aspergillosis: A case-control study

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic respiratory disease. In the current study, we aimed to evaluate the roles of miRNA-21 and miRNA132 as biomarkers in the diagnosis of ABPA.A total of 30 controls, 30 allergic asthmatic patients, 30 severe asthma with fungal sensitization (SAFS) patients, and 30 ABPA patients were included. Real-time polymerase chain reaction was used to quantify the level of miRNAs expression.The expression level of miRNA-21 was significantly higher in allergic asthmatic, SAFS, and ABPA patients in comparison with controls (p < 0.001). However, no significant difference was detected in the expression level of miRNA-21 among the different patient groups (p > 0.05). The ABPA patients had significantly higher levels of miRNA-132 expression compared to controls, allergic asthmatic patients, and SAFS patients (p < 0.001), but there was a non-significant difference between controls and allergic asthmatic patients (p = 0.09). At a cut-off of 1.52, the sensitivity of miRNA-132 expression was 93.3% and the specificity was 100% different ABPA from healthy controls. At a cut-off of 6.5, miRNA-132 expression was found to reliably differentiate between ABPA and SAFS, with a sensitivity of 86.7% and a specificity of 80%. In ABPA patients, miRNA-132 expression positively correlation with the levels of serum IL-5 (r = 0.91, p < 0.001).miRNA-132 has a role in ABPA detection and distinguishing ABPA from allergic asthma and SAFS. These preliminary data from case-control study need further studies to confirm its finding.

Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation.

Exposure to fungi can result in a wide range of comorbidities depending on the immune status of the host. Chronic exposure and reactivity to fungi such as Aspergillus fumigatus can result in conditions such as severe asthma with fungal sensitization (SAFS) or allergic bronchopulmonary aspergillosis (ABPA). However, the pathophysiology of SAFS and ABPA are not well understood. Here, we report that the chitinase-like protein YKL-40 is elevated in lung lavage fluid from human asthmatics that are sensitized to fungi. Initial studies demonstrated that mice deficient in the murine ortholog of YKL-40, breast regression protein-39 (BRP-39, chitinase-3-like 1, Chi3l1), were not more susceptible to acute infection with A. fumigatus. However, in an experimental model of fungal-associated allergic airway inflammation (fungal asthma), Chi3l1-/- mice had significantly increased airway hyperresponsiveness (AHR). Surprisingly, increased AHR in Chi3l1-/- mice occurred in the presence of significantly lower type 2 responses (decreased eosinophil numbers and decreased IL-4, IL-5, IL-33, CCL17 and CCL22 levels), although type 1 and type 17 responses were not different. Increased AHR was not associated with differences in Periodic-acid-Schiff staining of lung tissue, differences in the expression of Muc5ac and Clca3, nor differences in lung edema. Bone marrow chimera studies revealed that the presence of BRP-39 in either the hematopoietic or non-hematopoietic compartment was sufficient for controlling AHR during fungal asthma. Collectively, these results indicate that BRP-39 protects against AHR during fungal asthma despite contributing to type 2 inflammation, thus highlighting an unexpected protective role for BRP-39 in allergic fungal asthma.

Severe asthma with fungal sensitization

Bronchial asthma is an inflammatory disease of the airways, which may be worsened due to many extrinsic factors. The most common trigger is the continuous exposure to allergens, of which fungal agents are important factors. A new phenotype of asthma called severe asthma with fungal sensitization (SAFS) has been described. It is diagnosed by the presence of severe asthma, fungal sensitization, and absence of allergic bronchopulmonary aspergillosis. SAFS is more of a diagnosis of exclusion. Treatment of SAFS initially should be similar to that of severe asthma including humanized anti-IgE monoclonal antibody and other biologics. These patients usually do not have their symptoms relieved with conventional treatment of severe asthma, i.e. high-dose inhaled corticosteroids and long-acting bronchodilators. Prolonged use of oral corticosteroids and pulse high-dose intravenous corticosteroid is effective. There are some evidence implicating the role of antifungal agents including itraconazole, but its use as a specific therapy requires further studies.

The burden of serious fungal infections in Azerbaijan.

Background:Azerbaijan is an upper middle-income country in South Caucasus with an area of 86,600 km2 and a total population of 10 million people and gross domestic product of US $4480 per capita. The aim of this research is to estimate fungal infection burden and highlight the problem at national and international levels.Methods:Fungal infection burden was estimated using data from epidemiological papers and population at risk and LIFE (Leading International Fungal Education) modelling.Results:The number of people living with human immunodeficiency virus (PLHIV) in 2018 was 6193, 29% of them not receiving antiretroviral therapy. Based on 90% and 20% rates of oral and oesophageal candidiasis in patients with CD4 cell count <200 µl–1 we estimate 808 and 579 patients with oral and oesophageal candidiasis, respectively. The annual incidences of cryptococcal meningitis and Pneumocystis pneumonia are 5 and 55 cases, respectively. We estimated 2307 cases of chronic pulmonary aspergillosis (CPA), 4927 patients with allergic bronchopulmonary aspergillosis (ABPA), and 6504 with severe asthma with fungal sensitization (SAFS). Using data on chronic obstructive pulmonary diseases (COPD), lung cancer, acute myeloid leukaemia rates, and number of transplantations, we estimated 693 cases of invasive aspergillosis following these conditions. Using a low-European rate for invasive candidiasis, we estimated 499 and 75 patients with candidemia and intra-abdominal candidiasis respectively. The number of adult women (15–55 years) in Azerbaijan is ~2,658,000, so it was estimated that 159,490 women suffer from recurrent vulvovaginal candidiasis (rVVC).Discussion:In total, the estimated number of people suffering from fungal diseases in Azerbaijan is 225,974 (2.3% of the population). However, the fungal rate is underestimated due to lack of epidemiological data. The most imminent need is improvement in diagnostic capabilities. This aim should be achieved via establishing a reference laboratory and equipping major clinical centers with essential diagnostics assays.

The chemokine CX3CL1/fractalkine regulates immunopathogenesis during fungal-associated allergic airway inflammation.

Individuals that present with difficult-to-control asthma and sensitivity to one or more fungal species are categorized as a subset of severe asthma patients belonging to a group herein referred to as severe asthma with fungal sensitization (SAFS). We have previously reported the identification of numerous cytokines and chemokines that were elevated in human asthmatics that were sensitized to fungi vs. nonfungal sensitized asthmatics. Here, we show that the unique chemokine CX3CL1 (fractalkine) is elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with CX3CL1 in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that the absence of CX3CR1 signaling unexpectedly resulted in a profound impairment in lung function. Histological assessment of lung tissue revealed an unrestricted inflammatory response that was subsequently characterized by enhanced levels of neutrophils, eosinophils, and inflammatory monocytes. Neutrophilic inflammation correlated with elevated IL-17A, proinflammatory cytokines (TNF-α, IL-1α, and IL-1β), neutrophil survival factors (granulocyte colony-stimulating factor), and neutrophil-targeting chemokines (CCL3 and CCL4). Eosinophilia correlated with elevated type 2 responses (IL-5 and IL-13) whereas inflammatory monocyte levels correlated with elevated type 1 responses (IFN-γ and CXCL9) and survival factors (macrophage colony-stimulating factor). Despite enhanced inflammatory responses, the immunoregulatory cytokine IL-10 and the natural inhibitor of IL-1 signaling, IL-1RA, were significantly elevated rather than impaired. Regulatory T-cell levels were unchanged, as were levels of the anti-inflammatory cytokines IL-35 and IL-38. Taken together, the CX3CL1/CX3CR1 axis preserves lung function during fungal-associated allergic airway inflammation through a nonclassical immunoregulatory mechanism.

The impact of fungal allergic sensitization on asthma.

Fungal sensitization may contribute to the development of asthma as well as asthma severity. The purpose of this review is to summarize existing knowledge about the pathophysiology, diagnosis, and management of fungal sensitization in asthma and highlight unmet needs and target areas for future investigation. Fungal sensitization may occur by a normal or aberrant immune response. Allergic sensitization to fungi is mediated by the adaptive immune response driven by TH2 cells and the innate immune response driven by the innate lymphoid cells group 2. Diagnosis of fungal sensitization can be made by either skin prick testing or measurement of fungal-specific serum IgE. Fungal sensitization in asthma has been associated with worse disease severity, including reduced lung function, increased risk of hospitalizations, and life-threatening asthma. A spectrum of disease related to fungal sensitization has been described in asthma including allergic bronchopulmonary mycosis and severe asthma with fungal sensitization (SAFS). The role of antifungals and targeted biologic therapy in asthma with fungal sensitization need further investigation. There is increasing awareness of the contribution of fungal sensitization to asthma severity. However, there are no therapies with proven efficacy. Randomized clinical trials are needed to further investigate the role of biologics.

Aspergillus fumigatus.

Humans inhale hundreds of Aspergillus fumigatus conidia daily. Conidia germinate and produce hyphae or mycelia that eventually form a colony. The recognition of A. fumigatus pathogen-associated molecular patterns (PAMPs) by the pattern-recognition receptors (PRRs) of innate immune cells induces the phagocytosis and killing of the fungus and cytokine signaling that regulates the activation of adaptive immune responses and epithelial host defense. Severe asthma with fungal sensitization (SAFS), allergic bronchial pulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), invasive pulmonary aspergillosis (IPA), and invasive bronchial aspergillosis (IBA) are some of the human diseases caused by Aspergillus species. A. fumigatus is able to evade the host’s innate immune system through the production of conidial hydrophobin (that can mask PAMPs on the cell wall) and melanin (which blocks the acidification of the phagosome and inhibits the NADPH oxidase complex responsible for the production of antifungal reactive oxygen species).

Omalizumab Is an Effective Intervention in Severe Asthma with Fungal Sensitization

Severe asthma with fungal sensitization (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) are important complications of severe asthma. The evidence for treating them with omalizumab is limited. To determine the effectiveness of treatment with omalizumab in patients with severe allergic asthma comparing those with and without evidence of fungal sensitization using data recorded in the Australian Xolair Registry. Data from 205 patients who received omalizumab and recorded in the Australian Xolair Registry were analyzed to determine change in the Juniper 5-item Asthma Control Questionnaire (ACQ-5) score, exacerbation frequency, and oral corticosteroid dose over a 24-month period of omalizumab treatment. Patients were grouped into cohorts on the basis of fungal sensitization, and an analysis of improvement in outcomes between baseline and 24 months was conducted within each group. A further subgroup analysis of patients with ABPA was also conducted. Patients with SAFS (n= 62), including those with ABPA (ASAFS), were as likely to demonstrate significant improvements in ACQ-5 score and exacerbations and reduced regular oral corticosteroid dose over 24 months as those with severe asthma without sensitization to fungi (n= 156). After adjusting for age, sex, body mass index, smoking history, and baseline FEV1%, the effects still remained. A subgroup analysis of 11 patients with ABPA similarly demonstrated a significant improvement on omalizumab. Omalizumab is an effective therapy in ASAFS, leading to sustained improvements in symptoms and exacerbations for 24 months. The benefit for ABPA is less clear because of the small sample size.

Screening for triazole resistance in clinically significant Aspergillus species; report from Pakistan

BackgroundBurden of aspergillosis is reported to be significant from developing countries including those in South Asia. The estimated burden in Pakistan is also high on the background of tuberculosis and chronic lung diseases. There is concern for management of aspergillosis with the emergence of azole resistant Aspergillus species in neighbouring countries in Central and South Asia.Hence the aim of this study was to screen significant Aspergillus species isolates at the Microbiology Section of Aga Khan Clinical Laboratories, Pakistan, for triazole resistance.MethodsA descriptive cross-sectional study, conducted at the Aga Khan University Laboratories, Karachi, from September 2016–May 2019. One hundred and fourteen, clinically significant Aspergillus isolates [A. fumigatus (38; 33.3%), A. flavus (64; 56.1%), A. niger (9; 7.9%) A. terreus (3; 2.6%)] were included. The clinical spectrum ranged from invasive aspergillosis (IA) (n = 25; 21.9%), chronic pulmonary aspergillosis (CPA) (n = 58; 50.9%), allergic bronchopulmonary aspergillosis (ABPA) (n = 4; 3.5%), severe asthma with fungal sensitization (SAFS) (n = 4; 3.5%), saprophytic tracheobronchial aspergillosis (n = 23; 20.2%). Screening for triazole resistance was performed by antifungal agar screening method. The minimum inhibitory concentration (MIC) of 41 representative isolates were tested and interpreted according to the Clinical and Laboratory Standards Institute broth microdilution method.ResultsAll the isolates were triazole-susceptible on agar screening. MICs of three azole antifungals for 41 tested isolates were found to be ≤1 ml/L; all isolates tested were categorized as triazole-susceptible, including 4 isolates from patients previously on triazole therapy for more than 2 weeks. The minimum inhibitory concentration required to inhibit the growth of 90% organisms (MIC90) of itraconazole, voriconazole and posaconazole of the representative Aspergillus isolates was 1 mg/L, 1 mg/L and 0.5 mg/L, respectively.ConclusionTriazole resistance could not be detected amongst clinical Aspergillus isolates from the South of Pakistan. However, environmental strains remain to be tested for a holistic assessment of the situation. This study will set precedence for future periodic antifungal resistance surveillance in our region on Aspergillus isolates.

Diagnostic markers of allergic bronchopulmonary aspergillosis in patients with severe asthma.

Allergic bronchopulmonary aspergillosis (ABPA) is a lung disease in patients with asthma or cystic fibrosis (CF) caused by chronic allergic inflammation to Aspergillus spp. antigens. The role of different immunological mediators in the formation of chronic allergic inflammation in patients with ABPA is not sufficiently explored. This study aimed to investigate serum levels of thymic stromal lymphopoietin (TSLP), thymus and activated chemokine (TARC) as well as IL-8 in patients with ABPA, and to evaluate their diagnostic and monitoring value in the disease. Prospective study included 21 patients with ABPA, 25 patients with severe asthma with fungal sensitisation (SAFS), 37 patients with severe asthma without fungal sensitisation (SAwFS), and 16 healthy people. In patients with ABPA, the serum levels of biomarkers were determined at baseline and after 12weeks of itraconazole therapy. Serum levels of total IgE, Aspergillus-fumigatus-specific IgE, TSLP, TARC, IL-8 were analysed by enzyme-linked immunosorbent assay. In patients with ABPA we established significantly higher serum levels of TARC, IL-8, total IgE, Aspergillus-fumigatus-specific IgE and peripheral blood eosinophil counts, compared to patients with SAwFS. There were no differences in TSLP levels between the examined groups of patients. Serum TARC levels were positively correlated to serum total IgE levels, Afumigatus-specific IgE levels and peripheral blood eosinophil counts and also negatively correlated to lung function (FEV1 ). Longitudinally, serum levels TARC, total IgE and peripheral blood eosinophil counts significant decreased after treatment of ABPA. Thymus and activated chemokine is a useful test in diagnosing and monitoring response to the antifungal treatment of patients with ABPA.

The Complications of Aspergillus fumigatus Sensitization in Patients with Asthma

Background: Two major complications of Aspergillus sensitization in patients with asthma, including severe asthma with fungal sensitization (SAFS) and asthma associated with fungal sensitization (AAFS), have been recently described. Objectives: In the present study, we aimed to evaluate the prevalence of SAFS and AAFS in Iranian patients with asthma. Methods: Two hundred consecutive outpatients aged ≥ 18 years with moderate to severe allergic asthma, referred to a pulmonary subspecialty hospital (Tehran, Iran) for 25 months, were included in the study. Skin prick test (SPT), total IgE (tIgE), and specific IgE (sIgEAf) and IgG against Aspergillus fumigatus (sIgGAf) were determined for all subjects. Comprehensive criteria were applied for the diagnosis of SAFS and AAFS. Results: Of 200 included patients, 103 (51.5%) and 97 (48.5%) were with moderate and severe asthma, respectively. Of these patients, 111 (55.5%) were female. The mean (range) of age was 45.8 (18 - 78) years. Of 200 patients, 27 (13.5%), 22 (11.0%), 114 (57.0%), and 131 (65.5%) were positive for Aspergillus SPT, sIgEAf, sIgGAf, and tIgE, respectively. The overall prevalence of SAFS in patients with severe asthma and AASF in patients with moderate asthma were 7.2% (7/97) and 3.9% (4/103), respectively. Conclusions: According to the findings, the prevalence of SAFS and AAFS in Iranian patients with severe and moderate allergic asthma was lower than the previously published global data. This low-prevalence reported rate may be due to the fact that we applied strict criteria in the present study.