Sex Differences in Allergic Bronchopulmonary Aspergillosis and its Impact on Exacerbations.

The impact of sex on allergic bronchopulmonary aspergillosis (ABPA) outcomes remains uncertain. We retrospectively included ABPA subjects per the revised International Society for Human and Animal Mycology ABPA working group criteria over 13 years. We compared the clinical features, lung function, immunological tests, imaging, and ABPA exacerbation rates between men and women. Our primary objective was to assess whether women experience higher ABPA exacerbations than men. We included 731 ABPA subjects (mean age, 34.5 years; 49.5% women). Women with ABPA were older and had underlying asthma more frequently than men. There was no difference in lung function, immunological investigations, and imaging between men and women. ABPA exacerbations occurred in a slightly higher proportion of women than men (44.5% vs. 38.2%) but did not reach statistical significance (p = 0.09). We did not find a significant sex difference in ABPA exacerbation rates. Prospective studies should confirm our findings.

EQUAL ABPA Score 2024: A Tool to Measure Guideline Adherence for Managing Allergic Bronchopulmonary Aspergillosis.

OBJECTIVES: Allergic bronchopulmonary aspergillosis (ABPA) is a complex lung disease associated with significant morbidity. The ABPA Working Group (AWG) of the International Society for Human and Animal Mycology (ISHAM) revised their management guidelines in 2024, but there is currently no standardised tool to assess adherence to these recommendations. METHODS: We extracted key recommendations from the updated 2024 ISHAM-AWG guidelines, focusing on critical areas: screening and diagnosis of ABPA, managing acute and treatment-dependent ABPA, and monitoring treatment response. Each item was assigned a score ranging from zero to three. We assigned negative scores to interventions not recommended by the guidelines. RESULTS: We identified 38 items indicative of optimal clinical care for patients with ABPA. The score for screening asthmatics for ABPA was set at three points. For diagnosing ABPA, 16 items were included, with a score ranging from 12 to 16 points, depending on the specific components used (predisposing conditions, serum A. fumigatus-specific IgE and IgG, serum total IgE, blood eosinophil count and chest computed tomography). The management of acute ABPA comprised 11 items, with a maximum score of three points. For treatment-dependent ABPA, there were nine items (scores ranging from -3 to 6). Follow-up care comprised 10 items with a maximum score of 10-13 points, covering imaging, spirometry, testing serum total IgE levels and therapeutic drug monitoring. CONCLUSIONS: The EQUAL ABPA score has been developed as a comprehensive tool to quantify guideline adherence. Future studies will evaluate to which extent guideline adherence is associated with improved clinical outcomes for patients with ABPA.

Is the Prevalence of Allergic Bronchopulmonary Aspergillosis Greater in Severe Asthma?

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is thought to occur more frequently in severe than in mild asthma. However, there are no precise data to support this hypothesis. OBJECTIVE: To determine the prevalence of ABPA in subjects with varying asthma severity. METHODS: We conducted a secondary analysis of prospectively collected data from 543 adult asthma subjects classified according to the 2004 Global Initiative for Asthma (GINA) guidelines. The asthma severity was categorized into mild, moderate, and severe. We report the prevalence of ABPA in each asthma category. We also performed multivariable logistic regression analysis to identify factors associated with ABPA in subjects with asthma. RESULTS: We classified 81 (15%), 257 (47%), and 205 (38%) subjects as mild, moderate, and severe asthma. We diagnosed ABPA in 106 (19.5%) subjects. The prevalence of ABPA was 11.1% (9 of 81) in mild, 21% (54 of 257) in moderate, and 20.7% (43 of 205) in severe asthma (P = .12). Multivariable analysis identified age and asthma duration as significant factors associated with ABPA, whereas asthma severity was not significantly associated. CONCLUSIONS: The prevalence of ABPA does not vary significantly with the severity of asthma. These findings support the revised International Society of Human and Animal Mycology (ISHAM) ABPA working group (AWG) recommendation for screening all asthma patients for ABPA, irrespective of asthma severity. Further large-scale studies across different geographic regions are warranted to validate these findings.

Common single nucleotide polymorphisms associated with idiopathic pulmonary fibrosis: a systematic review.

BACKGROUND: Several genetic variants are associated with the risk of idiopathic pulmonary fibrosis (IPF). These have not been systematically reviewed. METHODS: We searched the PubMed, Embase and GWAS Catalog databases for studies indexed between inception and 15 January 2024 describing genetic variants associated with IPF susceptibility. We included studies describing common associated single nucleotide polymorphisms (SNPs). We excluded studies describing rare variants, non-SNP variants and those without an allelic model analysis. We recorded study type, participant characteristics, genotyping methods, IPF diagnostic criteria, the SNPs and the respective genes, odds ratios, and other details. We also searched databases for functions of the identified genes. RESULTS: The primary search retrieved 2697 publications; we included 42 studies. There were nine genome-wide association/linkage studies, while 27 were candidate gene studies. The studies included 22-11 160 IPF subjects. 88 SNPs in 58 genes or loci were found associated with IPF susceptibility. MUC5B rs35705950 was the most studied SNP. Most (n=51) SNPs were in the intronic or intergenic regions; only 11 were coding sequence variants. The SNPs had odds ratios ranging from 0.27 to 7.82 for an association with IPF. Only 22 SNPs had moderate-large effects (OR >1.5 or <0.67). Only 49.1% of the associated genes have a known functional role in IPF; the role of G protein-related signalling and transcriptional regulation (zinc-finger proteins) remain unexplored. CONCLUSION: Several common SNPs in over 50 genes have been found associated with IPF susceptibility. These variants may inform gene panels for future studies (PROSPERO CRD42023408912).

The minimal important difference of one-minute-sit-to-stand test in subjects with chronic pulmonary aspergillosis.

BACKGROUND AND OBJECTIVE: There is a need for simple functional test to assess treatment response in chronic pulmonary aspergillosis (CPA) in resource-constrained settings. The one-minute-sit-to-stand test (1-min-STS) is one such test. However, the minimal important difference (MID) for 1-min-STS in subjects with CPA remains unknown. Herein, we estimate the MID for 1-min-STS for CPA subjects. MATERIALS AND METHODS: We retrospectively reviewed the clinical details of CPA subjects treated with oral azoles for 6 months. We included only subjects who completed the 1-min-STS test at baseline and 6 months. We used the change in VAS (visual analogue scale, for overall improvement) as an external anchor. We used the anchor and the distribution (standard deviation-based) methods to determine the MID estimates. We used the anchor-based method only if there was correlation of 0.3 with the 1-min-STS test. RESULTS: One hundred-eight subjects completed the 1-min-STS test at baseline and 6 months. We did not find significant correlation between the change in VAS for overall improvement (r2 = 0.024, P value = 0.809) and the 1-min-STS test. The MID for the 1-min-STS test was 2 repetitions (range, 1.5-2.8 repetitions). CONCLUSION: The MID for the 1-min-STS test in subjects with CPA was 2 repetitions. Future studies using a global rating of change scale as an anchor must confirm our findings.

Role of serial fluorodeoxyglucose positron emission tomography-computed tomography (18FDG-PET-CT) in assessing treatment response in treatment naïve chronic pulmonary aspergillosis subjects.

BACKGROUND: The role of 2-deoxy-2-18(F) fluoro-D-glucose (FDG) positron emission tomography (PET)-computed tomography (CT) in assessing treatment response in chronic pulmonary aspergillosis (CPA) remains to be determined. OBJECTIVE: To compare changes in FDG-PET/CT parameters in CPA subjects with treatment success or failure. METHODS: We treated consecutive treatment-naïve CPA subjects with six months of oral itraconazole. We performed PET-CT at baseline and six months. A multi-disciplinary team categorized response as treatment success or failure. We recorded the maximum standardised uptake value (SUVmax), SUVpeak, and total glycolytic activity (TLG). After treatment, FDG uptake similar to the background uptake or ≥13 units decline in Z-score was considered a complete metabolic response (CMR). A >25%, >30%, and > 45% decline in SUVmax, SUVpeak, and TLG was labelled as a partial metabolic response (PMR). A >30%, >30%, or >75% increase in the SUVmax, SUVpeak, and TLG represented progressive metabolic disease. RESULTS: We included 94 CPA subjects (63 males) with a mean age of 46.2 years. A follow-up PET-CT was performed on 77 subjects. We recorded treatment success and failure in 43 and 34 subjects. The median SUVmax at baseline was 6.7, which significantly reduced with treatment. CMR was seen in 18.6% of those with treatment success and none with treatment failure. A higher proportion of subjects with treatment success achieved PMR. 19% of the subjects with treatment success had progressive metabolic disease. CONCLUSION: FGD-PET/CT demonstrated metabolic activity in all CPA subjects. Most PET-CT parameters improved with treatment; however, one-fifth of the subjects were misclassified on PET-CT.

Population prevalence of aspergillus sensitization and allergic bronchopulmonary aspergillosis in COPD subjects in North India.

BACKGROUND: Sensitization to Aspergillus fumigatus (AS) has been recently described in chronic obstructive pulmonary disease (COPD) patients. However, there is no data on the community prevalence of AS in COPD. OBJECTIVES: To assess the prevalence of AS among COPD subjects. The secondary objectives were to (1) assess the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in COPD and (2) compare the lung function in COPD subjects with and without AS. METHODS: We conducted a cross-sectional study in rural (29 villages) and urban (20 wards) communities in North India. We identified individuals with respiratory symptoms (IRS) through a house-to-house survey using a modified IUATLD questionnaire. We then diagnosed COPD through specialist assessment and spirometry using the GOLD criteria. We assayed A.fumigatus-specific IgE in COPD subjects. In those with A. fumigatus-specific IgE ≥0.35 kUA/L (AS), ABPA was diagnosed with raised serum total IgE and raised A.fumigatus-specific IgG or blood eosinophil count. RESULTS: We found 1315 (8.2%) IRS among 16,071 participants >40 years and diagnosed COPD in 355 (2.2%) subjects. 291 (82.0%) were men and 259 (73.0%) resided in rural areas. The prevalence of AS and ABPA was 17.7% (95% CI, 13.9-21.8) and 6.6% (95% CI, 4.4-8.8). We found a lower percentage predicted FEV1 in COPD subjects with AS than those without (p =.042). CONCLUSIONS: We found an 18% community prevalence of AS in COPD subjects in a specific area in North India. Studies from different geographical areas are required to confirm our findings. The impact of AS and ABPA on COPD requires further research.

A Randomized Control Trial Comparing the Yield of Bronchoalveolar Lavage Using Three Different Techniques in Patients Undergoing Flexible Bronchoscopy (BAL-3T).

BACKGROUND: Three techniques have been described for aspirating the bronchoalveolar lavage (BAL) fluid, namely the wall mount suction (WMS), manual suction (MS), and manual suction with tubing (MST). However, there is no direct comparison among the 3 methods. METHODS: We randomized patients undergoing flexible bronchoscopy and BAL in a 1:1:1 ratio to one of the 3 arms. The primary outcome was to compare the optimal yield, defined as at least 30% return of volume instilled and <5% bronchial cells. The key secondary outcomes were the percentage of volume and total amount (in millimeters) return of BAL, as well as complications (hypoxemia, airway bleeding, and others). RESULTS: We randomized 942 patients [MST (n = 314), MS (n = 314), WMS (n = 314)]. The mean age of the study population [58.7% (n = 553) males] was 46.9 years. The most common indication for BAL was suspected pulmonary infection. Right upper lobes and middle lobes were the commonest sampled lobes. The optimal yield was similar in all the groups [MST (35.6%) vs MS (42.2%) vs WMS (36.5%); P = 0.27]. A significantly higher proportion of patients had BALF return >30% (P = 0.005) in the WMS (54.2%) and MS (54%) than in the MST arm (42.9%). The absolute and the percentage volume of BALF was also higher in WMS and MS than in the MST arm. There was no difference in the complication rate or other secondary outcomes across the groups. CONCLUSION: We found no difference in the optimal yield of BAL or complications using any one of the 3 methods for BAL fluid retrieval.

A novel indirect ELISA for serodiagnosis of mucormycosis using antigens from Rhizopus arrhizus.

BACKGROUND: Due to a delay in diagnosis by conventional techniques and high mortality, the development of a standardised and rapid non-culture-based technique is an unmet need in pulmonary, gastrointestinal, and disseminated forms of mucormycosis. Though limited studies have been conducted for molecular diagnosis, there are no established serologic tests for this highly fatal infection. OBJECTIVE: To develop and evaluate an indirect in-house enzyme-linked immunosorbent assay (ELISA) utilising antigens of Rhizopus arrhizus for detecting anti-Rhizopus antibodies (IgG and IgM) in sera of patients with mucormycosis. METHODS: We extracted both secretory and mycelial Rhizopus antigens using standardised protocols. Bradford assay was used for protein quantification. We then standardised an indirect ELISA using R. arrhizus mycelial and secretory antigens (10.0 µg/mL in bicarbonate buffer pH 9.2) for detecting anti-Rhizopus IgG and IgM antibodies in patient sera. We included patients with mucormycosis, other fungal infections, and healthy controls. Antibody index value (E-value) was calculated for each patient sample. RESULTS: Asparagine broth culture filtrate utilising 85% ammonium sulphate salt fractionation and mycelial homogenate grown in yeast extract peptone dextrose (YPD) broth precipitated with trichloroacetic acid (TCA) yielded a large amount of good-quality protein for the assay. We included 55 patients with mucormycosis (rhino-orbito-cerebral mucormycosis [ROCM, n = 39], pulmonary [n = 15], gastrointestinal [n = 1]), 24 with other fungal infections (probable aspergillosis [n = 14], candidiasis [n = 10]), and healthy controls (n = 16). The sensitivity of the antibody test for diagnosing mucormycosis ranged from 83.6-92.7% for IgG and 72.7-87.3% for IgM, with a specificity of 91.7-92.5% for IgG and 80-82.5% for IgM. The sera from patients with other fungal infections and healthy individuals did not show significant cross-reactivity. CONCLUSION: The detection of anti-Rhizopus IgG antibody performed significantly better in comparison to IgM-based ELISA for diagnosing both ROCM (sensitivity of 84.6% vs. 69.2%) and pulmonary cases (86.6% vs. 80.0%). More extensive studies are required to confirm our findings.

Bronchial Valves for Persistent Air Leak: A Systematic Review and Meta-analysis.

BACKGROUND: Patients with persistent air leak (PAL) pose a therapeutic challenge to physicians, with prolonged hospital stays and high morbidity. There is little evidence on the efficacy and safety of bronchial valves (BV) for PAL. METHODS: We systematically searched the PubMed and Embase databases to identify studies evaluating the efficacy and safety of BV for PAL. We calculated the success rate (complete resolution of air leak or removal of intercostal chest drain after bronchial valve placement and requiring no further procedures) of BV for PAL in individual studies. We pooled the data using a random-effects model and examined the factors influencing the success rate using multivariable meta-regression. RESULTS: We analyzed 28 observational studies (2472 participants). The pooled success rate of bronchial valves in PAL was 82% (95% confidence intervals, 75 to 88; 95% prediction intervals, 64 to 92). We found a higher success rate in studies using intrabronchial valves versus endobronchial valves (84% vs. 72%) and in studies with more than 50 subjects (93% vs. 77%). However, none of the factors influenced the success rate of multivariable meta-regression. The overall complication rate was 9.1% (48/527). Granulation tissue was the most common complication reported followed by valve migration or expectoration and hypoxemia. CONCLUSION: Bronchial valves are an effective and safe option for treating PAL. However, the analysis is limited by the availability of only observational data.

Innate and adaptive immune responses in subjects with CPA secondary to post-pulmonary tuberculosis lung abnormalities.

BACKGROUND: Post-tuberculosis lung abnormality (PTLA) is the most common risk factor for chronic pulmonary aspergillosis (CPA), and 14%-25% of the subjects with PTLA develop CPA. The pathogenesis and the host immune response in subjects with PTLA who develop CPA need to be better understood. METHODS: We prospectively compared the innate and adaptive immune responses mounted by patients of PTLA with or without CPA (controls). We studied the neutrophil oxidative burst (by dihydrorhodamine 123 test), classic (serum C3 and C4 levels) and alternative (mannose-binding lectin [MBL] protein levels) complement pathway, serum immunoglobulins (IgG, IgM and IgA), B and T lymphocytes and their subsets in subjects with PTLA with or without CPA. RESULTS: We included 111 subjects (58 CPA and 53 controls) in the current study. The mean ± SD age of the study population was 42.6 ± 15.7 years. The cases and controls were matched for age, gender distribution and body weight. Subjects with CPA had impaired neutrophil oxidative burst, lower memory T lymphocytes and impaired Th-1 immune response (lower Th-1 lymphocytes) than controls. We found no significant difference between the two groups in the serum complement levels, MBL levels, B-cell subsets and other T lymphocyte subsets. CONCLUSION: Subjects with CPA secondary to PTLA have impaired neutrophil oxidative burst and a lower Th-1 response than controls.

Prevalence of co-existent COVID-19-associated pulmonary aspergillosis (CAPA) and its impact on early mortality in patients with COVID-19-associated pulmonary mucormycosis (CAPM).

BACKGROUND: Data on mixed mould infection with COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated pulmonary mucormycosis (CAPM) are sparse. OBJECTIVES: To ascertain the prevalence of co-existent CAPA in CAPM (mixed mould infection) and whether mixed mould infection is associated with early mortality (≤7 days of diagnosis). METHODS: We retrospectively analysed the data collected from 25 centres across India on COVID-19-associated mucormycosis. We included only CAPM and excluded subjects with disseminated or rhino-orbital mucormycosis. We defined co-existent CAPA if a respiratory specimen showed septate hyphae on smear, histopathology or culture grew Aspergillus spp. We also compare the demography, predisposing factors, severity of COVID-19, and management of CAPM patients with and without CAPA. Using a case-control design, we assess whether mixed mould infection (primary exposure) were associated with early mortality in CAPM. RESULTS: We included 105 patients with CAPM. The prevalence of mixed mould infection was 20% (21/105). Patients with mixed mould infection experienced early mortality (9/21 [42.9%] vs. 15/84 [17.9%]; p = 0.02) and poorer survival at 6 weeks (7/21 [33.3] vs. 46/77 [59.7%]; p = 0.03) than CAPM alone. On imaging, consolidation was more commonly encountered with mixed mould infections than CAPM. Co-existent CAPA (odds ratio [95% confidence interval], 19.1 [2.62-139.1]) was independently associated with early mortality in CAPM after adjusting for hypoxemia during COVID-19 and other factors. CONCLUSION: Coinfection of CAPA and CAPM was not uncommon in our CAPM patients and portends a worse prognosis. Prospective studies from different countries are required to know the impact of mixed mould infection.

Bronchiectasis Severity Index and FACED scores in patients with allergic bronchopulmonary aspergillosis complicating asthma: do they correlate with immunological severity or high-attenuation mucus?

BACKGROUND: The utility of two disease-severity indices, namely bronchiectasis severity index (BSI) and FACED score in allergic bronchopulmonary aspergillosis (ABPA) remains unknown. OBJECTIVE: To correlate the BSI and FACED scores with immunological parameters (serum IgE [total and A. fumigatus-specific], A. fumigatus-specific IgG, blood eosinophil count), and high-attenuation mucus on chest computed tomography in ABPA. The secondary objectives were to evaluate the correlation between BSI and FACED scores and correlate the BSI/FACED scores with the bronchiectasis health questionnaire (BHQ) and Saint George's Respiratory Questionnaire (SGRQ). METHODS: We included treatment-naïve ABPA subjects with bronchiectasis in a prospective observational study. We computed the BSI and FACED scores for each subject before initiating treatment. The subjects also completed two quality-of-life questionnaires (BHQ and SGRQ). RESULTS: We included 91 subjects. The mean (standard deviation) BSI and FACED scores were 3.43 (3.39) and 1.43 (1.27). We found no correlation between BSI or FACED with any immunological parameter or high-attenuation mucus. There was a strong correlation between BSI and FACED scores (r = 0.76, p < 0.001). We found a weak correlation between BSI and BHQ/SGRQ and FACED and SGRQ. CONCLUSION: We found no correlation between BSI and FACED with immunological parameters in ABPA. However, we found a significant correlation between BSI and FACED and a weak correlation between SGRQ and BHQ. ABPA likely requires a separate disease-severity scoring system.

Diagnostic Yield and Safety of the 19-Gauge versus 22-Gauge Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Needle in Subjects with Sarcoidosis (GUESS).

INTRODUCTION: Observational data suggest that the 19-gauge (G) needle for endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) offers a higher diagnostic yield than the 22-G needle in sarcoidosis. No randomized trial has compared the yield of the two needles. METHODS: We randomized consecutive subjects with suspected sarcoidosis and enlarged thoracic lymph nodes to undergo EBUS-TBNA with either the 19-G or the 22-G needle. We compared the study groups for diagnostic sensitivity (primary outcome) assessed by the yield of granulomas in subjects finally diagnosed with sarcoidosis. We also compared the sample adequacy, difficulty performing the needle puncture assessed on a visual analog scale (VAS), the subject's cough intensity on an operator-rated VAS, and procedure-related complications (secondary outcomes). RESULTS: We randomized 150 (mean age, 43.0 years; 55% women) subjects and diagnosed sarcoidosis in 116 subjects. The diagnostic sensitivity of the 19-G needle (45/60, 75.0%) was not higher (p = 0.52) than the 22-G needle (39/56, 69.6%). We obtained adequate aspirates in 90.0% and 85.7% of subjects in the respective groups (p = 0.48). The operators had greater difficulty puncturing lymph nodes with the 19-G needle (p = 0.03), while the operator-assessed cough intensity was similar in the groups (p = 0.41). Transient hypoxemia was the only complication encountered during EBUS-TBNA (two subjects in either group). CONCLUSION: We did not find the 19-G needle superior to the 22-G in diagnostic sensitivity, specimen adequacy, or safety of EBUS-TBNA in sarcoidosis. Puncturing the lymph nodes was more difficult with the 19-G needle.