Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans.

Th17 cells provide protection at barrier tissues but may also contribute to immune pathology. The relevance and induction mechanisms of pathologic Th17 responses in humans are poorly understood. Here, we identify the mucocutaneous pathobiont Candida albicans as the major direct inducer of human anti-fungal Th17 cells. Th17 cells directed against other fungi are induced by cross-reactivity to C. albicans. Intestinal inflammation expands total C. albicans and cross-reactive Th17 cells. Strikingly, Th17 cells cross-reactive to the airborne fungus Aspergillus fumigatus are selectively activated and expanded in patients with airway inflammation, especially during acute allergic bronchopulmonary aspergillosis. This indicates a direct link between protective intestinal Th17 responses against C. albicans and lung inflammation caused by airborne fungi. We identify heterologous immunity to a single, ubiquitous member of the microbiota as a central mechanism for systemic induction of human anti-fungal Th17 responses and as a potential risk factor for pulmonary inflammatory diseases.

Non-Contrast-Enhanced Functional Lung MRI to Evaluate Treatment Response of Allergic Bronchopulmonary Aspergillosis in Patients With Cystic Fibrosis: A Pilot Study.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients is associated with severe lung damage and requires specific therapeutic management. Repeated imaging is recommended to both diagnose and follow-up response to treatment of ABPA in CF. However, high risk of cumulative radiation exposure requires evaluation of free-radiation techniques in the follow-up of CF patients with ABPA. PURPOSE: To evaluate whether Fourier decomposition (FD) functional lung MRI can detect response to treatment of ABPA in CF patients. STUDY TYPE: Retrospective longitudinal. POPULATION: Twelve patients (7M, median-age:14 years) with CF and ABPA with pre- and post-treatment MRI. FIELD STRENGTH/SEQUENCE: 2D-balanced-steady-state free-precession (bSSFP) sequence with FD at 1.5T. ASSESSMENT: Ventilation-weighted (V) and perfusion-weighted (Q) maps were obtained after FD processing of 2D-coronal bSSFP time-resolved images acquired before and 3-9 months after treatment. Defects extent was assessed on the functional maps using a qualitative semi-quantitative score (0 = absence/negligible, 1 = <50%, 2 = >50%). Mean and coefficient of variation (CV) of the ventilation signal-intensity (VSI) and the perfusion signal-intensity (QSI) were calculated. Measurements were performed independently by three readers and averaged. Inter-reader reproducibility of the measurements was assessed. Pulmonary function tests (PFTs) were performed within 1 week of both MRI studies as markers of the airflow-limitation severity. STATISTICAL TESTS: Comparisons of medians were performed using the paired Wilcoxon-test. Reproducibility was assessed using intraclass correlation coefficient (ICC). Correlations between MRI and PFT parameters were assessed using the Spearman-test (rho correlation-coefficient). A P-value <0.05 was considered as significant. RESULTS: Defects extent on both V and Q maps showed a significant reduction after ABPA treatment (4.25 vs. 1.92 for V-defect-score and 5 vs. 2.75 for Q-defect-score). VSI_mean was significantly increased after treatment (280 vs. 167). Qualitative analyses reproducibility showed an ICC > 0.90, while the ICCs of the quantitative measurements was almost perfect (>0.99). Changes in VSI_cv and QSI_cv before and after treatment correlated inversely with changes of FEV1%p (rho = -0.68 for both). DATA CONCLUSION: Non-contrast-enhanced FD lung MRI has potential to reproducibly assess response to treatment of ABPA in CF patients and correlates with PFT obstructive parameters. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

Unveiling the potential of estrogen: Exploring its role in neuropsychiatric disorders and exercise intervention.

Neuropsychiatric disorders shorten human life spans through multiple ways and become major threats to human health. Exercise can regulate the estrogen signaling, which may be involved in depression, Alzheimer's disease (AD) and Parkinson's disease (PD), and other neuropsychiatric disorders as well in their sex differences. In nervous system, estrogen is an important regulator of cell development, synaptic development, and brain connectivity. Therefore, this review aimed to investigate the potential of estrogen system in the exercise intervention of neuropsychiatric disorders to better understand the exercise in neuropsychiatric disorders and its sex specific. Exercise can exert a protective effect in neuropsychiatric disorders through regulating the expression of estrogen and estrogen receptors, which are involved in neuroprotection, neurodevelopment, and neuronal glucose homeostasis. These processes are mediated by the downstream factors of estrogen signaling, including N-myc downstream regulatory gene 2 (Ndrg2), serotonin (5-HT), delta like canonical Notch ligand 1 (DLL1), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), etc. In addition, exercise can act on the estrogen response element (ERE) fragment in the genes of estrogenic downstream factors like ß-amyloid precursor protein cleavase 1 (BACE1). However, there are few studies on the relationship between exercise, the estrogen signaling pathway, and neuropsychiatric disorders. Hence, we review how the estrogen signaling mediates the mechanism of exercise intervention in neuropsychiatric disorders. We aim to provide a theoretical perspective for neuropsychiatric disorders affecting female health and provide theoretical support for the design of exercise prescriptions.

Aspergillus-sensitized asthma in children.

BACKGROUND: Asthma is the most common chronic respiratory disease in childhood. Aspergillus fumigatus sensitivity may be involved in the pathogenesis of asthma by leading to different clinical presentations. OBJECTIVE: To investigate the demographic, clinical, laboratory, and radiological characteristics of A. fumigatus sensitivity in childhood asthma and identify associated risk factors and diagnostic parameters. METHODS: A total of 259 children with asthma were included in the study, 7 (2.7%) with allergic bronchopulmonary aspergillosis (ABPA), 84 (32.4%) with A. fumigatus-sensitized asthma (Af-SA), and 168 (64.9%) with A. fumigatus-unsensitized asthma (Af-UA). RESULTS: Aspergillus sensitivity was associated with early asthma onset and longer asthma duration. Total IgE level and asthma severity are highest in ABPA and higher in Af-SA. Absolute eosinophil count was higher, and FEV1 was lower in Af-SA and ABPA. Aspergillus fumigatus was associated with greater odds of being male (odds ratio [OR], 2.45), having atopic dermatitis (OR, 3.159), Alternaria sensitivity (OR, 10.37), and longer asthma duration (OR, 1.266). The best cut-off values for detecting A. fumigatus positivity were 363.5 IU/mL for total IgE and 455 cells/µL for absolute eosinophil count. In Af-SA compared to Af-UA, centrilobular nodules and peribronchial thickening were more common, and the bronchoarterial ratio was higher. CONCLUSIONS: Aspergillus sensitivity is a strong allergic stimulus in asthma, leading to laboratory, structural, clinical, and functional consequences. Af-SA is a distinct asthma endotype independent of ABPA that is characterized by increased risk of severe clinical presentations and impaired lung function.

Efficacy of Biologics in Patients with Allergic Bronchopulmonary Aspergillosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Treatment of allergic bronchopulmonary aspergillosis (ABPA) is challenging. Biological therapies have been reported as adjunctive treatments for ABPA, primarily in case series or case reports. This study aimed to analyze the efficacy of biologics for managing ABPA both qualitatively and quantitatively. METHODS: All articles on APBA published in October 2023 were searched in PubMed, Web of Science, ClinicalTrials.gov, and Embase databases. The effects of interest were the mean changes from baseline for outcomes, including exacerbation rates, oral corticosteroids usage (OCS), and total immunoglobulin E (IgE) levels. Reported outcomes were quantitatively synthesized by usual or individual patient data (IPD) meta-analyses. PROSPERO registration number: CRD42022373396. RESULTS: A total of 86 studies were included in the systematic review including 346 patients. Sixteen studies on omalizumab were pooled for the usual meta-analysis. Omalizumab therapy significantly reduced exacerbation rates (- 2.29 [95%CI - 3.32, - 1.26]), OCS dosage (- 10.91 mg [95%CI - 18.98, - 2.85]), and total IgE levels (- 273.07 IU/mL [95%CI - 379.30, - 166.84]), meanwhile improving FEV1% predicted (10.09% [95%CI 6.62, 13.55]). Thirty-one studies on dupilumab, mepolizumab, or benralizumab were pooled to perform an IPD meta-analysis, retrospectively. Both dupilumab and mepolizumab significantly reduced exacerbation rates, OCS, and total IgE levels. Benralizumab showed a similar trend, but it was not statistically significant. Tezepelumab showed weak evidence of its effects on ABPA. All five biologics led to milder clinical symptoms (e.g., cough, wheezing) with serious adverse effects that happened once in omalizumab treatment. CONCLUSION: These results indicate the clinical benefit of omalizumab, dupilumab, and mepolizumab in patients with ABPA. Further randomized, controlled studies with a larger sample size and longer follow-up are needed to confirm these findings.

Exposure to bisphenol A affects transcriptome-wide N6-methyladenine methylation in ovarian granulosa cells.

Bisphenol A (BPA) is an endocrine disruptor of potential reproductive toxicities. Increasingly research elucidated that BPA exposure to the environment would change the epigenetic modifications of transcriptome, but the mechanism by which BPA affects m6A methylation in interfering with female reproductive health remains uncertain. Therefore, this study preliminarily proposed and tested the hypothesis that BPA exposure alters the m6A modification level in transcripts in female ovarian granulosa cells. After BPA was exposed to granulosa cells for 24 h, RNA methylation related regulatory genes (such as METTL3, METTL14, ALKBH5, FTO) and the global m6A levels showed significant differences. Next, we applied MERIP-seq analysis to obtain information on the genome-wide m6A modification changes and identified 1595 differentially methylated mRNA transcripts, and 50 differentially methylated lncRNA transcripts. Further joint analysis of gene common expression showed that 33 genes were hypermethylated and up-regulated, 71 were hypermethylated and down-regulated, 49 were hypomethylated and up-regulated, and 20 were hypomethylated and down-regulated. Enriched Gene Ontology (GO) and biological pathway analysis revealed that these unique genes were mainly enriched in lipid metabolism, cell proliferation, and apoptosis related pathways. Six of these genes (mRNAs IMPA1, MCOLN1, DCTN3, BRCA2, and lncRNAs MALAT1, XIST) were validated using RT-qPCR and IGV software. Through comprehensive analysis of epitranscriptome and protein-protein interaction (PPI) data, lncRNAs MALAT1 and XIST are expected to serve as new markers for BPA interfering with the female reproductive system. In brief, these data show a novel and necessary connection between the damage of BPA exposure on female ovarian granulosa cells and RNA methylation modification.

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.

Allergic Aspergillus diseases can make patients with asthma more unwell, but this is difficult to diagnose, especially in developing countries where tests are not widely available. We have found that a cheap, easy-to-use and fast test may be useful in diagnosing allergic Aspergillus diseases.

The minimal important difference of St.George's respiratory questionnaire in subjects with chronic pulmonary aspergillosis.

The estimates of the minimal important difference (MID) for the Saint George's respiratory questionnaire (SGRQ) score in CPA remain unknown. We performed a retrospective analysis on treatment-naïve CPA subjects (n = 148) treated with six-month oral itraconazole therapy and completed SGRQ at baseline and six months. The study's objective was to estimate the MID for SGRQ. We used an anchor-based method to determine the MID and found the MID for SGRQ of 7.3.

The estimates of the minimal important difference (MID) for the Saint George's respiratory questionnaire (SGRQ) score in CPA remain unknown. Using an anchor-based method, we found theMID for SGRQ of 7 in CPA.

Comparison of diagnostic efficiency of detecting IgG and IgE with immunoassay method in diagnosing ABPA: a meta-analysis.

BACKGROUND: Hitherto, the bulk of diagnostic criteria regards Aspergillus-specific immunoglobulin E as a key item, and regard IgG as an auxiliary method in diagnose. Nevertheless, there is no conclusive study in summarize the performance of IgG and IgE diagnosing ABPA. METHODS: We conducted a systematic review to identify studies report results of IgE and IgG detection in diagnosing ABPA. QUADAS-2 tool was used to evaluate included studies, and we applied the HSROC model to calculate the pooled sensitivity and specificity. Deeks' funnel was derived to evaluated the public bias of included studies, and Cochrane Q test and I2 statistic were used to test the heterogeneity. RESULTS: Eleven studies were included in this study (1127 subjects and 215 for IgE and IgG). Deeks's test for IgE and IgG were 0.10 and 0.19. The pooled sensitivity and specificity for IgE were 0.83 (95%CI: 0.77, 0.90) and 0.89 (0.83, 0.94), and for IgG were 0.93 (0.87, 0.97) and 0.73 (0.62,0.82), with P value < 0.001. The PLR and NLR for IgE were 7.80 (5.03,12.10) and 0.19 (0.13,0.27), while for IgG were 3.45 (2.40,4.96) and 0.09 (0.05,0.17). The combined diagnostic odds ratio and diagnostic score were 41.49 (26.74,64.36) and3.73 (3.29,4.16) for IgE, respectively, and were 38.42 (19.23,76.79) and 3.65 (2.96,4.34) for IgG. CONCLUSION: The sensitivity for IgG diagnosing ABPA is higher than IgE, while the specificity for IgE is higher. IgG might be able to play a more important role in filtering ABPA patients.

Infection Dynamics of Aspergillus fumigatus in Adults with Cystic Fibrosis (CF).

OBJECTIVE: Aspergillus fumigatus (A. fumigatus) has emerged as a significant pathogen in patients with cystic fibrosis (CF) and currently is within the top five isolated organisms reported in several international CF patient registries. A. fumigatus has been attributed to disease progression, although its role remains controversial. There is a paucity of reports on its infection dynamics, it was the aim of this study to examine time to first laboratory reports of A. fumigatus acquisition and to correlate this with patient gender and cystic fibrosis transmembrane conductance regulator (CFTR) mutation type. METHODS: One hundred adult (≥ 18 years) CF patients were examined (50 females, 50 males; mean age 24.6 years ± 6.25 (SD), median age 24 years; maximum age 76 years). CFTR mutation groups consisted (i) F508del/F508del homozygous (n = 45), (ii) F508del/other heterozygous (n = 45) and (iii) others (n = 10). CFTR mutation type, patient gender, presence/absence of A. fumigatus and time (months) to first isolation of A. fumigatus were examined. RESULTS: Microbiological data was examined from 100 patients from birth to present (31/12/2021), equating to 2455 patient years. A. fumigatus was isolated from 66/100 (66%) adult CF patients; (i) F508del/F508del homozygous (82%; 37/45), (ii) F508del/other heterozygous (56%; 25/45) and (iii) others (40%; 4/10). Within the F508del/other heterozygous group, 14 mutations were noted on the second allele, with R560T and R117H collectively accounting for 36% of the second mutations. Four unique allele/allele mutations were noted in the Other Mutations category. There was a trend to a higher A. fumigatus acquisition in F508del/F508del homozygous patients than with F508del/other patients (p = 0.0529). Of the 66 patients who were positive for A. fumigatus, 35(53%) were male and 31(47%) were female. The median and mean time to first isolation of A. fumigatus in all A. fumigatus-positive patients was 119.5 months and 128 months, respectively, shortest time was 12 months, longest time 288 months. There was a statistical significance in time-to-first isolation in relation to CFTR mutation group (p = 0.0272), whereby F508del homozygous individuals had their first isolation of A. fumigatus at 116.8 ± 7.9 months (mean ± standard error of the mean (SEM)) and F508del heterozygous patients had their first isolate of A. fumigatus at 150.4 months ± 13.7 months (mean ± SEM), approximately 2.75 years after their F508del homozygous peers. There was no significant difference (p = 0.12) in time to first acquisiton between males and females, whereby males had their first A. fumigatus isolate at 118 ± 9.4 months, whereas females had their first A. fumigatus isolate at 140 ± 10.8 months. The highest rate of first A. fumigatus isolation was from 4 years until 16 years and by the age of 16 years, approximately 85% of A. fumigatus-positive patients had recorded their first A. fumigatus isolate. CONCLUSION: To minimise the risk of first acquisition of A. fumigatus, it is important that infection prevention educational messaging is delivered in the paediatric clinic, to enhance health literacy around A. fumigatus acquisition.

Relationship between Aspergillus and asthma.

Fungal sensitization is highly prevalent in severe asthma. The relationship between fungus and asthma, especially Aspergillus fumigatus, has been the subject of extensive research. The ubiquitous presence of A. fumigatus, its thermotolerant nature, the respirable size of its conidia, and its ability to produce potent allergens are pivotal in worsening asthma control. Due to the diverse clinical manifestations of fungal asthma and the lack of specific biomarkers, its diagnosis remains intricate. Diagnosing fungal asthma requires carefully assessing the patient's clinical history, immunological tests, and imaging. Depending on the severity, patients with fungal asthma require personalized treatment plans, including inhaled corticosteroids and bronchodilators, and antifungal therapy. This review provides a comprehensive overview of the association between Aspergillus and asthma by reviewing the relevant literature and highlighting key findings. We discuss the diagnosis of various entities included in fungal asthma. We also debate whether newer definitions, including allergic fungal airway disease, offer any additional advantages over the existing ones. Finally, we provide the current treatment options for the individual entities, including A. fumigatus-associated asthma, severe asthma with fungal sensitization, and allergic bronchopulmonary mycoses.

Assessing the health risk of living near composting facilities on lung health, fungal and bacterial disease in cystic fibrosis: a UK CF Registry study.

AIM: To explore the health risk of living near permitted composting sites (PCSs) on disease severity in children and adults with cystic fibrosis (CF) across the UK.  METHODS: A semi-individual cross-sectional study was used to examine the risk of disease severity in people with CF (pwCF) within and beyond 4 km of PCSs in the UK in 2016. All pwCF registered in the UK CF Registry were eligible for this study. Linear and Poisson regressions, adjusted for age, gender, genotype, BMI, Pseudomonas aeruginosa and deprivation, were used to quantify associations between distance to a PCS and percent predicted forced expiratory volume in one second (ppFEV1), pulmonary exacerbations (#IVdays), and fungal and bacterial infections. RESULTS: The mean age of the 9,361 pwCF (3,931 children and 5,430 adults) studied was 20.1 (SD = 14.1) years; 53.3% were male; and 49.2% were homozygous F508del. Over 10% of pwCF (n = 1,015) lived within 4 km of a PCS. We found no statistically significant difference in ppFEV1 and #IVdays/year in children. However, in adults, ppFEV1 was -1.07% lower (95% confidence interval (CI): -2.29%, 0.16%) and #IVdays/year were 1.02 day higher (95%CI: 1.01, 1.04) within 4 km of a PCS. Furthermore, there were statistically significant differences in mean ppFEV1 in CF adults with Aspergillus fumigatus (58.2.% vs 62.0%, p = 0.005) and Candida spp. (56.9% vs 59.9%, p = 0.029) residing within 4 km of a PCS. No associations were identified for allergic bronchopulmonary aspergillosis, P. aeruginosa or Staphylococcus aureus. CONCLUSIONS: This novel national study provides evidence that adults with CF living near a PCS may experience small reductions in lung function, an increased risk of pulmonary exacerbations, and more frequent fungal infections. If confirmed by studies using refined exposure assessment methods accounting for bioaerosol dispersion, these results could have important implications for the living environment of pwCF.

Occurrence of Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutations in Patients with Allergic Bronchopulmonary Aspergillosis Complicating Asthma.

BACKGROUND: Whether cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations contribute to the high prevalence of allergic bronchopulmonary aspergillosis (ABPA) in India remains unknown. We aimed to evaluate the occurrence of CFTR mutations in subjects with ABPA complicating asthma. METHODS: We sequenced the CFTR gene using genomic DNA from blood on the Illumina NextSeq500 platform. Before undertaking zygosity analysis by genome analysis toolkit, the known or novel single nucleotide polymorphisms (SNPs) and indels were called. For rigorous analysis, we included only high-quality SNPs (scores > 500) and coverage ranging from 30 × 150x. RESULTS: We included 18, 12, and eight adult participants of ABPA, asthma, and healthy controls, respectively. The frequency of SNPs was higher in asthmatic subjects than ABPA or healthy controls, albeit not statistically significant (9/12 [75%] vs. 11/18 [61.1%] vs. 3/8 [37.5%], p = 0.24). Of the 38 subjects, 23 yielded 50 variants (healthy controls [n = 5], ABPA [n = 22], asthma [n = 23]) corresponding to six SNPs not previously linked with ABPA. Of these, four SNPs (rs213950, rs200735475, rs1800113, and rs1800136) were catalogued in the NCBI database. We identified two novel SNPs (chr7:117250703, chr7:117282655) in four (ABPA [n = 1], asthma [n = 3]) subjects without corresponding reference SNP. Most SNPs (85.5%) were heterozygous. The frequency of SNPs was higher in ABPA subjects with high-attenuation mucus (52.2%) and bronchiectasis (39.1%) than serological ABPA (8.7%). CONCLUSIONS: Our study suggests the role of CFTR mutations in the pathogenesis of ABPA. The SNPs in the CFTR gene may contribute to disease severity in ABPA. Larger studies are required to confirm our findings.

Can dose reduction be made in patients with allergic bronchopulmonary aspergillosis receiving high-dose omalizumab treatment?

Summary: Objective. To reduce the omalizumab dose in patients with allergic bronchopulmonary aspergillosis (ABPA) who were on long-term omalizumab treatment. Methods. Once asthma was controlled, two approaches were used to reduce total monthly omalizumab dose, 1) both extending dose intervals from 2 to 4 weeks and decrease omalizumab dose, 2) to reduce omalizumab dose while keeping dose intervals stable. Results. Thirteen patients with ABPA (8F/5M, mean age 53.4 ± 13.0 years) were included. Pre-omalizumab, mean blood eosinophil count was 723.1 ± 547.1 cells/mcL, mean numbers of attacks and hospitalizations were 2.5 ± 1.5 and 1.3 ± 0.8, respectively. Median total monthly omalizumab dose was 750 (min 300, max 900) mg. First and 2nd approach to reduce omalizumab dose was used in nine and four patients with a median time of reduction 32 (min 13, max 47) months. The 2nd dose reduction was made in four patients at median of 23.5 months. Pre-omalizumab, mean oral corticosteroid (OCS, as methylprednisolone) dose was 12.2 ± 10.4 mg daily, it decreased to 0.69 ± 0.95 mg (p = 0.001) in the 1st year of omalizumab and could be stopped in 11 patients. Attacks and hospitalizations decreased to 0.31 ± 0.86 (p less than 0.001) and 0 (p = 0.003), respectively, in the 1st year of omalizumab. Total omalizumab dose was reduced by median 40% (min 20, max 60) in 1st intervention and 50% (min 20, max 67) after 2nd intervention. After omalizumab reduction, asthma control did not deteriorate and there was no need to increase the omalizumab or OCS-dose. Conclusions. Decreasing the total omalizumab dose does not cause clinical deterioration in ABPA after the disease is controlled.

Pregnancy complicated by allergic bronchopulmonary aspergillosis: A case-control study.

BACKGROUND: Whether allergic bronchopulmonary aspergillosis (ABPA) affects maternal and perinatal outcomes during pregnancy or vice versa is unknown. OBJECTIVE: To evaluate the course of ABPA and its consequence on maternal and perinatal outcomes during pregnancy. METHODS: We retrospectively included pregnant women with ABPA (cases) and compared them with non-pregnant ABPA subjects (controls). We recorded the following details in cases and controls: demographical characteristics, radiological findings, pulmonary function, duration of symptoms and the number of asthma and ABPA exacerbations during follow-up. We also recorded the maternal and perinatal outcomes in the cases. RESULTS: We included nine cases and 38 controls with a similar age range. All the cases had achieved remission of ABPA before pregnancy and were receiving inhaled medications for asthma control. Serum total IgE levels, the extent of bronchiectasis on CT thorax and pulmonary function were comparable in the two groups. The mean number of asthma (53 vs 7) and ABPA (62 vs 16) exacerbations per 100 person-years was significantly higher in cases compared to the controls. We did not observe any maternal complications. One neonate had low birthweight. CONCLUSIONS: The risk of asthma and ABPA exacerbations is significantly higher in pregnant subjects with ABPA than non-pregnant women with ABPA. However, maternal and perinatal outcomes are good.

Allergic fungal airways disease (AFAD): an under-recognised asthma endotype.

The term allergic fungal airways disease has a liberal definition based on IgE sensitisation to thermotolerant fungi and evidence of fungal-related lung damage. It arose from a body of work looking into the role of fungi in asthma. Historically fungi were considered a rare complication of asthma, exemplified by allergic bronchopulmonary aspergillosis; however, there is a significant proportion of individuals with Aspergillus fumigatus sensitisation who do not meet these criteria, who are at high risk for the development of lung damage. The fungi that play a role in asthma can be divided into two groups; those that can grow at body temperature referred to as thermotolerant, which are capable of both infection and allergy, and those that cannot but can still act as allergens in IgE sensitised individuals. Sensitisation to thermotolerant filamentous fungi (Aspergillus and Penicillium), and not non-thermotolerant fungi (Alternaria and Cladosporium) is associated with lower lung function and radiological abnormalities (bronchiectasis, tree-in-bud, fleeting shadows, collapse/consolidation and fibrosis). For antifungals to play a role in treatment, the focus should be on fungi capable of growing in the airways thereby causing a persistent chronic allergenic stimulus and releasing tissue damaging proteases and other enzymes which may disrupt the airway epithelial barrier and cause mucosal damage and airway remodelling. All patients with IgE sensitisation to thermotolerant fungi in the context of asthma and other airway disease are at risk of progressive lung damage, and as such should be monitored closely.

The Use of Targeted Monoclonal Antibodies in the Treatment of ABPA-A Case Series.

Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disorder occurring in response to Aspergillus fumigatus that can complicate the course of asthma and cystic fibrosis. Here we present a case of acute ABPA without central bronchiectasis, a case of chronic active ABPA with central bronchiectasis, and a case of severe relapsing ABPA with central bronchiectasis. All three were initially treated with corticosteroids and antifungal agents but had an incomplete response. These patients were then treated with anti-IgE therapy with omalizumab before being switched to the anti-IL5R agent benralizumab. They responded well to both agents. These case reports highlight the potential role of omalizumab and benralizumab in the treatment of ABPA, but further studies are required to evaluate the effectiveness of these medications. Longer follow-up periods and objective measurements of the impact of treatment are necessary.

Intravenous immunoglobulin protects from experimental allergic bronchopulmonary aspergillosis via a sialylation-dependent mechanism.

Intravenous immunoglobuin (IVIG) exerts protective effects in experimental allergic bronchopulmonary aspergillosis (ABPA) via a sialylation-dependent mechanism. The protection was associated with reduced recruitment of eosinophils, diminished goblet cell hyperplasia, suppressed Th2 and Th17 responses and reciprocally enhanced regulatory T cells and IL-10, and decreased IgE levels in the circulation.

Analysis of serum polyunsaturated fatty acid metabolites in allergic bronchopulmonary aspergillosis.

BACKGROUND: The importance of lipid mediators in allergic diseases has been long recognized, whereas little is known about their role in allergic bronchopulmonary aspergillosis (ABPA). We investigated whether lipid mediators are associated with ABPA. METHODS: We recruited 12 ABPA patients, 23 asthma patients and 12 healthy control in our study. Serum of 11 ABPA patients were collected before and following treatment. 36 polyunsaturated fatty acid metabolites were measured in serum samples by using liquid chromatography-mass spectrometry. This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University, with ethics number GYFYY-2016-73. RESULTS: Levels of arachidonic acid (AA), 15(S)-hydroxyeicosatetraenoic acid (HETE), 12(S)-HETE, 8(S)-HETE, 5(S)-HETE, LTB4, PGB2, 12(S)-hydroxyeicosapentaenoic acid (HEPE), 12-hydro-xyheptadecatrienoic acid (HHTrE) were significantly higher in ABPA patients than that in HC groups. Compared with asthma group, ABPA group expressed lower levels of 15(S)-hy-droperoxyeicosatetraenoic acid (HPETE), 5(S)-HPETE, 13(S)-hydroperoxyoctadecadienoic acid (HPODE) and 9(S)-HPODE. In APBA patients, AA level was positively correlated with serumtotal IgE (tIgE). The levels of 12(S)-HPETE, 15(S)-HEPE and 12(S)-HEPE correlated with Asp-ergillus fumigatus specific IgE(A. fumigatus sIgE) positively. Peripheral blood eosinophilia correlated with high levels of 12(S)-HETE and 15(S)-HETE. In addition, the serum levels of15(S)-HETE and 12(S)-HETE in ABPA subjects both declined with the decrease of tIgE, A. fumigatus sIgE and sIgG concentrations after treatment. CONCLUSIONS: We present data regarding the role of polyunsaturated fatty acid metabolites in APBA for the first time. Most of the tested metabolites increased in ABPA when co-mpared with healthy controls and 15(S)-HETE and 12(S)-HETE may play a role in the pat-hogenesis of ABPA. These findings can provide new ideas for diagnosis, therapy and mon-itor of ABPA.

Association of Serum TGF-ß1 Levels with Different Clinical Phenotypes of Cystic Fibrosis Exacerbation.

PURPOSE: Cystic Fibrosis (CF) is a multi-organ genetic disorder and Transforming Growth Factor (TGF-ß1) is a modifier gene which modulates lung pathology in CF. There is great phenotypic variability among CF patients who even have similar genotype. The aim of the present study was to associate the serum levels of TGF-ß1 with several clinical phenotypes of CF. METHODS: The diagnosed cases of CF were recruited and the blood sample was withdrawn at different time points: during exacerbation (n = 26), non-exacerbation (n = 9) and after antibiotic therapy (n = 11). The concentration of the total TGF-ß1 in serum was measured with commercial ELISA kit. The ΔF508 mutation was assessed by the Amplification Refractory Mutation System (ARMS-PCR). RESULTS: The levels of TGF-ß1 were increased in exacerbation phase (119.89 ± 29.64 ng/mL), infection with P. aeruginosa (121.8 ± 28.83 ng/mL) and in subjects with ΔF508 mutation (139.2 ± 19.59 ng/mL). The levels of TGF-ß1 in CF patients with Allergic Bronchopulmonary Aspergillosis (ABPA) (109.97 ± 27.71 ng/mL) were decreased as compared to CF patients without ABPA (123.55 ± 30.20 ng/mL). It was observed that the serum levels of TGF-ß1 were decreased significantly after antibiotic therapy (p < 0.05). CONCLUSIONS: The present study has determined that the serum levels of TGF-ß1 vary with the type of infections, ΔF508 CFTR mutation, presence of ABPA and response to therapy.