Allergic Bronchopulmonary Aspergillosis Patients Research Articles

A challenge in diagnosis and treatment in asthma patients with allergic bronchopulmonary aspergillosis: a review

Allergic bronchopulmonary aspergillosis (ABPA) is a common form of fungal-related asthma disease mainly caused by Aspergillus fumigatus. The increasing prevalence of asthma globally and the characteristic of Aspergillus are very easily dispersed in the air to inhale, leading to increased cases of ABPA in asthma patients. Inhalation of conidia Aspergillus spp. can trigger asthma exacerbations due to poor mucociliary clearance. However, the exact pathogenesis is still unclear. Clinical features commonly found in ABPA patients are productive cough with dark green or brown mucus or even hemoptysis. Several criteria for establishing the diagnosis of ABPA can be based on clinical features, laboratory examinations, and imaging, but none has become the gold standard. However, the primary laboratory test utilized for ABPA screening is the measurement of serum-specific IgE levels to A. fumigatus, owing to its high sensitivity. Despite the challenges in finding the most fitting universal consensus, most clinicians still follow the criteria proposed by Rosenberg et al. in 1977. The recommended ABPA treatment is prednisone and/or azole antifungal agents such as itraconazole. In addition, the potential of monoclonal antibodies in ABPA therapy is still under further research. Long-term diagnosis and treatment delays can lead to complications such as bronchiectasis and fibrosis. This review aimed to highlight ABPA in asthma patients, from etiopathogenesis to managing the disease

Exploring the Epidemiology and Clinico-Demographic Characteristics of Allergic Bronchopulmonary Aspergillosis in Children with Cystic Fibrosis

Abstract Objective This study aimed to find the prevalence and clinico-demographic profile of cystic fibrosis (CF) children with allergic bronchopulmonary aspergillosis (ABPA). Methods A cross-sectional study was conducted at a CF clinic of a tertiary care hospital. Participants included the diagnosed cases of children with CF, of both genders, from 4 to 18 years of age. Results A total of 61 patients were enrolled. Sixteen patients (26.2%) had Aspergillus fumigatus sensitization—among these, 10 (16.4%) patients fulfilled the minimum diagnostic criteria for ABPA and 6 (9.8%) had A. fumigatus sensitization only. Two patients were below the age of 5 years, while eight patients were more than 6 years old. The female-to-male ratio was 6:4. High attenuated mucus was the specific finding in our study cohort on computed tomography (CT) chest. All patients with ABPA had significantly higher median (interquartile range [IQR]) levels of total IgE, specific IgE, and IgG for A. fumigatus, and total eosinophil count compared to patients without ABPA. There was also a significant decrease in forced exhalation volume in first second (FEV1) values (6 months apart) in ABPA patients. Conclusion Our study found that ABPA affects 16.4% of our CF population, with 20% of cases occurring in children aged 4 to 5 years. We observed a higher prevalence of ABPA in patients from rural areas. Eosinophilia and serial decline in FEV1 values were observed as potential early markers for ABPA.

Th2-skewed peripheral T-helper cells drive B-cells in allergic bronchopulmonary aspergillosis.

Patients with allergic bronchopulmonary aspergillosis (ABPA) suffer from repeated exacerbations. The involvement of T-cell subsets remains unclear. We enrolled ABPA patients, asthma patients and healthy controls. T-helper type 1 (Th1), 2 (Th2) and 17 (Th17) cells, regulatory T-cells (Treg) and interleukin (IL)-21+CD4+T-cells in total or sorted subsets of peripheral blood mononuclear cells and ABPA bronchoalveolar lavage fluid (BALF) were analysed using flow cytometry. RNA sequencing of subsets of CD4+T-cells was done in exacerbated ABPA patients and healthy controls. Antibodies of T-/B-cell co-cultures in vitro were measured. ABPA patients had increased Th2 cells, similar numbers of Treg cells and decreased circulating Th1 and Th17 cells. IL-5+IL-13+IL-21+CD4+T-cells were rarely detected in healthy controls, but significantly elevated in the blood of ABPA patients, especially the exacerbated ones. We found that IL-5+IL-13+IL-21+CD4+T-cells were mainly peripheral T-helper (Tph) cells (PD-1+CXCR5-), which also presented in the BALF of ABPA patients. The proportions of circulating Tph cells were similar among ABPA patients, asthma patients and healthy controls, while IL-5+IL-13+IL-21+ Tph cells significantly increased in ABPA patients. Transcriptome data showed that Tph cells of ABPA patients were Th2-skewed and exhibited signatures of follicular T-helper cells. When co-cultured in vitro, Tph cells of ABPA patients induced the differentiation of autologous B-cells into plasmablasts and significantly enhanced the production of IgE. We identified a distinctly elevated population of circulating Th2-skewed Tph cells that induced the production of IgE in ABPA patients. It may be a biomarker and therapeutic target for ABPA.

Clinicomycological Study of the Spectrum of Pulmonary Aspergillosis at a Tertiary Care Hospital in Central India.

Knowing the spectrum, prevalence, and modes of diagnosis of pulmonary aspergillosis (PA) will be beneficial to clinicians for its early diagnosis and management. This study aims to estimate the prevalence, spectrum, and role of serological tests and radiological findings in the diagnosis of PA. A total of 150 patients were suspected of having PA after obtaining relevant clinical history and radiological imaging. The patients were grouped into each spectrum of PA as invasive PA (IPA), chronic necrotizing PA (CNPA), aspergilloma, allergic bronchopulmonary aspergillosis (ABPA) based on predisposing factors, clinical and radiological findings, and the guidelines of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG). Samples (bronchoalveolar lavage (BAL), sputum, blood) were collected from these patients and processed in a microbiology lab. BAL and sputum were subjected to microscopy by potassium hydroxide mount, calcofluor white mount, and culture. The serum was separated from blood by centrifugation and subjected to specific serological tests based on the spectrum of PA that the patient was suspected to have. For IPA, serum and BAL galactomannan antigen enzyme-linked immunosorbent assay (ELISA) was performed. For CNPA and aspergilloma, the anti-Aspergillus IgG antibody ELISA was performed. For ABPA, the tests performed were total immunoglobulin E (IgE) ELISA, Aspergillus fumigatus-specific IgE ELISA, and anti-Aspergillus immunoglobulin G (IgG) antibody ELISA. After compiling the clinical, radiological, culture, and serological findings, patients were diagnosed to have a particular spectrum of PA. The prevalence of IPA was 1.4%, CNPA was 4%, ABPA was 3.2%, and aspergilloma was 2.9%. CNPA was the predominant spectrum of PA in our study. Culture positivity for Aspergillus species was seen the highest in aspergilloma patients, followed by IPA, ABPA, and CNPA patients. A. fumigatus was the most common causative agent of PA, except for IPA for which Aspergillus flavus was the most common causative. Aspergillus niger and Aspergillus terreus were less the frequent causes of PA. A combination of radiological, microbiological, and serological tests along with clinical correlation is needed to confirm the diagnosis of PA.

Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

Allergic fungal airway diseases: analysis of data in asthma patient register

Introduction. Allergy to microscopic fungi (micromycetes), which can colonize the respiratory tract, is associated with an eosinophilic endotype of inflammation and severe disease course. Among the hallmarks of fungal allergy, experts identify fixed airways obstruction, bronchiectasis, and fibrosis. Currently, there has been proposed the term “allergic fungal airways disease” (AFAD), which combines various clinical phenotypes, which pathogenesis is based on IgE-mediated allergic reaction against fungal spores colonizing the respiratory tract. According to this approach, the AFAD group includes severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis (ABPA). A promising direction in AFAD treatment implies the use of genetically engineered biological drugs against T-2 inflammation. The aim of the study was to evaluate the prevalence ofAspergillusspp. sensitization and allergic bronchopulmonaryAspergillosis in patients with asthma.&#x0D; Materials and methods. A retrospective single-center registry study was conducted in the I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russian Federation. The study included 523 patients with asthma of varying severity. The level of total and specific blood serum IgE against aeroallergens, includingAspergillusspp., was analyzed by enzyme immunoassay. The diagnosis of asthma was established in accordance with the recommendations of the GINA working group and the Clinical recommendations of the Ministry of Health of the Russian Federation, fungal sensitization and ABPA — in accordance with the recommendations of the ISHAM working group.Results. During the examination of patients with asthma, sensitization toAspergillusspp. recorded in 16.6% cases, severe asthma with sensitization toAspergillusspp. — in 7.4%, ABPA — in 6.1%. In patients with allergic asthma, the prevalence of sensitization toAspergillusspp. was 22%, severe asthma with sensitization toAspergillusspp. — 10.1%, ABLA — 8.1%. Among patients with ABPA, females (64%) aged 40 years and older prevailed. The major clinical manifestations of ABPA were presented as cough (96%) and shortness of breath (76%), CT scan radiological changes were in a form of bronchiectasis (72%).&#x0D; Conclusion. A high prevalence of sensitization toAspergillusspp. in patients with asthma was found. It is necessary to includeAspergillusspp. into the list of tested allergens while examining patients with chronic lung diseases for timely detection of AFAD and prescription of proper anti-inflammatory or antimycotic therapy.

Clinical, Microbiological, Serological and Radiological Profile of Patients With Mild-Moderate and Severe Allergic Bronchopulmonary Aspergillosis (ABPA).

Objective Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus antigen mostly Aspergillus fumigatus that occurs almost exclusively in patients with asthma and cystic fibrosis. ABPA is an underdiagnosed and undertreated disease because of its presentation with various grades of severity in asthma patients. Data available regarding the clinical, serological, and radiological profile of ABPA patients is limited due to lack of consensus on diagnostic criteria and treatment guidelines. Thus ABPA is a significant disease, especially in the Indian population where the incidence of allergic diseases like asthma is on the rise. Methods This prospective study was conducted in the Department of Pulmonary Medicine at one of the tertiary centers of north India. All consecutive patients diagnosed withallergic bronchopulmonary aspergillosis (ABPA) from 1st January 2017to 30th September 2017 were included in the study. A total of 67 consecutive patients diagnosedwithbronchial asthma were included in the study. The diagnosis of ABPA was based upon either criterion given by Rosenberg and Patersonor the International Society of Human and Animal Mycology (ISHAM) criteria. Patients diagnosed with ABPAwere finally divided into mild, moderate, and severe. Results The majority of patients showed an obstructive pattern on spirometry and moderate to severe obstruction was the most common pattern observed among patients who had an obstructive pattern on spirometry. Also, all three patients with the mixed pattern on spirometry had severe disease. Serological analysis revealed that patients in the moderate category had a higher level of absolute eosinophil count (AEC), total IgE, and Aspergillus-specific IgE antibodies, especially in patients who hadeither high attenuation mucus (HAM) or centrilobular nodules on their high-resolution computed tomography (HRCT) scan. Conclusion ABPA is a disease of divergent presentation. We concluded to have alternate or add-on criteria for the classification of ABPA which was not based on the sequelae of chronic inflammatory changes in the lungs.

Heterozygous CARD9 mutation favors the development of allergic bronchopulmonary aspergillosis.

Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA. A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease. The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production. Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.

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

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. To evaluate whether Fourier decomposition (FD) functional lung MRI can detect response to treatment of ABPA in CF patients. Retrospective longitudinal. Twelve patients (7M, median-age:14 years) with CF and ABPA with pre- and post-treatment MRI. 2D-balanced-steady-state free-precession (bSSFP) sequence with FD at 1.5T. 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. 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. 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). 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. 4 TECHNICAL EFFICACY: Stage 3.

Allergic Bronchopulmonary Aspergillosis in Patients with Dominant Negative IL6ST

Pathogenic variants in IL6ST cause a Hyper-IgE syndrome (HIES) that presents similarly to STAT3 dominant negative (DN) HIES. Severe structural lung disease with bronchiectasis and pneumatoceles is a major driver of morbidity in this disease. We describe clinical characteristics of four patients with heterozygous IL6ST variants with presentations consistent with allergic bronchopulmonary aspergillosis (ABPA).

Proportion of Allergic Bronchopulmonary Aspergillosis Presenting as Difficult-to-control Asthma in Patients Attending a Tertiary Care Centre using the Modified ISHAM Criteria: A Cross-sectional Study

Introduction: Difficult-to-control asthmatics, as defined by the Global Initiative for Management of Asthma (GINA), belong to a subset of patients whose symptoms remain uncontrolled despite adhering to maximal optimised therapy. Complex hypersensitivity reactions in response to airway colonization with Aspergillus fumigatus, which occurs in patients with asthma or cystic fibrosis, are established factors for a poor response to treatment and frequent exacerbations. Only limited data related to Allergic Bronchopulmonary Aspergillosis (ABPA) is available from India, particularly from Kerala. Aim: To assess the occurrence of ABPA in patients with difficultto-control asthma using the modified ISHAM criteria. Materials and Methods: This cross-sectional analysis was conducted in the Department of Pulmonary Medicine, Institute of Chest Diseases, Government Medical College, Kozhikode, Kerala, India from February 2019 to July 2020. The study population comprised asthmatics attending the Pulmonary Medicine Outpatient Services who were on regular medications, including optimal doses of inhaled corticosteroid and longacting beta-agonist combinations. Patients with two or more exacerbations per year requiring systemic steroids for symptom control and a positive skin test for Aspergillus fumigatus antigen were further analysed using the modified International Society for Human and Animal Mycology (IHAM) criteria to determine the proportion of difficult-to-control asthmatics with ABPA. A total of 185 subjects were enrolled. Twelve patients opted out of the study, and the remaining 173 patients were screened using the modified ISHAM criteria. Statistical analysis was performed using Stastistical Packages of Social Sciences (SPSS) software version 21.0. Continuous parameters were expressed as mean and median, while categorical parameters were measured as frequency and percentages. Results: It was observed that 104 (60.1%) patients belonged to the age group between 41-60 years, while approximately 60 patients (34.7%) were below 40 years of age. Among the 173 patients, 86 (49.7%) tested positive for Aspergillus fumigatus antigen. Applying the ISHAM criteria, it was found that only 17 (9.8%) of these patients satisfied the criteria for co-existent ABPA. A total of 101 patients (58.4%) required at least one hospital admission, while 4 (2.3%) patients required more than three hospital admissions per year. Total 21 (12.1%) patients had IgE specific to Aspergillus fumigatus, while total IgE levels were elevated in 46 (26.6%) cases. Thirty-six cases (20.8%) had a high peripheral eosinophil count. Conclusion: This study suggests the possibility of the treating physician overlooking 10% of asthmatics in this region who are being managed as difficult-to-control asthma, but who have co-existent ABPA. This subset should be identified early in the course and managed separately for better treatment response.

Unilateral pulmonary artery agenesis with unilateral interstitial lung disease in an allergic bronchopulmonary aspergillosis patient

Unilateral pulmonary artery agenesis with unilateral interstitial lung disease in an allergic bronchopulmonary aspergillosis patient

Omalizumab in Allergic Bronchopulmonary Aspergillosis: A Systematic Review and Meta-Analysis

An unmet clinical need exists in the management of treatment-refractory allergic bronchopulmonary aspergillosis (ABPA). Omalizumab has shown promising effects in case series and cohort studies; however, evidence to support its routine clinical use is lacking. The aim of this systematic review and meta-analysis was to evaluate the clinical effectiveness and safety of omalizumab in patients with ABPA. We conducted a systematic search across standard databases using specific key words until May 13, 2021. We performed a meta-analysis to compare the effectiveness (exacerbations, oral corticosteroid [OCS] use, lung function, and patient-reported asthma control) and safety of pre- and post-omalizumab treatment. Subgroup analyses were performed for treatment duration and underlying disease. In total, 49 studies (n= 267) were included in the qualitative synthesis and 14 case series (n= 186) in the quantitative meta-analysis. Omalizumab treatment significantly reduced the annualized exacerbation rate compared with pretreatment (mean difference,-2.09 [95% CI,-3.07 to-1.11]; P < .01). There was a reduction in OCS use (risk difference, 0.65 [95% CI, 0.46-0.84]; P < .01), an increase in termination of OCS use (risk difference, 0.53 [95% CI, 0.24-0.82]; P < .01), and a reduction in OCS dose (milligrams per day) (mean difference,-14.62 [95% CI,-19.86 to-9.39]; P < .01) in ABPA patients receiving omalizumab. Omalizumab improved FEV1 % predicted by 11.9% (95% CI, 8.2-15.6; P < .01) and asthma control, and was well-tolerated. Omalizumab treatment reduced exacerbations and OCS use, improved lung function and asthma control in patients with ABPA, and was well-tolerated. The results highlight the potential role of omalizumab in the treatment of ABPA.

A case of allergic bronchopulmonary aspergillosis complicated by nocardiosis and staphylococcus aureus infection

Nocardia is a ubiquitous organism and often causes serious fatal infections in immuno-compromised individuals. Staphylococcus aureus infection stimulates an inflammatory response that causes lung damage and facilitates subsequent chronic infection. Patients of allergic bronchopulmonary aspergillosis (ABPA) on steroids and immunosuppressants are particularly at risk of these infections. We present the case of a middle-aged man who was diagnosed to have ABPA by serological and radiographic criteria. He presented with fever, cough, and mucopurulent sputum. Subsequent sputum culture for bacteria and fungus revealed the growth of Staphylococcus aureus and Nocardia spp. respectively.

A joint normal‐binary (probit) model

SummaryIn biomedical research, often hierarchical binary and continuous responses need to be jointly modelled. In joint generalised linear mixed models, this can be done with correlated random effects, which allows examining the association structure between the various responses and the evolution of this association over time. In addition, the effect of covariates on all outcomes can be assessed simultaneously. Still, investigating this association is often limited to examining the correlations between the responses on an underlying scale. In addition, the interpretation of this hierarchical model is conditional on the subject‐specific random effects. This paper extends this approach and shows how manifest correlations can be computed, that is, the associations between the observed responses. Further, a marginal model is formulated, in which the interpretation is no longer conditional on the random effects. In addition, prediction intervals are derived of one subvector of responses conditional on the other. These methods are applied in a case study of the lung function and allergic bronchopulmonary aspergillosis in patients with cystic fibrosis.

Screening out serum protein biomarkers from both groups of asthma and ABPA patients

Clinical manifestations of asthma and allergic bronchopulmonary aspergillosis (ABPA) are very similar, so that they are easy to be misdiagnosed. To improve the diagnostic accuracy of these two diseases, the protein array was firstly applied for measuring serum proteins from asthma and ABPA patients,compared with normal control subjects in this study. Protein biomarkers associated to the disease processes and with diagnostic value were analyzed by bioinformatics. The multiple reaction monitoring mass spectrometry (MRM-MS) and enzyme linked immunosorbent assay (ELISA) were then used to verify the candidate biomarkers with enlarged size of samples. The diagnostic value of candidate proteins was additionally evaluated with the receiver operating characteristic (ROC) curve. Via the comparison analysis, the disease related-candidates were identified, including 7 differentially expressed proteins(DEPs) between asthma and normal groups, 15 DEPs between ABPA and normal groups, and 15 DEPs between ABPA and asthma groups. Using MRM method, SERPINF2, C6 and HABP2 proteins were showed differential expression significantly between asthma and normal groups,SERPINF2 and F10 were represented differential expression significantly between ABPA and normal control groups, and CPN2 and IGLL5 were displayed differential expression significantly between ABPA and asthma groups. Furthermore, ELISA validation data were also showed that serum CSF1 protein levels in ABPA patients were significantly lower than those in asthma patients, while TNFRSF10C levels in ABPA patients were significantly higher than those in asthma patients. ROC curve analysis revealed that the AUC of C6 were 0.9 with the sensitivity of 73.3% and the specificity of 99.9% in comparison between asthma and normal groups. The AUC of F10 was 0.871, with the sensitivity of 80.0% and the specificity of 85.7% in comparison between ABPA and normal groups. And the AUC of the combined diagnosis of CPN2 and IGLL5 was 0.867, with more sensitivity of 86.7% and the specificity of 80.0% in comparison those between ABPA and asthma groups. In conclusion, novel protein biomarkers in this study were closely related to the occurrence and development of asthma or ABPA, and might have potentials for assistant diagnostic and differential diagnosis of those two diseases in clinical application.

Clinical and immunological characteristics of Aspergillus fumigatus-sensitized asthma and allergic bronchopulmonary aspergillosis.

Background Aspergillus fumigatus (A.f) is a common airborne allergen that contributes to allergic asthma. In some patients, A.f can colonize in the airway and lead to allergic bronchopulmonary aspergillosis (ABPA). However, our understanding of the pathogenesis of A.f-sensitized asthma and ABPA remains inadequate.ObjectiveWe aimed to investigate the clinical and immunological characteristics of A.f-sensitized asthma and ABPA.MethodsA total of 64 ABPA and 57 A.f-sensitized asthma patients were enrolled in the study, and 33 non-A.f-sensitized asthma patients served as the control group. The clinical and immunological parameters included lung function, fractional exhaled nitric oxide (FeNO), induced sputum and blood cell analysis, specific IgE/IgG/IgA of A.f and its components, cytokines (IL-33, IL-25, and TSLP) and CD4+T cell subsets.ResultsThe eosinophils in blood, induced sputum, and FeNO were significantly higher in ABPA patients compared to that in A.f-sensitized patients. The combination of FeNO and eosinophils (EO) parameters presented good diagnostic efficiency in differentiating A.f (+) asthma from ABPA, with a sensitivity of 80% and a specificity of 100%. Specific IgE, IgG, and IgA against A.f also increased in ABPA patients. However, serum IL-25, IL-33, and TSLP showed no significant differences between the two groups. Cell analysis showed an increase in IFN-γ+Th1 cells in the ABPA patients. FlowSOM analysis further confirmed that the frequency of CD3+CD4+PD-1+CD127+IFN-γ+T cells was higher in ABPA patients.ConclusionOur findings suggest the distinct humoral and cell immunological responses in A.f-sensitized asthma and ABPA patients. ABPA patients have more severe eosinophilic inflammation and enhanced Th1 responses compared with A.f-sensitized asthma patients.

Biologic drugs in treating allergic bronchopulmonary aspergillosis in patients with cystic fibrosis: a systematic review.

Aspergillus fumigatus is a common saprophytic fungus causing allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (CF). The recommended first-line treatment for ABPA is oral steroids, followed by antifungal therapy. However, both treatments are not free from adverse effects; thus, efforts are being made to identify new drugs showing the same effectiveness but with fewer or no side-effects. Therein, biologic drugs have been significantly implemented in clinical practice in treating ABPA in patients with CF. To systematically review the available literature, providing evidence for the administration of biologic drugs as a new potential treatment of ABPA in both the paediatric and adult populations with CF. A systematic review of the literature published between January 2007 and July 2021 was performed, using a protocol registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42021270932). A total of 21 studies focusing on the use of biologics in treating ABPA in CF patients was included. We highlighted a paucity of data providing evidence for biologic drug use in ABPA. Scientific evidence is insufficient to support firm conclusions and randomised clinical trials are urgently required to investigate the efficacy and safety of biologics for ABPA in CF patients.

The adequacy of current diagnostic criteria for making a diagnosis of ABPA.

Currently, there are four different diagnostic criteria systems for allergic bronchopulmonary aspergillosis (ABPA): The Rosenberg-Patterson, Seropositive ABPA (ABPA-S), Central Bronchiectasis and ABPA (ABPA-CB), and the International Society for Human and Animal Mycology (ISHAM) ABPA study group criteria. This study aims to retrospectively compare these four diagnostic criteria in ABPA patients. Patients who were followed up with the diagnosis of ABPA were retrospectively re-evaluated using these four diagnostic criteria, and the superiority of these criteria to each other was determined. A total of 10 ABPA patients were included in the study. Seven patients were diagnosed according to ISHAM ABPA study group diagnostic criteria and six patients according to the Rosenberg-Patterson diagnostic criteria. None of the patients fulfilled the criteria when evaluated individually with ABPA-S and ABPA-CB. Of patients diagnosed by ISHAM, five had a total IgE level above 1000 IU/mL and two had below 1000 IU/mL. We demonstrated that the diagnostic criteria developed by the ISHAM ABPA study group were superior to the others in diagnosing ABPA in cases with a total IgE level above 1000 IU/mL. However, all these criteria seem to be sufficient to diagnose ABPA in patients with a total IgE below 1000 IU/mL. We believe the necessity to demonstrate presence of Aspergillus fumigatus precipitating antibodies or specific IgG positivity should be questioned particularly in patients with radiologic findings compatible with ABPA and a total IgE level below 1000 IU/mL.

Clinical Characteristics and Prognosis of Allergic Bronchopulmonary Aspergillosis: A Retrospective Cohort Study

BackgroundThe clinical features, treatment, and prognosis of allergic bronchopulmonary aspergillosis (ABPA) are not well-defined.ObjectiveWe aimed to investigate the clinical characteristics, therapy, and prognosis of ABPA to aid its clinical recognition.MethodsA total of 232 patients with ABPA were analyzed retrospectively. The characteristics of ABPA in terms of its misdiagnosis, computed tomography classification, therapy, and its relationship with asthma were analyzed, and risk factors for acute exacerbation of ABPA were analyzed based on follow-up data.ResultsOf the 232 ABPA patients, 132 had a history of misdiagnosis. Compared with the misdiagnosed patients, ABPA patients with central bronchiectasis, a high total eosinophil count, and mucus plugs were less likely to be misdiagnosed. Compared with serological ABPA, ABPA with central bronchiectasis was more likely to occur in older people and in patients with mucus plugs, and decreased forced vital capacity and diffusing capacity for carbon monoxide. ABPA patients with asthma were more likely to have bronchiectasis, decreased lung function in 1 s FEV1 and FEV1/FVC, and shorter time to first acute exacerbation compared with ABPA patients without asthma. Patients receiving glucocorticoids plus antifungal therapy had a longer time to first exacerbation than those receiving glucocorticoid therapy alone. Univariate and multivariate analyses revealed that duration of asthma history, duration of misdiagnosis, mucus plugs, and poor pulmonary function were risk factors for acute exacerbation of ABPA.ConclusionTo our knowledge, this is the largest sample size study of ABPA in China. ABPA patients with a history of asthma and/or central bronchiectasis on high-resolution computed tomography are prone to frequent acute exacerbations. The use of glucocorticoids combined with antifungal drugs can prolong the time to the first acute exacerbation in ABPA patients. Longer durations of asthma history and misdiagnosis, mucus plugs, and poor pulmonary function are risk factors for acute exacerbation of ABPA.