Suboptimal Response to Biologics in Severe Asthma-A Marker of Humoral Immunodeficiencies.

BACKGROUND: Asthmatic patients with antibody deficiencies (AD) have more severe disease and higher risk of exacerbations. No data exist about the efficacy of biologics in severe asthma (SA) patients with AD. OBJECTIVE: To evaluate the efficacy of biologics in SA patients with and without AD. METHODS: A case-control real-life study was conducted including 68 patients divided into 2 groups: group 1 with SA-AD and group 2 with SA. RESULTS: Treatment with biologics for 6 months was effective for decreasing the number of exacerbations, hospitalizations, and emergency department (ED) visits and improving the Asthma Control Questionnaire (ACQ) score; biologics also proved a systemic corticosteroid-sparing effect. Despite benefits, the number of exacerbations, hospitalizations, and ED visits, the mean ACQ score, and the cumulative dose of systemic corticosteroids remain higher in group 1 than in group 2, with lower lung function parameters. The rates of responses in group 1 were inferior to those in group 2, with a decrease by ≥50% of exacerbation rate in 76% versus 97% of patients (P = .006), no hospitalization in 44% versus 91% of patients (P < .001), no ED visit in 56% versus 82% of patients (P = .018), a significant improvement of the ACQ score by ≥0.5 in 68% versus 100% of patients (P < .001), and an increase of forced expiratory volume in the first second by >10% in 32% versus 65% of patients (P = .007). CONCLUSIONS: Despite evident benefits, SA patients with AD have suboptimal responses to biologics compared with those immunocompetent. A multidisciplinary approach is necessary to optimize the management of these patients in practice.

The IL-4/13-induced production of M2 chemokines by human lung macrophages is enhanced by adenosine and PGE2.

BACKGROUND AND PURPOSE: Lung macrophages (LMs) are critically involved in respiratory diseases. The primary objective of the present study was to determine whether or not an adenosine analog (NECA) and prostaglandin E2 (PGE2) affected the interleukin (IL)-4- and IL-13-induced release of M2a chemokines (CCL13, CCL17, CCL18, and CCL22) by human LMs. EXPERIMENTAL APPROACH: Primary macrophages isolated from resected human lungs were incubated with NECA, PGE2, roflumilast, or vehicle and stimulated with IL-4 or IL-13 for 24 h. The levels of chemokines and PGE2 in the culture supernatants were measured using ELISAs and enzyme immunoassays. KEY RESULTS: Exposure to IL-4 (10 ng/mL) and IL-13 (50 ng/mL) was associated with greater M2a chemokine production but not PGE2 production. PGE2 (10 ng/mL) and NECA (10-6 M) induced the production of M2a chemokines to a lesser extent but significantly enhanced the IL-4/IL-13-induced production of these chemokines. At either a clinically relevant concentration (10-9 M) or at a concentration (10-7 M) that fully inhibited phosphodiesterase 4 (PDE4) activity, roflumilast did not increase the production of M2a chemokines and did not modulate their IL-13-induced production, regardless of the presence or absence of PGE2. CONCLUSIONS: NECA and PGE2 enhanced the IL-4/IL-13-induced production of M2a chemokines. The inhibition of PDE4 by roflumilast did not alter the production of these chemokines. These results contrast totally with the previously reported inhibitory effects of NECA, PGE2, and PDE4 inhibitors on the lipopolysaccharide-induced release of tumor necrosis factor alpha and M1 chemokines in human LMs.

Multivariate analysis and data mining help predict asthma exacerbations.

BACKGROUND: Work-related asthma has become a highly prevalent occupational lung disorder. OBJECTIVE: Our study aims to evaluate occupational exposure as a predictor for asthma exacerbation. METHOD: We performed a retrospective evaluation of 584 consecutive patients diagnosed and treated for asthma between October 2017 and December 2019 in four clinics from Western Romania. We evaluated the enrolled patients for their asthma control level by employing the Asthma Control Test (ACT < 20 represents uncontrolled asthma), the medical record of asthma exacerbations, occupational exposure, and lung function (i.e. spirometry). Then, we used statistical and data mining methods to explore the most important predictors for asthma exacerbations. RESULTS: We identified essential predictors by calculating the odds ratios (OR) for the exacerbation in a logistic regression model. The average age was 45.42 ± 11.74 years (19-85 years), and 422 (72.26%) participants were females. 42.97% of participants had exacerbations in the past year, and 31.16% had a history of occupational exposure. In a multivariate model analysis adjusted for age and gender, the most important predictors for exacerbation were uncontrolled asthma (OR 4.79, p < .001), occupational exposure (OR 4.65, p < .001), and lung function impairment (FEV1 < 80%) (OR 1.15, p = .011). The ensemble machine learning experiments on combined patient features harnessed by our data mining approach reveal that the best predictor is professional exposure, followed by ACT. CONCLUSIONS: Machine learning ensemble methods and statistical analysis concordantly indicate that occupational exposure and ACT < 20 are strong predictors for asthma exacerbation.

Epithelial alarmins: a new target to treat chronic respiratory diseases.

INTRODUCTION: In response to injury, epithelial cells release alarmins including thymic stromal lymphopoietin (TSLP), high mobility group-box-1 (HMGB1), interleukin (IL)-33 and -25 that can initiate innate immune responses. These alarmins are recognized as activators of T2-immune responses characteristic for asthma, but recent evidence highlighted their role in non-T2 inflammation, airway remodeling, and pulmonary fibrosis making them an attractive therapeutic target for chronic respiratory diseases (CRD). AREAS COVERED: In this review, firstly we discuss the role of TSLP, IL-33, IL-25, and HMGB1 in the pathogenesis of asthma, COPD, idiopathic pulmonary fibrosis, and cystic fibrosis according to the published data. In the second part, we summarize the current evidence concerning the efficacy of the antialarmin therapies in CRD. Recent clinical trials showed that anti-TSLP and IL-33/R antibodies can improve severe asthma outcomes. Blocking the IL-33-mediated pathway decreased the exacerbation rate in COPD patients with more important benefit for former-smokers. EXPERT OPINION: Despite progress in the understanding of the alarmins' role in the pathogenesis of CRD, all their mechanisms of action are not yet identified. Blocking IL-33 and TSLP pathways offers an interesting option to treat severe asthma and COPD, but future investigations are needed to establish their place in the treatment strategies.

Effects of elexacaftor-tezacaftor-ivacaftor on daily treatment burden and airflow obstruction in adults with cystic fibrosis.

BACKGROUND: The drug combination elexacaftor-tezacaftor-ivacaftor (ETI) proved highly effective in the improvement of the respiratory symptoms, the percentage of predicted forced expiratory volume in 1 s (FEV1), and to reduce rates of pulmonary exacerbations in people with cystic fibrosis (CF) with at least one F508del mutation. The objectives of the study were to evaluate the impact of ETI on the daily treatment burden due to patient decision and the evolution of lung function parameters at 6 months of treatment in real life. METHODS: A single-center observational study was realized including adult patients starting ETI therapy from March 10, 2020 to April 5, 2022. Clinical characteristics were collected at initiation (T0) and at 6 months (T6) of treatment. Outcome measures included names and number of chronic daily medications, respectively lung function parameters: FEV1, forced vital capacity (FVC), FEV1/FVC ratio, peak expiratory flow (PEF), forced expiratory flow at 25-75% of FVC (FEF25-75), ß-angle and FEF50/PEF ratio. RESULTS: Sixty-five patients were included with a mean age of 29.4 ± 8.5 years old, 48% of them F508del homozygous previously treated by lumacaftor-ivacaftor. At T6, the median number of daily medications decreased from 13 [2-24] to 9 [1-19] (p < 0.001). All the studied functional respiratory parameters were improved: FEV1 +18%, FVC +14%, FEF25-75% + 18% (all p < 0.001), as well the airflow obstruction: FEV1/FVC +6%, FEF50/PEF by 0.1 ± 0.1 and ß-angle by 10° ± 13° (all p ≤ 0.007). CONCLUSION: ETI therapy can reduce the daily treatment burden in real-life at 6 months of treatment, increase a large number of lung function parameters and improve airflow obstruction.

Criteria to evaluate efficacy of biologics in asthma: a Global Asthma Association survey.

BACKGROUND: Currently, there are no universally accepted criteria to measure the response to biologics available as treatment for severe asthma. This survey aims to establish consensus criteria to use for the evaluation of response to biologics after 4 months of treatment. METHOD: Using Delphi methodology, a questionnaire including 10 items was validated by 13 international experts in asthma. The electronic survey circulated within the Interasma Scientific Network platform. For each item, five answers were proposed graduated from 'no importance' to 'very high importance' and by a score (A = 2 points; B = 4 points; C = 6 points; D = 8 points; E = 10 points). The final criteria were selected if the median score for the item was ≥7 and > 60% of responses according 'high importance' and 'very high importance'. All selected criteria were validated by the experts. RESULTS: Four criteria were identified: reduce daily systemic corticosteroids dose by ≥50%; decrease the number of asthma exacerbations requiring systemic corticosteroids by ≥50%; have no/minimal side effects; and obtain asthma control according validated questionnaires. The consensual decision was that ≥3 criteria define a good response to biologics. CONCLUSIONS: Specific criteria were defined by an international panel of experts and could be used as tool in clinical practice.

Severe asthma patients' and physicians' perspectives of disease burden: do they match?

A novel open-ended survey revealed contrasting viewpoints and priorities between patients with severe asthma and clinicians. These divergences must be considered when treating individual patients in multidisciplinary treatment teams. https://bit.ly/40Fsr9o.

Does asthma-bronchiectasis overlap syndrome (ABOS) really exist?

OBJECTIVE: To analyze the relationship between asthma and bronchiectasis, as well as the necessary conditions that this connection must meet for this group of patients to be considered a special phenotype. DATA SOURCES: We performed a PubMed search using the MeSH terms "asthma" and "bronchiectasis." The literature research was limited to clinical trials, meta-analyses, randomized controlled trials, cohort studies, and systematic reviews, involving adult patients, published until November 30th, 2022. STUDY SELECTIONS: Selected papers were initially evaluated by the Authors, to assess their eligibility in contributing to the statements. RESULTS: The prevalence of bronchiectasis is higher than expected in patients with asthma, particularly in those with more severe disease, and in some patients, between 1.4% and 7% of them, asthma alone could be the cause of bronchiectasis. Both diseases share etiopathogenic mechanisms, such as neutrophilic and eosinophilic inflammation, altered airway microbiota, mucus hypersecretion, allergen sensitization, immune dysfunction, altered microRNA, dysfunctional neutrophilic activity, and variants of the HLA system. Besides that, they also share comorbidities, such as gastroesophageal reflux disease and psychiatric illnesses. The clinical presentation of asthma is very similar to patients with bronchiectasis, which could cause mistakes with diagnoses and delays in being prescribed the correct treatment. The coexistence of asthma and bronchiectasis also poses difficulties for the therapeutic focus. CONCLUSIONS: The evidence available seems to support that the asthma-bronchiectasis phenotype really exists although longitudinal studies which consistently demonstrate that asthma is the cause of bronchiectasis are still lacking.

Unattended home sleep studies for the diagnosis of obstructive sleep apnea in a population of French children.

BACKGROUND: Ambulatory exams were preferred in children during the COVID-19 pandemic. Polysomnography (PSG), the gold standard for obstructive sleep apnea (OSA) diagnosis, requires several leads and sensors to be attached to the child's body. Children are more comfortable with respiratory polygraphic (RP) recording, which needs fewer sensors. OBJECTIVE: To compare respiratory parameters obtained by home RP with those obtained by home PSG with the device installed at the child's home by a trained sleep nurse from a national health care provider. METHODS: Data from home PSGs performed in children aged 2-19 years were retrospectively included. The obstructive apnea-hypopnea index (OAHI) was computed in PSG and then in RP after removing the sleep signals. The two indexes were compared using non-parametric paired Wilcoxon rank test, Bland-Altman analysis and sensitivity-specificity analysis. RESULTS: 44 PSGs of 44 children were included with only 34 (77%) PSGs interpretable. Median (min-max) OAHI was significantly underestimated in RP than in PSG (2.2 (0-25) vs 4.0 (0.4-28), p < 0.0001), confirmed also by the Bland-Altman diagram, the magnitude of the difference being mean ± standard deviation -1.7 ± 1.7. The sensitivity and specificity of OAHI in RP to identify an OAHI ≥2/h in PSG was 0.91 for both. CONCLUSION: Unattended ambulatory RP performed at child's house and installed under carefully controlled conditions is a useful exam for diagnosing OSA in children with or without comorbidities. However, RP must be installed in a supervised environment and interpreted with caution as it tends to underestimate OSA severity.

Real-Life Effectiveness of Benralizumab, Mepolizumab and Omalizumab in Severe Allergic Asthma Associated with Nasal Polyps.

Biological therapies are available for the treatment of the severe allergic asthma (SAA) with blood eosinophil count ≥ 0.3 × 109/L. Several of them also showed benefits on nasal polyps (NP), one of the most frequent comorbidities of the severe asthma, but comparative studies on their effectiveness in the association SAA-NP are currently lacking. The aim of this study is to compare the effectiveness of benralizumab, mepolizumab and omalizumab in patients with SAA-NP in real-life settings. A retrospective, observational, multicenter real-life study was realized including patients with SAA-NP treated by benralizumab, mepolizumab or omalizumab for 6 months. We analysed the nasal and respiratory symptoms, the number of asthma attacks and salbutamol use/week, acute sinusitis and severe exacerbation rates, the asthma control score, the lung function parameters, the NP endoscopic score, the sinus imaging and the blood eosinophil count 6 months before and after treatment. Seventy-two patients with SAA-NP were included: 16 treated by benralizumab, 21 by mepolizumab and 35 by omalizumab. After 6 months of treatment, almost all studied parameters were improved (except sinus imaging) with a greater effect of omalizumab on the nasal pruritus (p = 0.001) and more benefits of benralizumab on exacerbations rate, asthma attacks per week and lung function (all p < 0.05). Benralizumab and mepolizumab were more effective to improve the NP endoscopic score and the blood eosinophil count (both p < 0.001). All three biological therapies showed effectiveness by improving asthma and nasal outcomes in patients with SAA-NP. Several differences have been found that should be confirmed by larger comparative studies.

Triggering Receptors Expressed on Myeloid Cells 1 : Our New Partner in Human Oncology?

Inflammation is recognized as one of the hallmarks of cancer. Indeed, strong evidence indicates that chronic inflammation plays a major role in oncogenesis, promoting genome instability, epigenetic alterations, proliferation and dissemination of cancer cells. Mononuclear phagocytes (MPs) have been identified as key contributors of the inflammatory infiltrate in several solid human neoplasia, promoting angiogenesis and cancer progression. One of the most described amplifiers of MPs pro-inflammatory innate immune response is the triggering receptors expressed on myeloid cells 1 (TREM-1). Growing evidence suggests TREM-1 involvement in oncogenesis through cancer related inflammation and the surrounding tumor microenvironment. In human oncology, high levels of TREM-1 and/or its soluble form have been associated with poorer survival data in several solid malignancies, especially in hepatocellular carcinoma and lung cancer. TREM-1 should be considered as a potential biomarker in human oncology and could be used as a new therapeutic target of interest in human oncology (TREM-1 inhibitors, TREM-1 agonists). More clinical studies are urgently needed to confirm TREM-1 (and TREM family) roles in the prognosis and the treatment of human solid cancers.

Adverse roles of mast cell chymase-1 in COPD.

BACKGROUND: COPD is the third leading cause of death worldwide. Cigarette smoke (CS)-induced chronic inflammation inducing airway remodelling, emphysema and impaired lung function is the primary cause. Effective therapies are urgently needed. Human chymase (hCMA)1 and its orthologue mCMA1/mouse mast cell protease (mMCP)5 are exocytosed from activated mast cells and have adverse roles in numerous disorders, but their role in COPD is unknown. METHODS: We evaluated hCMA1 levels in lung tissues of COPD patients. We used mmcp5-deficient (-/-) mice to evaluate this protease's role and potential for therapeutic targeting in CS-induced experimental COPD. In addition, we used ex vivo/in vitro studies to define mechanisms. RESULTS: The levels of hCMA1 mRNA and CMA1+ mast cells were increased in lung tissues from severe compared to early/mild COPD patients, non-COPD smokers and healthy controls. Degranulated mast cell numbers and mMCP5 protein were increased in lung tissues of wild-type mice with experimental COPD. mmcp5 -/- mice were protected against CS-induced inflammation and macrophage accumulation, airway remodelling, emphysema and impaired lung function in experimental COPD. CS extract challenge of co-cultures of mast cells from wild-type, but not mmcp5 -/- mice with wild-type lung macrophages increased in tumour necrosis factor (TNF)-α release. It also caused the release of CMA1 from human mast cells, and recombinant hCMA-1 induced TNF-α release from human macrophages. Treatment with CMA1 inhibitor potently suppressed these hallmark features of experimental COPD. CONCLUSION: CMA1/mMCP5 promotes the pathogenesis of COPD, in part, by inducing TNF-α expression and release from lung macrophages. Inhibiting hCMA1 may be a novel treatment for COPD.

Pleural Effusion Occurring During Lung Cancer Immunotherapy: A Challenge for the Clinician / Derrame pleural durante inmunoterapia por cáncer de pulmón: un desafío para el médico

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Manifesto on inhaled triple therapy in asthma: an Interasma (Global Asthma Association - GAA) document.

Objective: The optimal use of drug combinations for the management of asthma is providing significant results. This has prompted Interasma (Global Asthma Association) to take a position on inhaled triple therapy in asthma.Methods: We performed an extensive literature research to clinical trials, meta-analyses, randomized controlled trials and systematic reviews.Results: Starting from an extensive literature review, Interasma executive committee discussed and approved this Manifesto, developed by Interasma scientific network (INES) members.Conclusions: The manifesto describes the evidence gathered to date and states, advocates, and proposes issues on inhaled corticosteroid (ICS) plus long-acting beta 2 agonist (LABA) and long-acting muscarinic antagonists (LAMA) with the aim of challenging assumptions, fostering commitment, and bringing about change.

Asthma and obstructive sleep apnoea in adults and children - an up-to-date review.

Obstructive sleep apnoea (OSA) and asthma are two common respiratory disorders in children and adults. Apart from common risk factors, such as obesity, gastroesophageal reflux disease and allergic rhinitis, emerging evidence suggest that the two diseases may complicate the clinical course of each other. On one hand, OSA modifies asthmatic airway inflammation and is associated with poor asthma control. On the other hand, asthma and its medications increase the collapsibility of the upper airways contributing to the development and worsening of OSA. The overnight respiratory symptoms of OSA and asthma are often similar, and an inpatient polysomnography is often necessary for a proper diagnosis, especially in children. Continuous positive pressure, the gold standard treatment for OSA can improve asthma control in patients suffering from both diseases. However, there is limited evidence how anti-asthma medications act in the same patients. Nevertheless, adenotonsillectomy seems to be effective in children with concomitant asthma and OSA. This review summarises the evidence for the bidirectional link between asthma and OSA, focuses on diagnostic and therapeutic challenges and highlights the need for further research.

Association of Differential Mast Cell Activation with Granulocytic Inflammation in Severe Asthma.

Rationale: Mast cells (MCs) play a role in inflammation and both innate and adaptive immunity, but their involvement in severe asthma (SA) remains undefined. Objectives: We investigated the phenotypic characteristics of the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) asthma cohort by applying published MC activation signatures to the sputum cell transcriptome. Methods: Eighty-four participants with SA, 20 with mild/moderate asthma (MMA), and 16 healthy participants without asthma were studied. We calculated enrichment scores (ESs) for nine MC activation signatures by asthma severity, sputum granulocyte status, and three previously defined sputum molecular phenotypes or transcriptome-associated clusters (TACs) 1, 2, and 3 using gene set variation analysis. Measurements and Main Results: MC signatures except unstimulated, repeated FcεR1-stimulated and IFN-γ-stimulated signatures were enriched in SA. A FcεR1-IgE-stimulated and a single-cell signature from asthmatic bronchial biopsies were highly enriched in eosinophilic asthma and in the TAC1 molecular phenotype. Subjects with a high ES for these signatures had elevated sputum amounts of similar genes and pathways. IL-33- and LPS-stimulated MC signatures had greater ES in neutrophilic and mixed granulocytic asthma and in the TAC2 molecular phenotype. These subjects exhibited neutrophil, NF-κB (nuclear factor-κB), and IL-1ß/TNF-α (tumor necrosis factor-α) pathway activation. The IFN-γ-stimulated signature had the greatest ES in TAC2 and TAC3 that was associated with responses to viral infection. Similar results were obtained in an independent ADEPT (Airway Disease Endotyping for Personalized Therapeutics) asthma cohort. Conclusions: Gene signatures of MC activation allow the detection of SA phenotypes and indicate that MCs can be induced to take on distinct transcriptional phenotypes associated with specific clinical phenotypes. IL-33-stimulated MC signature was associated with severe neutrophilic asthma, whereas IgE-activated MC was associated with an eosinophilic phenotype.

Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study.

INTRODUCTION: Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication. METHODS: Baseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12-18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods. RESULTS: A total of 90 metabolites were identified, with 40 significantly altered (p<0.05, false discovery rate <0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10-20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10-4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings. CONCLUSIONS: This is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.

Manifesto on united airways diseases (UAD): an Interasma (global asthma association - GAA) document.

OBJECTIVE: The large amount of evidence and the renewed interest in upper and lower airways involvement in infectious and inflammatory diseases has led Interasma (Global Asthma Association) to take a position on United Airways Diseases (UAD). METHODS: Starting from an extensive literature review, Interasma executive committee discussed and approved this Manifesto developed by Interasma scientific network (INES) members. RESULTS: The manifesto describes the evidence gathered to date and defines, states, advocates, and proposes issues on UAD (rhinitis, rhinosinusitis and nasal polyposis), and concomitant/comorbid lower airways disorders (asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, obstructive sleep apnoea) with the aim of challenging assumptions, fostering commitment, and bringing about change. UAD refers to clinical pictures characterized by the coexistence of upper and lower airways involvement, driven by a common pathophysiological mechanism, leading to a greater burden on patient's health status and requiring an integrated diagnostic and therapeutic plan. The high prevalence of UAD must be taken into account. Upper and lower airways diseases influence disease control and patient's quality of life. CONCLUSIONS: Patients with UAD need to have a timely and adequate diagnosis, treatment, and, when recommended, referral for management in a specialized center. Diagnostic testing including skin prick or serum specific IgE, lung function, fractional exhaled nitric oxide (FeNO), polysomnography, allergen-specific immunotherapies, biological therapies and home based continuous positive airway pressure (CPAP) whenever these are recommended, should be part of the management plan for UAD. Education of medical students, physicians, health professionals, patients and caregivers on the UAD is needed.