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.

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.

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.

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.

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.

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.

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.

Sputum macrophage diversity and activation in asthma: Role of severity and inflammatory phenotype.

BACKGROUND: Macrophages control innate and acquired immunity, but their role in severe asthma remains ill-defined. We investigated gene signatures of macrophage subtypes in the sputum of 104 asthmatics and 16 healthy volunteers from the U-BIOPRED cohort. METHODS: Forty-nine gene signatures (modules) for differentially stimulated macrophages, one to assess lung tissue-resident cells (TR-Mφ) and two for their polarization (classically and alternatively activated macrophages: M1 and M2, respectively) were studied using gene set variation analysis. We calculated enrichment scores (ES) across severity and previously identified asthma transcriptome-associated clusters (TACs). RESULTS: Macrophage numbers were significantly decreased in severe asthma compared to mild-moderate asthma and healthy volunteers. The ES for most modules were also significantly reduced in severe asthma except for 3 associated with inflammatory responses driven by TNF and Toll-like receptors via NF-κB, eicosanoid biosynthesis via the lipoxygenase pathway and IL-2 biosynthesis (all P < .01). Sputum macrophage number and the ES for most macrophage signatures were higher in the TAC3 group compared to TAC1 and TAC2 asthmatics. However, a high enrichment was found in TAC1 for 3 modules showing inflammatory pathways linked to Toll-like and TNF receptor activation and arachidonic acid metabolism (P < .001) and in TAC2 for the inflammasome and interferon signalling pathways (P < .001). Data were validated in the ADEPT cohort. Module analysis provides additional information compared to conventional M1 and M2 classification. TR-Mφ were enriched in TAC3 and associated with mitochondrial function. CONCLUSIONS: Macrophage activation is attenuated in severe granulocytic asthma highlighting defective innate immunity except for specific subsets characterized by distinct inflammatory pathways.

Allergen immunotherapy in asthma: current evidence.

Background: Allergic asthma is the predominant phenotype in clinical practice. Allergen immunotherapy is the only curative and specific approach for the treatment of allergies with clinical benefits for several years after its discontinuation. Despite advances, the use of allergen immunotherapy in allergic asthma is still suboptimal and controversial.Objective: The purpose of this article is to review the published data about the impact of allergen immunotherapy with the most commonly used allergen extracts on allergic asthma outcomes, including both clinical parameters and patients' subjective experience (quality of life).Methods: As data sources several databases were used, including PubMed, Scopus, Web of Science (2002-2019) and search in English and Spanish languages was performed using the following terms: "allergen immunotherapy" and "asthma" in combination with "house dust mite", "birch pollen", "grass pollen", "olive tree pollen", "molds", "pets" and "asthma quality of life". Randomised control trials and meta-analysis from reviewed publications were selected.Results: Emerging data relating to the positive impact on asthma outcomes of allergen immunotherapy allows the addition of this treatment as a therapeutic option in mild to moderate asthmatics sensitized to house dust mite and pollens. Limited data are available for patients sensitized to molds and pets, as well in severe allergic asthma population.Conclusion: Allergen immunotherapy remains a potential therapeutic option for some patients with allergic asthma. Further research is needed to define the optimal period of treatment, the possible therapeutic role in the treatment of severe allergic asthma, and the cost-effectiveness of allergen immunotherapy in asthmatic patients.

Applying personalized medicine to adult severe asthma.

Background: Severe asthma is a heterogeneous disease that consists of various phenotypes driven by different pathways. Associated with significant morbidity, an important negative impact on the quality of life of patients, and increased health care costs, severe asthma represents a challenge for the clinician. With the introduction of various antibodies that target type 2 inflammation (T2) pathways, severe asthma therapy is gradually moving to a personalized medicine approach. Objective: The purpose of this review was to emphasize the important role of personalized medicine in adult severe asthma management. Methods: An extensive research was conducted in medical literature data bases by applying terms such as "severe asthma" associated with "structured approach," "comorbidities," "biomarkers," "phenotypes/endotypes," and "biologic therapies." Results: The management of severe asthma starts with a structured approach to confirm the diagnosis, assess the adherence to medications and identify confounding factors and comorbidities. The definition of phenotypes or endotypes (phenotypes defined by mechanisms and identified through biomarkers) is an important step toward the use of personalized medicine in asthma. Severe allergic and nonallergic eosinophilic asthma are two defined T2 phenotypes for which there are efficacious targeted biologic therapies currently available. Non-T2 phenotype remains to be characterized, and less efficient target therapy exists. Conclusion: Despite important progress in applying personalized medicine to severe asthma, especially in T2 inflammatory phenotypes, future research is needed to find valid biomarkers predictive for the response to available biologic therapies to develop more effective therapies in non-T2 phenotype.

Efficacy of immunoglobulin replacement therapy and azithromycin in severe asthma with antibody deficiency.

BACKGROUND: Although antibody deficiency (AD) is a well-known cause of recurrent respiratory infections, there are few data on its impact in adults with asthma. The objective of the present study was to assess outcomes in adults with severe asthma and AD after treatment with either azithromycin or subcutaneous immunoglobulins (SCIg). METHODS: We performed a 5-year, prospective, observational, two-centre study of adults with severe asthma and AD in France. Bronchiectasis was ruled out by high-resolution computed tomography. Patients were treated for one year with either azithromycin (250 mg every other day) or SCIg (0.4-0.6 g/kg/months, weekly). All patients were evaluated for exacerbations, asthma control and lung function at baseline and then one year after treatment initiation. RESULTS: Thirty-nine patients with severe asthma were included in the study: 14 had been treated with azithromycin and 25 had been treated with SCIg. Before the initiation of treatment for AD, all patients had an Asthma Control Questionnaire (ACQ-7) score > 1.5 (mean ± SD: 2.71 ± 0.53) despite treatment at GINA step 4 or 5, and had a high exacerbation rate requiring oral corticosteroids and/or rescue antibiotics (∼7.2 ± 2.1/patient/year). One year after treatment initiation, we observed a significantly higher FEV1 (mean: 0.18 ± 0.22 L) and ACQ-7 score (1.26 ± 0.68), and a significantly lower exacerbation rate (1.63 ± 1.24/patient/year). CONCLUSIONS: Treatment of AD dramatically improved asthma outcomes - suggesting that adults with severe asthma and recurrent respiratory infections should be screened and (if appropriate) treated for AD.

Gamma globulin replacement therapy in uncontrolled, severe asthma associated with humoral immunodeficiency: A series of five case reports.

We report on five adult cases of the rare association of asthma with humoral immunodeficiency (huID). All patients had uncontrolled asthma related to recurrent respiratory infections. Asthma was diagnosed according to the Global Initiative for Asthma (GINA) guidelines, and bronchiectasis was ruled out by a CT chest scan. Two men (aged 28 and 60) presented with pollen allergies, chronic rhinosinusitis, and IgG deficiency (7.8 and 7.6 g/L, respectively). Both patients underwent surgery for nasal polyposis but relapsed with acute sinusitis and severe asthma exacerbations requiring treatment with oral corticosteroids and antibiotics. The immunoglobulin replacement therapy (IRT) partially relieved the asthma by reducing the number of exacerbations. A 55-year-old woman presented with nonallergic, corticosteroid-dependent asthma (20 mg/day prednisone) and IgG deficiency (5.72 g/L). IRT improved asthma control (fall in the Asthma Control Questionnaire (ACQ)-7 score from 3.5 to 1.7) and enabled withdrawal of the corticosteroids. In a 47-year-old woman with an IgG2 subclass deficiency (1.9 g/L) and asthma, IRT increased the degree of asthma control (fall in the ACQ-7 score from 2.8 to 1.1). A 75-year-old woman presented with corticosteroid-dependent asthma (40 mg/day prednisone), IgM and IgG deficiencies (0.28 g/L and 5.36 g/L, respectively), and recurrent respiratory, skin and urinary infections. Again, IRT improved asthma control (fall in the ACQ-7 score from 2.5 to 1.2), reduced the number of hospitalizations for asthma exacerbations, and enabled a 10-mg reduction in the daily dose of prednisone. These observations suggest that IRT may improve disease control in some patients with asthma and associated huID.

Prognostic Value of Exon 19 Versus 21 EGFR Mutations Varies According to Disease Stage in Surgically Resected Non-small Cell Lung Cancer Adenocarcinoma.

BACKGROUND: The prognostic value of exon 19 and 21 EGFR mutations in stage IV non-small cell lung cancer (NSCLC) is well established. OBJECTIVE: We aimed to evaluate the prognostic value of the mutations in surgically resected NSCLC. METHODS: We retrospectively reviewed data from 1798 surgically resected NSCLC adenocarcinomas between 2007 and 2017 in three departments of thoracic surgery (Nancy/Strasbourg, France, and Torino, Italy) for whom mutational status was known. Overall survival (OS) was evaluated using log-rank and Cox proportional hazard models. RESULTS: EGFR exon 19 deletion was observed in 108 patients (55.1%) and exon 21 L858R mutations were observed in 88 patients (44.9%). In stage I, the median OS was not significantly different between exons 19 and 21 (p = 0.54), while, in stage II, the median OS reached 65 months [95% confidence interval (CI) 41.67-88.33] for exon 19 mutations and decreased to 48 months for exon 21 mutations (95% CI 44.21-51.79; p = 0.027). In multivariate analysis, exon 19 deletion remained a favorable prognostic factor [hazard ratio (HR) 0.314, 95% CI 0.098-0.997; p = 0.05]. In stage III, the median OS reached 66 months (95% CI 44.67-87.32) for exon 19 mutations and decreased to 32 months for exon 21 mutations (95% CI 29.86-34.14; p = 0.03). In multivariate analysis, exon 19 deletion remained a significantly favorable prognostic factor (HR 0.165, 95% CI 0.027-0.999; p = 0.05). CONCLUSION: The prognostic value of EGFR exon 19 and 21 mutations appears to be different according to disease stage in surgically resected NSCLC.

Urtica dioica pollen allergy: Clinical, biological, and allergomics analysis.

BACKGROUND: The most emblematic members of Urticaceae at allergic risk level are wall pellitories (Parietaria), whereas nettle (Urtica) pollen is considered as poorly allergenic. No allergen from nettle pollen has yet been characterized, whereas 4 are listed for Parietaria pollen by the International Union of Immunological Societies. Clinical and biological profiles of 2 adult men who developed symptoms against nettle pollen and/or leaves were studied. OBJECTIVE: To characterize the allergic reaction and identify the potential nettle pollen sensitizing allergens. METHODS: IgE-mediated reaction to nettle pollen extract was evaluated by skin prick test, immunoassay, nasal provocation, and basophil activation test. To characterize specific nettle pollen allergens, an allergomic (IgE immunoproteomic) analysis was performed combining 1- and 2-dimensional electrophoresis, IgE immunoblots of nettle pollen extract, identification of allergens by mass spectrometry, and database queries. RESULTS: The results of biological and immunochemical analyses revealed that the allergic rhinitis was due to Urtica dioica pollen in both patients. The allergomic analysis of nettle pollen extract allowed the characterization of 4 basic protein allergens: a thaumatin-like protein (osmotin) with a relative molecular mass of 27 to 29 kDa, a pectinesterase (relative molecular mass, 40 kDa), and 2 other basic proteins with relative molecular masses of 14 to 16 kDa and 43 kDa. There is no or only very weak allergen associations between pellitory and nettle pollen. CONCLUSION: Exposure to nettle pollen can be responsible of allergic symptoms, and several allergens were characterized. Unravelling the allergens of this underestimated allergy might help to improve diagnosis and care for patients, to predict cross-reactivities and design adapted specific immunotherapy.

Desensitization of the cough reflex during limb muscle contraction in anesthetized rabbits.

The 'cough network' exhibits plasticity at the sensor and integration levels leading to modulation of the strength or pattern of the cough reflex. Little is known about the interactions between cough and human activities, especially during exercise. The present study was designed to determine whether exercise, mimicked by electrically induced muscle contractions, can modify the incidence and/or strength of cough following mechanical stimulation of the trachea in anesthetized rabbits. Thirteen anesthetized, tracheotomized rabbits were studied by a total of 311 tracheal stimulations: 196 at rest and 115 during exercise. During muscle contractions, the incidence of the cough reflex (CR) decreased and the expiration reflex (ER) increased (p < 0.0001). The sensitivity of the CR and ER both decreased during exercise compared to the sensitivity of the CR at rest (p < 0.02), while the strength of the expulsive response remained unchanged. These results indicate that adjustments occurring during muscle contractions likely downregulate tracheal defensive reflexes in anesthetized rabbits.

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.

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.