Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4⁺ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56^dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56^dim NK cells and CCR6⁻CCR4⁻ T helper 1–enriched CD4⁺ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV₁) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A₄/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A₄–exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma.

Skeletal muscle ischemia reperfusion is very frequent in humans and results not only in muscle destruction but also in multi-organ failure and death via systemic effects related to inflammation and oxidative stress. In addition to overabundance of pro-inflammatory stimuli, excessive and uncontrolled inflammation can also result from defects in resolution signaling. Importantly, the resolution of inflammation is an active process also based on specific lipid mediators including lipoxins, resolvins and maresins that orchestrate the potential return to tissue homeostasis. Thus, lipid mediators have received growing attention since they dampen deleterious effects related to ischemia–reperfusion. For instance, the treatment of skeletal muscles with resolvins prior to ischemia decreases polymorphonuclear leukocyte (PMN) infiltration. Additionally, remote alterations in lungs or kidneys are reduced when enhancing lipid mediators’ functions. Accordingly, lipoxins prevented oxidative-stress-mediated tissue injuries, macrophage polarization was modified and in mice lacking DRV2 receptors, ischemia/reperfusion resulted in excessive leukocyte accumulation. In this review, we first aimed to describe the inflammatory response during ischemia and reperfusion in skeletal muscle and then discuss recent discoveries in resolution pathways. We focused on the role of specialized pro-resolving mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) and their potential therapeutic applications.

Background: Cardiopulmonary exercise testing (CPET) is an important clinical tool that provides a global assessment of the respiratory, circulatory and metabolic responses to exercise which are not adequately reflected through the measurement of individual organ system function at rest. In the context of critical COVID-19, CPET is an ideal approach for assessing long term sequelae. Methods: In this prospective single-center study, we performed CPET 12 months after symptom onset in 60 patients that had required intensive care unit treatment for a severe COVID-19 infection. Lung function at rest and chest computed tomography (CT) scan were also performed. Results: Twelve months after severe COVID-19 pneumonia, dyspnea was the most frequently reported symptom although only a minority of patients had impaired respiratory function at rest. Mild ground-glass opacities, reticulations and bronchiectasis were the most common CT scan abnormalities. The majority of the patients (80%) had a peak O₂ uptake (V′O₂) considered within normal limits (median peak predicted O₂ uptake (V′O₂) of 98% [87.2–106.3]). Length of ICU stay remained an independent predictor of V′O₂. More than half of the patients with a normal peak predicted V′O₂ showed ventilatory inefficiency during exercise with an abnormal increase of physiological dead space ventilation (VD/Vt) (median VD/VT of 0.27 [0.21–0.32] at anaerobic threshold (AT) and 0.29 [0.25–0.34] at peak) and a widened median peak alveolar-arterial gradient for O₂ (35.2 mmHg [31.2–44.8]. Peak PetCO₂ was significantly lower in subjects with an abnormal increase of VD/Vt (p = 0.001). Impairments were more pronounced in patients with dyspnea. Peak VD/Vt values were positively correlated with peak D-Dimer plasma concentrations from blood samples collected during ICU stay (r² = 0.12; p = 0.02) and to predicted diffusion capacity of the lung for carbon monoxide (D_LCO) (r² = − 0.15; p = 0.01). Conclusions: Twelve months after severe COVID-19 pneumonia, most of the patients had a peak V′O₂ considered within normal limits but showed ventilatory inefficiency during exercise with increased dead space ventilation that was more pronounced in patients with persistent dyspnea. Trial registration: NCT04519320 (19/08/2020).

Background: The French RAMSES study is an observational prospective multicentre real-life cohort including severe asthmatic subjects. The objective of the study was to compare the characteristics of patients, in terms of phenotype and asthma care trajectories, between those managed by tertiary referral centres (TRCs) or secondary care centres (SCCs).Methods: Patients were prospectively recruited and enrolled for a 5-year follow-up. Patients’ characteristics were analysed at inclusion and compared between TRCs and SCCs.Results: 52 centres (24 TRCs and 28 SCCs) included 2046 patients: 1502 (73.4%) were included by a TRC and 544 (26.6%) by a SCC. Patients were mainly women (62%), 53±15 years old, 67% with Asthma Control Test <20; at inclusion, 14% received oral corticosteroids (OCS) and 66% biologics. Compared with the SCC group, the TRC group had more frequent comorbidities and lower blood eosinophil counts (262versus340 mm⁻³; p=0.0036). OCS and biologics use did not differ between groups, but patients in the TRC group benefited more frequently from an educational programme (26%versus18%; p=0.0008) and received more frequently two or more sequential lines of biologics (33%versus24%; p=0.0105). In-depth investigations were more frequently performed in the TRC group (allergy tests: 74%versus62%; p<0.0001; exhaled nitric oxide fraction: 56%versus21%; p<0.0001; induced sputum: 6%versus3%; p=0.0390).Conclusions: Phenotypes and care trajectories differed in the RAMSES cohort between SCCs and TRCs, probably related to different levels of asthma severity and differences in medical resources and practices among centres. This highlights the need for standardisation of severe asthma care.

Background: Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient‐tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome‐wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy).Methods: Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5–11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism‐corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve‐Bayes approach) combined with high‐dimensional logistic regression models (LASSO).Results: Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism‐corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5–6 years).Conclusion: Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers.