Daily Respiratory Research Analysis

PURPOSE: Despite optimal antimicrobial therapy, the treatment failure rate of hospital-acquired pneumonia (HAP) routinely reaches 40% in critically ill patients. Subphenotypes have been identified within sepsis and acute respiratory distress syndrome with important predictive and possibly therapeutic implications. We derived prognosis subphenotypes for HAP and explored whether they were associated with biological markers and response to treatment. METHODS: We separately analysed data from four cohorts of critically ill patients in France (PNEUMOCARE, n = 511, ATLANREA, n = 401), Netherlands (MARS, n = 1351) and Europe-South America (ENIRRI, n = 900) to investigate HAP heterogeneity using unsupervised clustering based on clinical and routine biological variables available at HAP diagnosis. Then, we developed a machine learning-based workflow to create a simplified classification model using discovery data sets. This model was validated by applying it to an independent replication data set from an international randomized clinical trial comparing linezolid and tedizolid for the treatment of HAP (VITAL, n = 726 patients). The primary outcome was the association of subphenotypes with 28-day all-cause mortality. Secondary analyses included subphenotype associations with treatment failure at test-of-cure, respiratory microbiome and cytokine profiles in the ATLANREA subgroup, and treatment response in the VITAL trial. RESULTS: We tested twelve metrics and determined that a two-cluster model best fits all cohorts. HAP subphenotype 2 had greater disease severity, lower body temperature, and worse PaO2/FiO2 ratio than subphenotype 1 patients. Although the prevalence of subphenotype 2 ranged from 26.9 to 66.9% across the four derivation cohorts, the rates of 28-day mortality and treatment failure at test-of-cure were consistently higher to subphenotype 1 (p < 0.01 for all comparisons). Subphenotype 2 was associated with greater respiratory microbiome dysbiosis and higher levels of proinflammatory cytokines in the ATLANREA cohort, as well as with statistically significant tedizolid effect modification in the VITAL trial (Relative Risk of treatment failure with tedizolid = 1.52; 95% CI 1.12-2.06 in subphenotype 1 vs. = 0.98; 95% CI 0.7-1.38 in subphenotype 2). CONCLUSIONS: We identified two robust clinical subphenotypes by extensively analyzing HAP data sets. Their associations with respiratory microbiome composition, systemic inflammation, and treatment efficacy in independent data sets highlight their potential for prognostic value and predictive enrichment in future clinical trials aimed at personalized therapies.

INTRODUCTION: Post-treatment surveillance is recommended for NSCLC owing to a high risk of recurrence, but evidence on the optimal surveillance method is lacking. This trial evaluates fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([ METHODS: In this multicenter, randomized controlled trial (SUPE_R, ClinicalTrials.gov NCT03740126), patients with stage IA-to-IIIC NSCLC were randomized one-to-one to standard surveillance (ceCT) or surveillance with [ RESULTS: Between February 2019 and February 2022, 750 patients were randomized to PET/CT (n = 373) or CT (n = 377). Recurrences occurred in 164 patients (22%). The proportion of recurrences treated with curative intent was identical in the PET group (42/87) and CT group (37/77), both 48% (p = 0.98). More recurrences were detected through scheduled follow-up in the PET group (90%) than in the CT group (77%; p = 0.02). There were no significant differences in TTR (hazard ratio 1.12, 95% confidence interval 0.82-1.52, p = 0.48) or OS (hazard ratio 0.97, 95% confidence interval 0.66-1.43, p = 0.89) between groups. CONCLUSIONS: Surveillance with [

Pharmacological rescue of F508del-CFTR by the triple combination CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) leads to unprecedented clinical benefits in patients with cystic fibrosis (CF). However, previous studies in CF primary human airway epithelial cultures demonstrated that chronic treatment with the potentiator ivacaftor can render the F508del protein unstable, thus limiting restoration of CFTR chloride channel function. Even so, quantitative studies of this unwanted effect of ivacaftor on F508del channel function with dependency on cell culture conditions remain limited, and the impact of chronic ivacaftor exposure on restoration of mucociliary clearance that is impaired in patients with CF has not been studied. In patient-derived primary nasal epithelial cultures, we found that different culture conditions (UNC-ALI medium vs. PneumaCult medium) have profound effects on ETI-mediated restoration of F508del-CFTR function. Chronic treatment with ivacaftor as part of ETI triple therapy limited the rescue of F508del-CFTR chloride channel function when CF nasal epithelial cultures were grown in UNC-ALI medium but not in PneumaCult medium. In PneumaCult medium, both chronic and acute addition of ivacaftor as part of ETI treatment led to constitutive CFTR-mediated chloride secretion in the absence of exogenous cAMP-dependent stimulation. This constitutive CFTR-mediated chloride secretion was essential to improve viscoelastic properties of the mucus layer and to restore mucociliary transport on CF nasal epithelial cultures. Furthermore, nasal potential difference measurements in patients with CF showed that ETI restored constitutive F508del-CFTR activity in vivo. These results demonstrate that ivacaftor as a component of ETI therapy is essential to restore mucociliary clearance and suggest that this effect is facilitated by its constitutive activation of F508del channels following their folding correction in patients with CF.