American journal of respiratory and critical care medicine最新文献

Rationale: Race-based estimates of pulmonary function in children could influence the evaluation of asthma in children from racial and ethnic minoritized backgrounds.

Objectives: To determine if race-neutral (GLI-Global) versus race-specific (GLI-Race-Specific) reference equations differentially impact spirometry evaluation of childhood asthma.

Methods: The analysis included 8,719 children aged 5 to <12 years from 27 cohorts across the United States grouped by parent-reported race and ethnicity. We analyzed how the equations affected forced expiratory volume in 1 second (FEV₁), forced vital capacity (FVC), and FEV₁/FVC z-scores. We used multivariable logistic models to evaluate associations between z-scores calculated with different equations and asthma diagnosis, emergency department (ED) visits, and hospitalization.

Measurements and main results: For Black children, the GLI-Global vs. Race-Specific equations estimated significantly lower z-scores for FEV₁ and FVC but similar values for FEV₁/FVC, thus increasing the proportion of children classified with low FEV₁ by 14%. While both equations yielded strong inverse relationships between FEV₁ and FEV₁/FVC z-scores and asthma outcomes, these relationships varied across racial and ethnic groups (p<0.05). For any given FEV₁ or FEV₁/FVC z-score, asthma diagnosis and ED visits were higher among Black and Hispanic versus White children (p<0.05). For FEV₁, GLI-Global equations estimated asthma outcomes that were more uniform across racial and ethnic groups.

Conclusions: Parent-reported race and ethnicity influenced relationships between lung function and asthma outcomes. Our data show no advantage to race-specific equations for evaluating childhood asthma, and the potential for race-specific equations to obscure lung impairment in disadvantaged children strongly supports using race-neutral equations.

Rationale: C-reactive protein (CRP)-based tuberculosis (TB) screening is recommended for people with HIV (PWH). However, its performance among people without HIV and in diverse settings is unknown. Objectives: In a multi-country study, we aimed to determine whether CRP meets the minimum accuracy targets (sensitivity ≥90%, specificity ≥70%) for an effective TB screening test. Methods/Measurements: Consecutive outpatient adults with cough ≥2 weeks from five TB endemic countries in Africa and Asia had baseline blood collected for point-of-care CRP testing and HIV and diabetes screening. Sputum samples were collected for Xpert MTB/RIF Ultra (Xpert) testing and culture. CRP sensitivity and specificity (5 mg/L cut-point) was determined in reference to sputum test results and compared by country, sex, and HIV and diabetes status. Variables affecting CRP performance were identified using a multivariate receiver operating characteristic (ROC) regression model. Results: Among 2904 participants, of whom 613 (21%) had microbiologically-confirmed TB, CRP sensitivity was 84% (95% CI: 81-87%) and specificity was 61% (95% CI: 59-63%). CRP accuracy varied geographically, with higher sensitivity in African countries (≥91%) than Asian countries (64-82%). Sensitivity was higher among men than women (87% vs. 79%, difference +8%, 95% CI: 1-15%) and specificity was higher among people without HIV than PWH (64% vs. 45%, difference +19%, 95% CI: 13-25%). ROC regression identified country and measures of TB disease severity as predictors of CRP performance. Conclusions: Overall, CRP did not achieve the minimum accuracy targets and its performance varied by setting and in some sub-groups, likely reflecting population differences in mycobacterial load.

Rationale: Systemic molecular phenotypes of critical illness are prognostically informative, yet their temporal kinetics and implications of changing phenotypes remain incompletely understood.

Objectives: To determine the temporal nature of the Hyperinflammatory and Hypoinflammatory phenotypes and assess the impact of transition between the phenotypes on mortality.

Methods: We used data from one prospective observational cohort (MARS) and two randomized controlled trials in ARDS (ALVEOLI) and sepsis (CLOVERS). Critically ill patients having biomarkers available at multiple timepoints (Day 0-4) were included. We employed a validated classifier model incorporating plasma interleukin-8, protein C and serum bicarbonate to assign phenotypes on each day. We determined the association of longitudinal phenotype transition and 90-day all-cause mortality.

Measurements and main results: Data from 2407, 527 and 868 patients were included in MARS, ALVEOLI and CLOVERS, respectively. In MARS, 36.0% were classified by the parsimonious model as Hyperinflammatory at day 0, decreasing to 15.6% by day 2 and 6.3% by day 4. In ALVEOLI and CLOVERS, 26.4% and 24.8% of patients were Hyperinflammatory at day 0, decreasing to 13.4% and 5.7% at day 3, respectively. In all three cohorts, switching classification from Hyperinflammatory (Day 0) to Hypoinflammatory over time was associated with significantly improved mortality compared to persistently Hyperinflammatory patients. Mediation analysis indicated that only a minor proportion of this improvement could be attributed to ameliorating organ failure.

Conclusion: The prevalence of the Hyperinflammatory phenotype, as assigned by a parsimonious biomarker classifier model, decreases over the first several days of critical illness, irrespective of ARDS diagnosis. The transition from Hyperinflammatory to Hypoinflammatory mediates a trajectory towards recovery beyond the resolution of organ failure.

Rationale: Idiopathic Pulmonary Fibrosis (IPF) is a lethal disease with limited therapeutic options. FGF21, an endocrine fibroblast growth factor that acts through the FGFR1/KLB pathway, mitigates liver fibrosis.

Objectives: We hypothesized that FGF21 could exert anti-fibrotic properties in the lung.

Methods: The concentrations of FGF21 and KLB in the plasma of IPF patients and control subjects were assessed. Pulmonary fibrosis development was assessed in Fgf21-deficient mice as compared to Wild Type littermates, at Day 14 after intra-tracheal injection of bleomycin. We determined the effect of repeated subcutaneous injections of a PEGylated FGF21 analog (PEG-FGF21) at D7, 10, 14 and 17 after bleomycin on the development of pulmonary fibrosis. Mice were sacrificed at D21. The effects of FGF21, alone or with KLB, on apoptosis in MLE15 cells and on the phenotype of human lung fibroblasts were assessed in vitro.

Results: In the plasma of IPF patients, FGF21 concentration was increased, while KLB levels were decreased. Fgf21 deficient mice presented an increased sensitivity to bleomycin, in comparison to their Wild Type littermate. Treatment with PEGylated FGF21 mitigated lung fibrogenesis, as evidenced by a lower injury score, decreased fibrosis markers and pro-fibrotic mediators expression as compared to the control group receiving the diluent. In MLE15 cells, stimulation with FGF21 and KLB inhibited apoptosis, through the decrease of BAX and BIM. Fibroblastic phenotype remained unaltered.

Conclusion: Our data indicate a possible anti-fibrotic effect of FGF21 in the lung achieved through the inhibition of alveolar type 2 cells apoptosis.