American journal of respiratory and critical care medicine最新文献

Rationale: Identifying the root causes of racial disparities in childhood asthma is critical for health equity. Objectives: To determine whether the racist policy of redlining in the 1930s led to present-day disparities in childhood asthma by increasing community-level poverty and decreasing neighborhood socioeconomic position (SEP). Methods: We categorized census tracts at the birth address of participants from the Children's Respiratory and Environmental Workgroup birth cohort consortium into categories A, B, C, and D as defined by the Home Owners Loan Corporation, with D being the highest perceived risk. Surrogates of present-day neighborhood-level SEP were determined for each tract, including the percentage of low-income households, the CDC's Social Vulnerability Index, and other tract-level variables. We performed causal mediation analysis, which, under the assumption of no unmeasured confounding, estimates the direct and mediated pathways by which redlining may cause asthma disparities through tract-level mediators adjusting for individual-level covariates. Measurements and Main Results: Of 4,849 children, the cumulative incidence of asthma through age 11 was 26.6%, and 13.2% resided in census tracts with a Home Owners Loan Corporation grade of D. In mediation analyses, residing in Grade-D tracts (adjusted odds ratio = 1.03 [95% confidence interval = 1.01, 1.05]) was significantly associated with childhood asthma, with 79% of this increased risk mediated by percentage of low-income households; results were similar for the Social Vulnerability Index and other tract-level variables. Conclusions: The historical structural racist policy of redlining led to present-day asthma disparities in part through decreased neighborhood SEP. Policies aimed at reversing the effects of structural racism should be considered to create more just, equitable, and healthy communities.

Rationale: Fibrotic hypersensitivity pneumonitis (FHP) is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives: To elucidate immune aberrations in FHP in single-cell resolution. Methods: Single-cell 5' RNA sequencing was conducted on peripheral blood mononuclear cells and BAL cells obtained from 45 patients with FHP, 63 patients with idiopathic pulmonary fibrosis (IPF), 4 patients with nonfibrotic hypersensitivity pneumonitis, and 36 healthy control subjects in the United States and Mexico. Analyses included differential gene expression (Seurat), TF (transcription factor) activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3 and Velocyto-scVelo-CellRank). Measurements and Main Results: Overall, 501,534 peripheral blood mononuclear cells from 110 patients and control subjects and 88,336 BAL cells from 19 patients were profiled. Compared with control samples, FHP has elevated classical monocytes (adjusted-P = 2.5 × 10^-3) and is enriched in CCL3^hi/CCL4^hi and S100A^hi classical monocytes (adjusted-P < 2.2 × 10^-16). Trajectory analyses demonstrate that S100A^hi classical monocytes differentiate into SPP1^hi lung macrophages associated with fibrosis. Compared with both control subjects and IPF, cells from patients with FHP are significantly enriched in GZM^hi cytotoxic T cells. These cells exhibit TF activities indicative of TGFβ and TNFα and NFκB pathways. These results are publicly available at http://ildimmunecellatlas.com. Conclusions: Single-cell transcriptomics of patients with FHP uncovered novel immune perturbations, including previously undescribed increases in GZM^hi cytotoxic CD4⁺ and CD8⁺ T cells-reflecting this disease's unique inflammatory T cell-driven nature-as well as increased S100A^hi and CCL3^hi/CCL4^hi classical monocytes also observed in IPF. Both cell populations may guide the development of new biomarkers and therapeutic interventions.

Rationale: Uncertainty remains regarding the risks associated with single-dose use of etomidate. Objectives: To assess the use of etomidate in critically ill patients and compare outcomes for patients who received etomidate versus ketamine. Methods: We assessed patients who received invasive mechanical ventilation (IMV) and were admitted to an ICU in the Premier Healthcare Database between 2008 and 2021. The exposure was receipt of etomidate on the day of IMV initiation, and the main outcome was hospital mortality. Using multivariable regression, we compared patients who received IMV within the first 2 days of hospitalization who received etomidate with propensity score-matched patients who received ketamine. We also assessed whether receipt of corticosteroids in the days after intubation modified the association between etomidate and mortality. Measurements and Main Results: Of 1,689,945 patients who received IMV, nearly half (738,855; 43.7%) received etomidate. Among those who received IMV in the first 2 days of hospitalization, we established 22,273 matched pairs administered either etomidate or ketamine. In the primary analysis, receipt of etomidate was associated with greater hospital mortality relative to ketamine (21.6% vs. 18.7%; absolute risk difference, 2.8%; 95% confidence interval, 2.1%, 3.6%; adjusted odds ratio, 1.28, 95% confidence interval, 1.21,1.34). This was consistent across subgroups and sensitivity analyses. We found no attenuation of the association with mortality with receipt of corticosteroids in the days after etomidate use. Conclusions: Use of etomidate on the day of IMV initiation is common and associated with a higher odds of hospital mortality than use of ketamine. This finding is independent of subsequent treatment with corticosteroids.

Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Objectives: Does residence at higher altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, and mortality? Methods: From the SPIROMICS (Subpopulation and Intermediate Outcome Measures in COPD Study) cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation (n = 1,367) versus above 4,000 ft (1,219 m) elevation (n = 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Measurements and Main Results: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6-minute-walk distance (-32.3 m [95% confidence interval, -49.8 to -14.8 m]). There were no differences in patient-reported outcomes as defined by symptoms (COPD Assessment Test and modified Medical Research Council dyspnea scale), or health status (St. George's Respiratory Questionnaire). Higher altitude was not associated with a different rate of FEV₁ decline. Higher altitude was associated with lower odds of severe exacerbations (incidence rate ratio, 0.65 [95% confidence interval, 0.46 to 0.90]). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (hazard ratio, 1.25 [95% confidence interval, 1.0 to 1.55]); however, this association was no longer significant when accounting for air pollution. Conclusions: Long-term altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. In addition, long-term high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Rationale: The influence of the lung bacterial microbiome, including potential pathogens, in patients with influenza-associated pulmonary aspergillosis (IAPA) or coronavirus disease (COVID-19)-associated pulmonary aspergillosis (CAPA) has yet to be explored. Objectives: To explore the composition of the lung bacterial microbiome and its association with viral and fungal infection, immunity, and outcome in severe influenza versus COVID-19 with or without aspergillosis. Methods: We performed a retrospective study in mechanically ventilated patients with influenza and COVID-19 with or without invasive aspergillosis in whom BAL for bacterial culture (with or without PCR) was obtained within 2 weeks after ICU admission. In addition, 16S rRNA gene sequencing data and viral and bacterial load of BAL samples from a subset of these patients, and of patients requiring noninvasive ventilation, were analyzed. We integrated 16S rRNA gene sequencing data with existing immune parameter datasets. Measurements and Main Results: Potential bacterial pathogens were detected in 20% (28/142) of patients with influenza and 37% (104/281) of patients with COVID-19, whereas aspergillosis was detected in 38% (54/142) of patients with influenza and 31% (86/281) of patients with COVID-19. A significant association between bacterial pathogens in BAL fluid and 90-day mortality was found only in patients with influenza, particularly patients with IAPA. Patients with COVID-19, but not patients with influenza, showed increased proinflammatory pulmonary cytokine responses to bacterial pathogens. Conclusions: Aspergillosis is more frequently detected in the lungs of patients with severe influenza than bacterial pathogens. Detection of bacterial pathogens associates with worse outcome in patients with influenza, particularly in those with IAPA, but not in patients with COVID-19. The immunological dynamics of tripartite viral-fungal-bacterial interactions deserve further investigation.