American journal of respiratory and critical care medicine最新文献

Rationale: C-reactive protein (CRP)-based tuberculosis (TB) screening is recommended for people with HIV. However, its performance among people without HIV and in diverse settings is unknown. Objectives: In a multicountry study, we aimed to determine whether CRP meets the minimum accuracy targets (sensitivity ⩾ 90%, specificity ⩾ 70%) for an effective TB screening test. Methods: 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 curve regression model. Measurements and Main Results: Among 2,904 participants, of whom 613 (21%) had microbiologically confirmed TB, CRP sensitivity was 84% (95% confidence interval [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 (86% vs. 78%; difference, +8%; 95% CI, 1-15%) and specificity was lower among people with HIV than people without HIV (64% vs. 45%; difference, +19%; 95% CI, 13-25%). Receiver operating curve 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 subgroups, 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 [Molecular Diagnosis and Risk Stratification of Sepsis]) and two randomized controlled trials in acute respiratory distress syndrome (ALVEOLI [Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury]) and sepsis (CLOVERS [Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis]). Critically ill patients with biomarkers available at multiple time points (Days 0-4) were included. We used a validated classifier model incorporating plasma IL-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 2,407, 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 with persistently Hyperinflammatory patients. Mediation analysis indicated that only a minor proportion of this improvement could be attributed to ameliorating organ failure. Conclusions: The prevalence of the Hyperinflammatory phenotype, as assigned using a parsimonious biomarker classifier model, decreases over the first several days of critical illness, irrespective of acute respiratory distress syndrome diagnosis. The transition from Hyperinflammatory to Hypoinflammatory mediates a trajectory toward recovery beyond the resolution of organ failure.

Rationale: The global burden of sepsis is concentrated in sub-Saharan Africa, where inciting pathogens are diverse and HIV coinfection is a major driver of poor outcomes. Biological heterogeneity inherent to sepsis in this setting is poorly defined. Objectives: To identify dominant pathobiological signatures of sepsis in sub-Saharan Africa and their relationship to clinical phenotypes, patient outcomes, and biological classifications of sepsis identified in high-income countries (HICs). Methods: We analyzed two prospective cohorts of adults hospitalized with sepsis (severe infection with quick Sepsis-related Organ Failure Assessment score ⩾1) at disparate settings in Uganda (discovery cohort [Entebbe, urban], n = 242; validation cohort [Tororo, rural], n = 253). To identify pathobiological signatures in the discovery cohort, we applied unsupervised clustering to 173 soluble proteins reflecting key domains of the host response to severe infection. A random forest-derived classifier was used to predict signature assignment in the validation cohort. Measurements and Main Results: Two signatures (Uganda Sepsis Signature [USS]-1 and USS-2) were identified in the discovery cohort, distinguished by expression of proteins involved in myeloid cell and inflammasome activation, T-cell costimulation and exhaustion, and endothelial barrier dysfunction. A five-protein classifier (area under the receiver operating characteristic curve, 0.97) reproduced two signatures in the validation cohort with similar biological profiles. In both cohorts, USS-2 mapped to a more severe clinical phenotype associated with HIV and related immunosuppression, severe tuberculosis, and increased risk of 30-day mortality. Substantial biological overlap was observed between USS-2 and hyperinflammatory and reactive sepsis phenotypes identified in HICs. Conclusions: We identified prognostically enriched pathobiological signatures among patients with sepsis with diverse infections and high HIV prevalence in Uganda. Globally inclusive investigations are needed to define generalizable and context-specific mechanisms of sepsis pathobiology, with the goal of improving access to precision medicine treatment strategies.