Identification of persistent and resolving subphenotypes of acute hypoxemic respiratory failure in two independent cohorts

Abstract

Background Acute hypoxemic respiratory failure (HRF) is associated with high morbidity and mortality, but its heterogeneity challenges the identification of effective therapies. Defining subphenotypes with distinct prognoses or biologic features can improve therapeutic trials, but prior work has focused on ARDS, which excludes many acute HRF patients. We aimed to characterize persistent and resolving subphenotypes in the broader HRF population. Methods In this secondary analysis of 2 independent prospective ICU cohorts, we included adults with acute HRF, defined by invasive mechanical ventilation and PaO2-to-FIO2 ratio ≤ 300 on cohort enrollment (n = 768 in the discovery cohort and n = 1715 in the validation cohort). We classified patients as persistent HRF if still requiring mechanical ventilation with PaO2-to-FIO2 ratio ≤ 300 on day 3 following ICU admission, or resolving HRF if otherwise. We estimated relative risk of 28-day hospital mortality associated with persistent HRF, compared to resolving HRF, using generalized linear models. We also estimated fold difference in circulating biomarkers of inflammation and endothelial activation on cohort enrollment among persistent HRF compared to resolving HRF. Finally, we stratified our analyses by ARDS to understand whether this was driving differences between persistent and resolving HRF. Results Over 50% developed persistent HRF in both the discovery (n = 386) and validation (n = 1032) cohorts. Persistent HRF was associated with higher risk of death relative to resolving HRF in both the discovery (1.68-fold, 95% CI 1.11, 2.54) and validation cohorts (1.93-fold, 95% CI 1.50, 2.47), after adjustment for age, sex, chronic respiratory illness, and acute illness severity on enrollment (APACHE-III in discovery, APACHE-II in validation). Patients with persistent HRF displayed higher biomarkers of inflammation (interleukin-6, interleukin-8) and endothelial dysfunction (angiopoietin-2) than resolving HRF after adjustment. Only half of persistent HRF patients had ARDS, yet exhibited higher mortality and biomarkers than resolving HRF regardless of whether they qualified for ARDS. Conclusion Patients with persistent HRF are common and have higher mortality and elevated circulating markers of lung injury compared to resolving HRF, and yet only a subset are captured by ARDS definitions. Persistent HRF may represent a clinically important, inclusive target for future therapeutic trials in HRF.

Rapidly improving acute respiratory distress syndrome in COVID-19: a multi-centre observational study

“…On the other hand, our findings regarding persistent severe ARDS seem anticipated. The prevalence of persistent severe ARDS seems similar to non-COVID ARDS [ 11 ] (or even non-COVID acute hypoxemic respiratory failure) [ 25 ] and so is the mortality. This is also in line with findings of a recent observational study from the United Kingdom, which reported that refractory hypoxemia remains a major determinant of mortality in the COVID-19 era [ 15 ].…”

Insights Regarding the Berlin Definition of ARDS from Prospective Observational Studies

“…15 74 Despite its ubiquitous nature there is no clear definition of AHRF, with most studies and reviews focusing on the ARDS subset of these patients, where the Berlin definition offers a more unambiguous demarcation of the study population. Various AHRF definitions used in the literature can be expressed as a PaO2/FiO2 ratio of <300 mm Hg only, 75 76 a PFR of <200 mm Hg with respiratory support, 73 and a PFR of <300 mm Hg with new pulmonary infiltrates and ventilator support with a PEEP of ≥5 cmH 2 O in the LUNG-SAFE trial. 15 74 The Berlin definition improved on previous classifications by removing the requirement for invasive ventilation, 15 Consequently, there is a significant overlap between currently used AHRF definitions and the Berlin definition, so the question emerges: does ARDS per se confer an additional mortality burden over similarly severe 'other causes' of AHRF?…”

Mechanical Ventilation in ARDS: Quo Vadis?

“…This includes varied clinical presentations such as lobar versus diffuse lung injury, severity of hypoxemia, and most recently the interactions between pro-inflammatory mediators with markers of endothelial dysfunction that distinguish early resolution from persistent hypoxemia. 213 Newer still is examining specific gene expression governing inflammation that might provide a more comprehensive understanding of ARDS, and also the possibility for highly specific novel drug therapies for certain ARDS phenotypes, or perhaps targeting current therapies more effectively. Research in this area already has discerned ARDS sub-phenotypes associated with the spectrum of inflammatory response (ie, uninflamed, reactive, hyporeactive, and hyperreactive), suggesting the existence of treatable traits with implications beyond ARDS.…”