Identifying clinical and biochemical phenotypes in acute respiratory distress syndrome secondary to coronavirus disease- 2019

ABSTRACT

RationaleAcute respiratory distress syndrome (ARDS) secondary to Coronavirus Disease-2019 (COVID-19) is characterized by substantial heterogeneity in clinical, biochemical, and physiological characteristics. However, the pathophysiology of severe COVID-19 infection is poorly understood. Among “classical' ARDS cohorts, previous studies established two predominant biological phenotypes - patients with and without evidence of a hyperinflammatory response - with important prognostic and therapeutic implications. The phenotypic profile of COVID-19 associated ARDS remains unknown. Methods We used latent class modeling via a multivariate mixture model to identify phenotypes from clinical and biochemical data collected from 263 patients admitted to Massachusetts General Hospital intensive care unit with COVID-19-associated ARDS between March 13 and August 2, 2020. Classdefining variables included demographic features, respiratory parameters, hematologic and inflammatory biomarkers, and markers of end-organ function. Interleukin-6 (IL-6) and fibrinogen levels, which were available for n = 53 and n = 189 patients, respectively, were incorporated post-hoc. Results We identified two distinct latent classes representing 74.4% (Class 1, n = 193) and 26.6% (Class 2, n = 70) of the cohort, respectively. Posterior probability of class assignment was high (median 98.2%, IQR [98.0%, 100%]). To understand each class's distinguishing biological features, we compared the standardized mean of the continuous class-defining variables (Fig. 1A). The minority phenotype (class 2, n = 70, 26.6%) demonstrated increased markers of vascular dysregulation, with mild relative hyper-inflammation and dramatically increased markers of end-organ dysfunction (e.g., creatinine, troponin). There was little distinction according to respiratory parameters. The class 2 phenotype was characterized by significantly decreased fibrinogen and increased IL- 6 compared to Class 1 (Fig. 1B), even though these variables were not used in the statistical inference. Furthermore, the 28-day mortality among the class 2 phenotype was more than double that of the class 1 phenotype (40.0% vs. 23.3%, OR 2.3, 95% CI [1.3, 4.1]). Conclusion We identified distinct phenotypic profiles in COVID-19 associated ARDS, with little variation according to respiratory physiology but with important variation according to systemic and extra-pulmonary markers. Phenotypic identity was highly associated with shortterm mortality risk. The class 2 phenotype exhibited prominent signatures of vascular dysregulation, suggesting that vascular dysfunction may play an important role in the clinical progression of severe COVID-19-related disease.