Identification of Three Endotypes in Pediatric Acute Respiratory Distress Syndrome by Nasal Transcriptomic Profiling

ABSTRACT

Acute respiratory distress syndrome (ARDS) and pediatric ARDS (PARDS) can be triggered by multiple pulmonary and non-pulmonary insults and are the source of substantial morbidity and mortality. The nasal epithelium is similar to that of the lower conducting airways and nasal transcriptomic profiling identifies disease and endotypes in lung cancer, COPD, and asthma. We conducted a prospective trial of testing whether this technique could identify PARDS endotypes in 26 control and 25 PARDS subjects <18 admitted to the PICU extracting RNA from inferior turbinate brushings on days 1, 3, 7, and 14. Standard RNA processing and mRNA-seq yielded ~25% usable specimens and a modified, low-input RNA protocol yielded 95% usable specimens. Sixty-four low-input specimens from 10 control and 15 PARDS subjects were used for initial analysis. Control and some PARDS subjects clustered together in both by-day and combined analysis into Groups A while some day 1, 3, and 7 specimens from the same subjects clustered into Groups B and C with specimens from these subjects moving to Group A with PARDS resolution. In multivariate analysis, the only clinical variables predictive of Group B or C status was severity of lung injury or viral PARDS trigger. Compared to Group A, Group B had upregulation of innate immune processes and group C had upregulation of cilia-associated processes. Analysis of the 15 specimens processed and analyzed by standard techniques identified the same processes as differentiating Groups A, B, and C. Mortality appeared to be higher in group B (25%) and C subjects (28.6%) compared to A subject (5%, p=0.1). Our findings demonstrate three distinct PARDS endotypes which may be useful for prognostic and therapeutic enrichment. ClinicalTrials.gov Identifier <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT03539783">NCT03539783</ext-link>