PROJECT SUMMARY
Current approaches to classifying critical illness focus on broad clinical syndromes including sepsis and the
acute respiratory distress syndrome (ARDS). However, application of consensus definitions of these
syndromes has not translated to syndrome-specific, targeted therapies. Recent transformative studies of
ARDS have revealed underlying (latent) biological phenotypes, termed hyper- and hypo-inflammatory, that are
remarkably consistent across multiple ARDS cohorts. Further, in post hoc analysis, these phenotypes respond
differentially to both process of care (fluids, PEEP) and pharmacologic (simvastatin) treatments. These findings
suggest that biological phenotyping in ARDS, pneumonia and sepsis may pave the way towards a deeper
understanding of the biology of critical illness that will translate, for the first time, into targeted, personalized
therapies. Our multidisciplinary team of investigators and clinical enrollment sites brings together deep
scientific expertise in pathophysiologic mechanisms and phenotyping of ARDS, sepsis and pneumonia, world-
class infrastructure for collecting long-term outcomes after critical illness, strong experience in designing and
implementing observational clinical cohort studies that include long-term follow-up, and proven ability to enroll
large numbers of critically ill patients in observational and clinical studies. Our team proposes two studies: (1) a
Consortium-wide 5,000 patient observational cohort study, the MUltidimenSional phenotyping In Critical care
(MUSIC) Study. The primary Aim of this study is to test the hypothesis that latent phenotypes are generalizable
across critical illness syndromes and associate with both short- and long-term outcomes. Determining whether
inflammatory phenotypes are identifiable across common critical illness syndromes can fundamentally alter our
approach to classifying critical illness in a way that captures a more uniform biological phenotype agnostic to
syndromic diagnosis. (2) a Clinical Center Study that addresses the critical need to better understand airspace
biology in patients with ARDS and other etiologies of acute respiratory failure (ARF). It has long been
recognized that airspace biology differs significantly from that of the circulation, but the field has lacked a non-
invasive, inexpensive, simple, and safe method of sampling the distal airspace in ARF. Our group has
pioneered a new method for sampling the airspace in intubated, mechanically ventilated patients with ARF
using fluid extracted from heat moisture exchanger (HME) filter. The HARMONY study (HME for Acute
Respiratory failure MultidimensiONal phenotYping) has a primary goal of identifying lung-specific phenotypes
in ARF that will be tested for associations with long term functional and structural respiratory outcomes. Our
Center will leverage our expertise in critical illness phenotyping, robust ED/ICU patient enrollment (37,756
patients in 5 years), pioneering work in long term outcomes in ICU survivors, decades of experience studying
biomarkers of critical illness and novel approaches to study airspace biology, to play a key role in the APS
Consortium and have a major and sustained impact in the field of ARDS, pneumonia, and sepsis.
