Understanding clinical and biological heterogeneity to advance precision medicine in paediatric acute respiratory distress syndrome

Abstract

Paediatric acute respiratory distress syndrome (PARDS) is a heterogeneous clinical syndrome that is associated with high rates of mortality and long-term morbidity. Factors that distinguish PARDS from adult acute respiratory distress syndrome (ARDS) include changes in developmental stage and lung maturation with age, precipitating factors, and comorbidities. No specific treatment is available for PARDS and management is largely supportive, but methods to identify patients who would benefit from specific ventilation strategies or ancillary treatments, such as prone positioning, are needed. Understanding of the clinical and biological heterogeneity of PARDS, and of differences in clinical features and clinical course, pathobiology, response to treatment, and outcomes between PARDS and adult ARDS, will be key to the development of novel preventive and therapeutic strategies and a precision medicine approach to care. Studies in which clinical, biomarker, and transcriptomic data, as well as informatics, are used to unpack the biological and phenotypic heterogeneity of PARDS, and implementation of methods to better identify patients with PARDS, including methods to rapidly identify subphenotypes and endotypes at the point of care, will drive progress on the path to precision medicine.

Figure 1:. Potential strategies for personalised ventilator management of PARDS

CMV=conventional mechanical ventilation. ECMO=extracorporeal membrane oxygenation. HFOV=high-frequency oscillatory ventilation. P_0·1=pressure generated during the first 100 ms of a breath. PARDS=paediatric acute respiratory distress syndrome. PEEP=positive end-expiratory pressure.

Figure 2:. The pathway to precision medicine for PARDS

A personalised or precision medicine approach to PARDS is needed to meet the needs of individuals in this diverse patient population, which encompasses differences in age, sex, race, ethnicity, socioeconomic status, and geographical region. The pathway to precision medicine starts with a heterogeneous cohort of children admitted to the paediatric ICU with acute respiratory failure. A range of factors including age (stage of development and lung maturation), sex, causative infectious agent, underlying disease, genetics, and comorbidities, among others, might contibute to clinical and biological heterogeneity. Most of these patients are supported with high-flow oxygen therapy or non-invasive mechanical ventilation. Some of these patients meet the PALICC criteria for PARDS—ie, acute onset of disease with a triggering event <7 days before confirmation with PARDS criteria, one or more infiltrates on chest x-ray, and impaired oxygenation (ie, OI ≥4). Severity of PARDS is stratified into mild (OI 4 to <8), moderate (OI 8 to <16), or severe (OI ≥16). This heterogeneous cohort of children could be subphenotyped on the basis of charactersitics such as demographics, lung mechanics, inflammatory profile, and underlying disease (and, potentially, genetics in the future). Such phenotyping would enable individualised ventilator management based on lung mechanics and respiratory monitoring, and individualised treatment and escalation to second-tier interventions such as HFOV or ECMO. In future, individualised care, including the use of novel, targeted treatments, could be advanced using big data analysis and machine learning. ECMO=extracorporeal membrane oxygenation. HFOV=high-frequency oscillatory ventilation. ICU=intensive care unit. OI=oxygenation index. PALICC=Pediatric Acute Lung Injury Consensus Conference. PARDS=paediatric acute respiratory distress syndrome.