Refining the Syndrome

Critical illness syndromes like sepsis and acute respiratory distress syndrome (ARDS) have been defined using clinical criteria that are easy to apply.[1-3] However, this has left ARDS with high heterogeneity and poor recognition.[4-6] Unfortunately, in patients that die after a diagnosis of ARDS, there appears to be poor correlation with the original pathologic description of diffuse alveolar damage.[7] This heterogeneity and poor specificity may have contributed to the paucity of successful clinical trials in critical care, despite promising pre-clinical interventions. Biomarkers have been proposed to reduce heterogeneity in sepsis and ARDS in both adults and children, most commonly using peripherally circulating protein markers.[8-20] However, for primarily pulmonary processes like ARDS and pediatric ARDS (PARDS), a criticism of this approach is the possibility that investigators are sampling the wrong compartment. Specifically, bronchoalveolar lavage (BAL) in pediatric intubated respiratory failure is uncommon, limiting the number of biomarker studies which sample the lower respiratory tract of children.

In this issue of Pediatric Critical Care Medicine, Halstead and colleagues report their work, “Cytokine Panels and Pediatric Acute Respiratory Distress Syndrome: A Translational Investigation” (21). This was a translational study that measured chemokines in serum and bronchoalveolar lavage fluid (BALF) in a murine infectious lung injury model, and then sought to validate the findings in children with acute respiratory failure due to respiratory tract infections. C57BL6/J mice were treated with intranasal influenza A or Toll-like receptor (TLR) agonists (TLR-4 and −2). Children were 0-17 years old, admitted to a single center pediatric intensive care unit (PICU) from April 2015 to March 2019, intubated and mechanically ventilated with laboratory evidence of respiratory tract infection, and control patients were intubated for surgical procedures. Respiratory tract fluids were obtained in subjects and controls by tracheal aspirate or mini-BAL.

The authors found changes in inflammatory biomarkers consistent with previous murine models of infection and ARDS. They investigated the kinetics and performed analyses to account for BALF dilution. Their data suggest that elevated CCL7 levels in serum and BALF at the peak of inflammation correlated with lethality in mice, and that the BALF ratio of CCL7:CCL22 had the strongest association with mortality with good sensitivity and specificity. The pediatric respiratory infection cohort data showed that CCL7 was not commonly found in respiratory tract fluids, but that its presence was associated with worse outcome measured by ventilator free days.

Discovery of biomarkers that improve pediatric respiratory failure and PARDS prognostication has been the focus of recent research.[20, 22-29] Despite the enthusiasm for biomarkers for trial enrichment and for reducing heterogeneity, the utility of any of these biomarkers have yet to be demonstrated in critical illness. Although several biomarkers have been associated with higher mortality, less than 20% of children with PARDS die. More common is severe morbidity from PARDS related to prolonged mechanical ventilation and its associated complications. Many of the implicated biomarkers reflect severity of inflammation or degree of organ failure, without necessarily being causal for either. Biomarkers that improve understanding of the underlying mechanisms driving severity of lung injury and identify children at higher risk for prolonged ventilation may be more relevant in pediatrics. It is plausible that examination of lower respiratory tract fluids is required to identify biomarkers most likely to be associated with severity of lung injury.

This highlights another promising feature of the manuscript by Halstead et al (21): its willingness to move from bench to bedside. Ultimately, differentiation of biomarkers which are worth targeting versus those which are merely distracting bystanders requires interventional studies in pre-clinical models. Progress in this space requires increased multidisciplinary collaboration between the basic scientists, the clinical investigators, and their translational link.

The manuscript by Halstead et al in this issue of PCCM is another step towards improved prognostication of children with respiratory failure and PARDS. Small endotracheal tube sizes and the inability to place a bronchoscope with an instillation and suction ports have been a persistent problem for advancing knowledge in the field of pediatric lung injury. The ability to identify a potentially promising inflammatory biomarker with suboptimal sampling techniques (relative to BAL), particularly one with a possible correlation with outcome, is notable. Certainly, tracheal aspiration (TA) is a universal procedure, and several institutes perform mini-BAL routinely. In the mouse studies in this manuscript, BAL levels approximately mirrored serum levels. However, the authors did not differentiate the patients in whom tracheal aspirate versus mini-BAL was performed. Studies have shown that TA is less sensitive than mini-BAL in detecting lower respiratory tract pathogens in adults.[30] In addition, although mini-BAL (nonbronchoscopic or nondirected BAL) has been shown to be safe in adults, this procedure is not free of risk and there are conflicting data regarding whether it reliably samples the lower respiratory tract.[31-35]

Despite the fact that neither tracheal aspirates nor mini-BAL are precisely sampling the alveolar space, this study represents an advancement in biomarker studies of pediatric respiratory failure by moving beyond the blood compartment, while simultaneously highlighting the challenges associated with recovering lower respiratory tract fluid in children. Future studies should explicitly compare simultaneously collected blood and respiratory samples with promising candidate cytokines. This will disentangle which biomarkers may be informative of a pulmonary-specific inflammatory process, versus which markers may simply reflect overall systemic inflammation.