SCCM Resource Library-29-TNF Receptor Soluble Factor 1A but Not Other Biomarkers Correlates With Changing PARDS Severity

Video Transcription

Hello, my name is Garrett Williams. I'm a second year Pediatric Critical Care Medicine Fellow at Cincinnati Children's Hospital. Today I'm going to be talking about the correlation  between increasing levels of TNF-RSF1A and worsening Pediatric Acute Respiratory Distress  Syndrome. I have no conflicts of interest or other disclosures. Pediatric ARDS is a common cause of morbidity and mortality in the Pediatric Intensive Care Unit. It affects  over 7,000 children a year and leads to 1,800 deaths per year. There have been multiple  large randomized control trials studying different therapies, and they have unfortunately mostly  failed to demonstrate a benefit in mortality. Adult ARDS patients subgrouped by serum biomarkers  have shown differential response to therapies, which suggests that if we are able to subgroup  ARDS patients, this might provide for diagnostic and prognostic enrichment in future trials  that would increase the likelihoods of a positive trial. To date, there have been no pediatric  studies that have examined the change in biomarkers over time with changing part severity. Our study examines the relationship between changing serum biomarkers versus changing  part severity. We designed a prospective observational single center study in a PICU at a large quaternary  children's hospital. We enrolled control and PARDS patients. Control patients were defined as patients admitted to the PICU with no apparent respiratory disease. PARDS patients  were under 18 years old, met the consensus PARDS definition, and were all mechanically ventilated. Serum samples were collected on days 1, 3, 7, and 14. Samples were analyzed  using the Luminex multiplex assay, and all of our statistical analyses were performed using the R statistical package. Our first result slide shows serum biomarker concentrations  by group. The x-axis shows control versus ARDS patients, and the y-axis shows the z-score  for the concentration of the serum biomarker. As you can see, there are several serum biomarkers  that are significantly elevated in pediatric ARDS patients compared to controls. These biomarkers include Granzyme B, ICAM-1, interferon gamma, TNF-alpha, TNF-RSF1A, among others.  And these results are consistent with both other adult and pediatric studies that have shown these biomarkers are elevated in ARDS patients. This slide looks at serum biomarkers  by PARDS severity. So along the x-axis is the classification of the severity, so none being control patients, and then mild, moderate, and severe as determined by the patient's  OSI. The z-score of the concentration of the biomarker is, again, along the y-axis. As you can see, ICAM-1 and SPD trended towards significance when looking at the severity,  although we will need more data to confirm this relationship. This slide shows the correlation  between biomarkers. So you can see the boxes are different shades. The darker red indicates a positive correlation, the darker green a negative correlation, and the boxes with stars  show statistical significance. If you look at the graph, you can see that the biomarkers at the bottom tend to correlate together, and those are biomarkers involved in inflammation  and neutrophil function. And then biomarkers up at the top left corner, including RAGE, MMP9, MPO, also tend to correlate together. Those biomarkers are thought to represent  markers of barrier integrity. And taken together, these results could show that there are possibly  two different biological programs involved in pediatric ARDS pathobiology, although we  will need more subjects to confirm this relationship. This slide shows the correlation between changing  heart severity as measured by OSI on the x-axis, as well as the change in serum concentration of each biomarker, and the z-score of that is on the y-axis. As you can see, of all the  biomarkers, the only one with statistical significance is TNF-RSF1A. It shows an R of 0.54 and a P that is statistically significant, showing that increasing levels of TNF-RSF1A  are correlated with increasing levels, or an increase, rather, in OSI, indicating worsening  acute lung injury. The conclusions from our study, several serum biomarkers that are elevated  in adults with ARDS are also elevated in pediatric ARDS patients. Certain groups of biomarkers  are correlated with each other, suggesting distinct programs involved in the pathology of  ARDS, and the increasing concentration of TNF-RSF1A is correlated with worsening heart severity over  time. I think a big future direction of our research is going to be increasing the numbers  that we have of patients so that we can get a larger sample size and confirm these relationships,  and my hope is that our research, as well as others, will be able to provide for an increased  knowledge of the pathobiology of pediatric ARDS and hopefully provide means for more diagnostic  and prognostic enrichment in future trials to increase the likelihood of having a positive trial that shows a benefit in mortality. I would like to thank Dr. Brian Verisco,  who has been my research mentor since residency. I would like to thank him for his hard work and  his diligence in helping me with this research project. Other lab members, Rashika Joshi,  Patrick Lani, from the Department of Critical Care Medicine, Dr. Hector Wong, Dr. Matt Alder,  and Dr. Will Zacharias, who works at UC Medical Center, and then Dr. Krishna Roskin for his help  with the bioinformatics portion. I would also like to thank the Society of Critical Care Medicine,  specifically the Discovery Network, for their support in this amazing opportunity, and then  thank CCHMC, CPG Innovation Fund, and Scott Proctor Scholar Program, as well as the NHLBI. Thank you.

Video Summary

Garrett Williams, a Pediatric Critical Care Medicine Fellow, discusses the correlation between increasing levels of TNF-RSF1A and worsening Pediatric Acute Respiratory Distress Syndrome (PARDS). Currently, there are no effective therapies for PARDS, and Williams suggests that sub-grouping patients based on serum biomarkers could lead to better diagnostic and prognostic enrichment in future trials. Williams conducted a study at a PICU in a large children's hospital, analyzing serum samples from control and PARDS patients. The results showed that several serum biomarkers were significantly elevated in pediatric ARDS patients compared to controls. Additionally, increasing levels of TNF-RSF1A were correlated with worsening heart severity over time. Williams hopes that this research will contribute to a better understanding of pediatric ARDS and lead to improved outcomes in future trials.

Asset Subtitle

Pediatrics, Pulmonary, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

James Williams

Introduction/Hypothesis: Pediatric acute respiratory distress syndrome (PARDS) is a significant cause of morbidity and mortality in the pediatric intensive care unit (PICU). To date, there have only been a few positive clinical trials in ARDS and PARDS. In ARDS, inflammatory serum biomarker profiles have identified sub-phenotypes that respond differently to interventions such as fluid administration and PEEP. In PARDS, biomarkers have been shown to correlate with PARDS severity, and no PARDS subgroups have been identified. We reasoned that PARDS biomarkers should correlate with PARDS severity and change with PARDS improvement or worsening.

Methods: This single center prospective observational study was conducted in a large PICU at a quaternary children's hospital. Control patients were defined as patients admitted to the PICU with no apparent respiratory disease. PARDS patients were under 18 years of age, mechanically ventilated, and met the consensus PARDS definition. Serum samples were collected on study days 1, 4, 7, and 14 and analyzed using Luminex. Statistical analyses were performed using the R statistical package.

Results: A total of 82 specimens from 11 control patients and 24 PARDS patients were analyzed. Levels of Granzyme B, ICAM-1, IFN-Î³, IL-18, SPD, and TNF-Î± were all found to be significantly (Wilcoxon Rank Sum, p < 0.05) elevated in the serum of PARDS patients compared with control. However, there was no significant difference in the levels of these biomarkers comparing mild, moderate, and severe PARDS. In comparing change in biomarker level with changing PARDS severity, only TNF-Î± and TNFRSF1A were both positively and significantly correlated with increasing lung injury severity (Pearson correlation, R 0.31, p = 0.048 and R 0.54, p = 2.3 x 10-4 respectively).

Conclusions: In conclusion, several serum proteins are elevated in PARDS patients when compared to controls, but none were significantly greater with higher PARDS severity. Only changes in TNF-Î± and TNFRSF1A levels correlated with changing PARDS severity. While serum TNF-Î± and TNFRSF1A levels correlate with disease status in a given patient, the failure of any biomarker to correlate with PARDS severity suggests that distinct sub-classes of PARDS exist which need to be identified.

Meta Tag

Content Type Presentation

Knowledge Area Pediatrics

Knowledge Area Pulmonary

Knowledge Level Advanced

Membership Level Select

Tag Acute Respiratory Distress Syndrome ARDS

Year 2021

Keywords

TNF-RSF1A

Pediatric Acute Respiratory Distress Syndrome

serum biomarkers

heart severity

outcomes

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