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Study Finds Immune Flaws in COVID-19 Patients With Lung Failure

Discoveries Could Improve Therapies for Life-Threatening Acute Respiratory Distress Syndrome

Patients with severe COVID-19 (coronavirus) disease who develop respiratory failure have malfunctions in their immune systems that distinguish them from other COVID-19 patients, according to a new study led by Cedars-Sinai. The findings, published Dec. 16 in the journal Cell Reports, could help doctors develop new ways to prevent and treat this life-threatening complication.

The study focused on acute respiratory distress syndrome (ARDS), a type of sudden-onset respiratory failure that can occur when the lung's lining is damaged by illness or injury. ARDS causes fluid to accumulate in the lungs and also causes the lungs' air sacs to collapse, impeding breathing and lowering the oxygen level in the blood.

Although most COVID-19 patients have mild respiratory illness, about 20% become seriously ill and require hospitalization due to pneumonia that can progress to ARDS and systemic inflammation, according to recent research. ARDS is associated with poorer outcomes, including death and lasting lung damage.Peter Chen, MD

"Because ARDS has such serious consequences for coronavirus patients, it is critical that we understand why it happens and what we can do to treat it," said Peter Chen, MD, professor of Medicine and director of the Division of Pulmonary and Critical Care Medicine at Cedars-Sinai. "That is why we did this research."

The research team analyzed the immune systems of 17 COVID-19 patients—five with moderate coronavirus disease, six with ARDS and six who were recovering from ARDS—and compared these patients against three people without COVID-19.

They looked at the transcription process, which is how genes transfer their instructions to proteins that construct a cell's chemical processes, in so-called peripheral blood mononuclear cells. This category includes various types of highly specialized immune cells that fight infections.

The investigators uncovered a range of distinctive defects in the transcription processes of peripheral blood mononuclear cells in the ARDS patients, as compared with the other subjects in the study. These defects appeared in cells in both of the body's immune systems: the innate immune system, which initially responds to viruses and bacteria, and the adaptive immune system, which kicks in later. The defects also affected how the body switched between innate and adaptive immunity.

Helen Goodridge, PhD"Our study supports the concept that COVID-19, and especially severe cases that have progressed to ARDS, is characterized by multifaceted impairment of the body's regulation of immune responses," said Helen Goodridge, PhD, associate professor of Biomedical Sciences and Medicine at Cedars-Sinai. "This defective regulation is not uniformly hyperinflammatory. Instead, it can be more accurately described as a state of immune imbalance."

Future research using larger sample sizes is needed to further delineate the transcriptional landscape of immune cells in different ARDS populations, according to the study team. In the meantime, Goodridge said, the implications of the findings are clinically relevant and indicate that treatment of patients with ARDS arising from COVID-19 infections may require a targeted approach instead of broad, immunosuppressive therapy.

Goodridge was a co-senior author of the study, along with Chen and Sina Gharib, MD, professor in the Division of Pulmonary, Critical Care and Sleep Medicine at the University of Washington School of Medicine in Seattle. The co-first authors were Changfu Yao, PhD, and Stephanie Bora, PhD, from the Women's Guild Lung Institute at Cedars-Sinai.

Funding: This study was funded by the Parker B. Francis Foundation Fellowship; Plum Foundation; Erwin Rautenberg Foundation Fellowship; the National Institutes of Health (NIH) under award numbers T32HL134637, P01HL108793), R01HL135163), R01AI127406, R01AI103542, R21AI151987, R01AI134987, R01AI137111 and R01HL137076; and the National Center for Advancing Translational Sciences of the NIH through the UCLA CTSI under award number KL2TR001882.

DOI: 10.1016/j.celrep.2020.108590

Read more in Discoveries: The Heart of COVID-19