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Investigating Age Differences in COVID-19 Immune Response

Dr. Cheng’s team identified several differences in immune and inflammatory responses that may help explain the elevated risk for severe illness and death observed in older COVID-19 patients.


A new Cleveland Clinic study suggests that age-specific immune and inflammatory responses may help explain why the risk for severe COVID-19 increases with age. Published in Aging Cell, the findings point to specific immuno-inflammatory factors that could be therapeutically targeted to reduce morbidity and mortality in older COVID-19 patients.

“COVID-19 poses a serious risk at any age, but clinical reports indicate that it is particularly debilitating and deadly for older patients,” said the study’s lead author Feixiong Cheng, PhD, assistant staff in the Genomic Medicine Institute. “While we currently do not have a full explanation for this age-related vulnerability, previous studies suggest that impaired immune response and increased inflammation may be involved.”

In this study, the researchers leveraged large-scale patient data from the U.S. Centers for Disease Control and Prevention and the Cleveland Clinic COVID-19 registry to investigate the underlying basis for the increased rates of severe COVID-19 in older patients (defined as 65 years and older).

Age-specific immune and inflammatory responses may influence COVID-19 severity

Comparing older COVID-19 patients to younger patients, the researchers confirmed that older COVID-19 patients had an elevated likelihood of severe illness and death even after adjusting for sex, race, smoking and multiple disease comorbidities. Their analysis also uncovered multiple immuno-inflammatory determinants that may promote age-associated COVID-19 severity.

For example, the researchers found that hospitalized older COVID-19 patients had elevated levels of pro-inflammatory markers associated with COVID-19 severity and death, including neutrophil-lymphocyte ratio, D-dimer, C-reactive peptide and certain cytokines. Notably, the older patients displayed increased levels of the cytokines IL-8 and IL-27 while younger patients had significantly higher levels of IL-10.

“Serious COVID-19 complications can stem from an immune reaction that releases a large amount of pro-inflammatory cytokines, known as a cytokine storm,” noted Dr. Cheng. “Our observations suggest that differences in cytokine expression between older and younger patients could influence age-related hospitalization and admission to the intensive care unit. Furthermore, targeting IL-10 might reduce mortality in younger patients with severe COVID-19, whereas IL-8- and IL-27-based therapies might benefit older patients.”

In addition, they discovered that hospitalized older COVID-19 patients had decreased levels of naïve CD8 T lymphocytes (a type of white blood cell involved in immune function), which is a hallmark of immunosenescence, or the gradual deterioration of the immune systems associated with age. Their analysis determined that the naïve CD8 T cells had increased expression of apoptosis genes that cause cell death (e.g., CTSD27), indicating that targeting CD8 naïve T cell dysfunction, especially the apoptosis pathway, could provide a new treatment strategy for severe COVID-19 in older patients.

“Altogether, our study results pinpoint several immuno-inflammatory factors that may be associated with increased COVID-19 severity in older patients and could help pave the way toward age-specific prevention and treatment strategies for COVID-19,” said Dr. Cheng. ”As a next step, we are working to develop new risk assessment tools that integrate artificial intelligence methods into Cleveland Clinic’s electronic health record system and biorepository databases to help provide care for older patients with various neurological symptoms, such as cognitive impairment.”

Yuan Hou, PhD, a postdoctoral fellow in Dr. Cheng’s lab, is first author on the study, which was supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke (all part of the National Institutes of Health) and Cleveland Clinic’s VeloSano Pilot Program.

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