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Study Implicates Immune Alterations, Delayed Viral Clearance in Age-Related COVID-19 Severity

NEW YORK – Altered immune system activity appears to explain why aging individuals tend to be more prone to severe COVID-19 than their younger counterparts, according to new research published in Science Translational Medicine on Wednesday.

"[W]e find that aging has marked impacts on host immune and viral dynamics in patients hospitalized for COVID-19," senior and corresponding author Charles Langelier, an infectious diseases researcher affiliated with the University of California, San Francisco and the Chan Zuckerberg Biohub, and his colleagues wrote, adding that results from the study "will help inform therapeutic strategies for this at-risk population."

For their study, the researchers used a combination of nasal swab RNA sequencing, metatranscriptomic microbiome profiling, and blood RNA-seq to characterize immune and upper airway features in 1,031 unvaccinated adults between the ages of 18 and 96 years who were hospitalized with COVID-19 in the US. To that, they added Standard BioTools mass cytometry on whole blood samples, Olink assay-based serum inflammatory protein profiling, and antibody assays targeting SARS-CoV-2.

"[W]e used a multiomic approach evaluating gene expression, protein levels, immune cell populations, antibody levels, SARS-CoV-2 load and the respiratory microbiome at multiple time points following hospitalization," Langelier noted in an email.

"This allowed us to comprehensively understand age-related changes in both host immune and microbial factors, understand interactions between host response and virus, and identify subtle but biologically important signals that might be missed in studies with smaller sample sizes," he explained.

Along with higher-than-usual levels of the SARS-CoV-2 virus in blood samples from older individuals during infection, the team saw delayed clearance of the coronavirus in the older COVID-19 patients.

In addition, Langelier explained, consistent with findings from past studies that unearthed upticks in inflammatory protein and inflammatory gene expression in aging individuals with COVID-19, the new results pointed to the presence of persistent pro-inflammatory gene and protein expression in older individuals infected with SARS-CoV-2.

In particular, participants of a more advanced age showed an increase in pro-inflammatory contributors such as cytokines, coupled with rising blood monocyte levels and a decline in adaptive immune signaling pathway activity.

"Our results identify discrete innate and adaptive immune signaling pathways that are altered with age," the authors reported, "suggesting potential targets for age-dependent therapeutic intervention."

While sets of naïve T and B cells turned up at lower levels in blood samples from the elderly, the team's results suggested that enhanced type I interferon expression in the blood and nasal swab samples from elderly patients reflected high levels of SARS-CoV-2 found in these participants.

"We found that older age was associated with increased type I interferon signaling in both the blood and respiratory tract," Langelier said, "but that the relationship was principally driven by aging-related increases in SARS-CoV-2 viral load."

That delayed viral clearance, in turn, appeared to reflect impaired T cell- and B cell-based immune processes, he explained, together with reduced MHC antigen presentation — immune shifts that were spelled out with the available transcriptomic, protein profiling, and cell level data generated.

"Delayed viral clearance due to these age-related factors could facilitate the evolution of SARS-CoV-2 variants," Langelier said, noting that such results hint that older adults may remain infectious for longer stretches of time and may also benefit from longer antiviral therapy courses.

From these and other findings, the researchers suggested that the severe COVID-19 symptoms described in older individuals likely reflect a combination of delayed viral clearance, dysregulation in immune signaling pathways, and ongoing activation of pro-inflammatory processes.

"We found consistent evidence of prolonged, potentially pathologic inflammatory responses in the oldest adults from transcriptomics and protein analyses," Langelier said, adding that such findings "suggest that age-related changes may exacerbate inflammatory signaling in severe COVID-19, supporting hypotheses from earlier studies."

The authors noted that the study's participants were enrolled prior to the availability of SARS-CoV-2 vaccines during a time when the B.1.1.7 alpha variant of SARS-CoV-2 was starting to emerge. Consequently, they cautioned that "age-related differences in host immune responses may differ from a contemporary cohort due to variations in both vaccination status and the circulating SARS-CoV-2 variants."

Even so, the researchers explained, the results highlight the possibility of developing treatments that target the immune system dysregulation detected in older individuals with SARS-CoV-2 infections.

"These differences raise the possibility that older adults with severe COVID-19 may respond differently, and perhaps more favorably, to immunomodulatory therapies directed at certain inflammatory cytokines," Langelier said.