Long COVID includes a wide range of symptoms that present or persist three or more months after SARS-CoV-2 infection. Although in recent years researchers have gained greater insight into the prevalence, symptoms and effects of long COVID through the longitudinal Researching COVID to Enhance Recovery (RECOVER) Initiative, social risk factors for developing long COVID remain incompletely understood. In a new analysis of the RECOVER-Adult cohort, Mass General Brigham researchers found a two- to three-times higher risk of long COVID in those with social risk factors, including financial hardship, food insecurity, experiences of medical discrimination, and skipped medical care due to cost. Findings are published in Annals of Internal Medicine.

"During the pandemic, we saw the overwhelming role that social risk factors played in determining who was infected with COVID-19 and what the severity and mortality from disease was," said lead author Candace Feldman, MD, MPH, ScD, of the Division of Rheumatology, Inflammation and Immunity at Brigham and Women's Hospital (BWH), a founding member of the Mass General Brigham healthcare system. "We wanted to understand whether those risk factors also play a significant role in the longer-term, chronic symptoms that can affect people months and even years after SARS-CoV-2 infection."

In this study, the researchers analyzed 3,700 participants from the RECOVER-Adult cohort, who had a SARS-CoV-2 infection during the Omicron variant outbreak, completed a baseline survey about social and economic factors at the time of infection, and completed a six-month follow-up survey assessing long COVID symptoms. The RECOVER-Adult participants were from 33 states, Washington, D.C., and Puerto Rico, and joined the study between October 2021 and November 2023.

In the baseline survey, the researchers assessed four major individual-level social risk factors: economic instability, education and language access barriers, health care access and quality challenges, and lack of social and community support using a series of questions and previously validated surveys. They also used ZIP code data to study area-level measures of risk, like household crowding.

After adjusting for variables including hospitalization for SARS-CoV-2 infection (as a marker of disease severity), vaccination history, pregnancy status, age, sex, race and ethnicity, the researchers found significant associations between nearly all the individual-level social risk factors studied and increased risk of developing long COVID. Furthermore, a greater number of social risk factors conferred a higher risk of long COVID. Living in areas with more household crowding was also associated with a greater risk of long COVID.

There was a significantly higher burden of social risk factors among racially or ethnically minoritized groups. However, the researchers found that social risk factors appeared to affect white, Black and Hispanic people's risks of long COVID similarly.

Going forward, RECOVER Initiative researchers hope to determine whether these findings extend to children with long COVID and whether certain long COVID symptoms may be linked to specific social risk factors. They also hope to study symptoms of COVID-19 lasting a year or longer to better understand how social factors might contribute to these symptoms' persistence.

"While rates of COVID-19 have decreased, long COVID is a chronic disease that many people still suffer from," said senior author Elizabeth Karlson, MD, MS, of the Division of Rheumatology, Inflammation and Immunity at BWH. "As with other chronic diseases, many different parts of people's social environment influence long COVID risk. Future interventions must address these factors to effectively reduce adverse outcomes among people with high burden of social risk factors."

Authorship: In addition to Feldman and Karlson, Mass General Brigham authors include Leah Santacroce, Ingrid V. Bassett, Tanayott Thaweethai, Yuri Quintana, Bruce D. Levy, and Cheryl R. Clark.

Additional authors include Radica Alicic, Rachel Atchley-Challenner, Alicia Chung, Mark P. Goldberg, Carol R. Horowitz, Karen B. Jacobson, J. Daniel Kelly, Stacey Knight, Karen Lutrick, Praveen Mudumbi, Sairam Parthasarathy, Heather Prendergast, Nasser Sharareh, Judd Shellito, Zaki A. Sherif, Brittany D. Taylor, Emily Taylor, Joel Tsevat, Zanthia Wiley, Natasha J. Williams, Lynn Yee, Lisa Aponte-Soto, Jhony Baissary, Jasmine Berry, Alexander W. Charney, Maged M. Costantine, Alexandria M. Duven, Nathaniel Erdmann, Kacey C. Ernst, Elen M. Feuerriegel, Valerie J. Flaherman, Minjoung Go, Kellie Hawkins, Vanessa Jacoby, Janice John, Sara Kelly, Elijah Kindred, Adeyinka Laiyemo, Emily B. Levitan, Jennifer K. Logue, Jai G. Marathe, Jeffrey N. Martin, Grace A. McComsey, Torri D. Metz, Tony Minor, Aoyjai P. Montgomery, Janet M. Mullington, Igho Ofotukun, Megumi J. Okumura, Michael J. Peluso, Kristen Pogreba-Brown, Hengameh Raissy, Johana M. Rosas, Upinder Singh, Timothy VanWagoner.

Disclosures: Feldman receives grant support to her institution for health equity research and consults for several organizations on unrelated content. Knight receives research funding from Janssen. Alicic, Parthasarathy, Aponte-Soto, Singh, Levitan, and Mullington receive NIH or other research funding or consulting support unrelated to this manuscript.

Funding: This study was funded in part by the National Institutes of Health (OTA OT2HL161841, OTA OT2HL161847, and OTA OT2HL156812).

It causes the immune system's first-line viral defenses -- known as interferons -- to attack the body. Nearly every organ is at risk, leading to conditions like kidney and heart disease.

But unlike many other autoimmune or chronic illnesses, lupus can improve as patients reach their 60s and 70s.

"I see my younger lupus patients in their 20s, 30s, and 40s every few months, monitoring them closely for signs of severe disease, but many of my older patients just once a year to touch base," said Sarah Patterson, MD, assistant professor of medicine in the division of rheumatology at UCSF. "If patients make it through those risky decades, they sometimes see a dramatic improvement."

Now, Patterson and colleagues have published a study in Science Translational Medicine that reveals how this works.

By analyzing blood samples from patients across the age spectrum, the team discovered that aging turns down the activity of certain immune genes in people with lupus, leading to fewer interferons and other inflammatory proteins in the body.

The study found that in healthy adults, inflammation-related genes and proteins rose slowly over the years, a process that has been dubbed "inflammaging." In patients with lupus, however, the expression of these genes and proteins were abnormally high in mid-life but decreased as the decades went by.

"Inflammaging seemed to be reversed in the lupus patients," said Chaz Langelier, MD, PhD, associate professor of medicine at UCSF and senior author of the paper. "But it wasn't fully reversed. The lupus patients still had a greater level of inflammatory signaling compared to healthy adults in older age."

That reversal reflected what Patterson has seen in her patients -- a return to something approaching healthy older age.

Next, the team intends to test whether drugs that block interferons are more or less effective in lupus patients at different ages. They also hope to extend the approach to understand other inflammation-related conditions, such as rheumatoid arthritis, COPD, and atherosclerosis.

Authors: Other UCSF authors are Rithwik Narendra, Hoang Van Phan, Ana Almonte-Loya, Emily C. Lydon, MD, Christina Love, Michiko Shimoda, PhD, Padmini Deosthale, MS, Lenka Maliskova, Walter Eckalbar, PhD, Gabriela K. Fragiadakis, PhD, Jinoos Yazdany, MD, MPH, Maria Dall'Era, MD, Patricia Katz, PhD, Chun Jimmie Ye, PhD, and Marina Sirota, PhD. For a complete author list see the paper.

Funding: This work was funded by the National Institutes of Health (R01 AR069616, K23AT011768, P30 AI027763), the US Centers for Disease Control and Prevention (CDC), and the Chan Zuckerberg Biohub.