Patients with rheumatic disease are at least half as likely to develop long COVID after a SARS-CoV-2 infection if they have been fully vaccinated against COVID-19, according to research published November 28 in Annals of the Rheumatic Diseases.

Dr Zachary Wallace

“Moreover, those who were vaccinated prior to getting COVID-19 had less pain and fatigue after their infection,” Zachary S. Wallace, MD, MSc, an assistant professor of medicine at Harvard Medical School, Boston, Massachusetts, and a study author, told Medscape Medical News. “These findings reinforce the importance of vaccination in this population.”

Messaging around the value of COVID vaccination has been confusing for some with rheumatic disease “because our concern regarding a blunted response to vaccination has led many patients to think that they do not provide much benefit if they are on immunosuppression,” Wallace said. “In our cohort, which included many patients on immunosuppression of varying degrees, being vaccinated was quite beneficial.”

Leonard H. Calabrese, DO, director of the RJ Fasenmyer Center for Clinical Immunology and a professor of medicine at the Cleveland Clinic, told Medscape that the study is an “extremely important contribution to our understanding of COVID-19 and its pattern of recovery in patients with immune-mediated inflammatory diseases (IMIDs).” Remaining unanswered questions are “whether patients with IMIDs develop more frequent PASC [postacute sequelae of COVID-19] from COVID-19 and, if so, is it milder or more severe, and does it differ in its clinical phenotype?”

Long COVID Risk Assessed at 4 Weeks and 3 Months After Infection

The researchers prospectively tracked 280 adult patients in the Mass General Brigham healthcare system in the greater Boston, Massachusetts, area who had systemic autoimmune rheumatic diseases and had an acute COVID-19 infection between March 2020 and July 2022. Patients were an average 53 years old, and most were White (82%) and female (80%). More than half (59%) had inflammatory arthritis, a quarter (24%) had connective tissue disease, and most others had a vasculitis condition or multiple conditions.

A total of 11% of patients were unvaccinated, 28% were partially vaccinated with one mRNA COVID-19 vaccine dose, and 41% were fully vaccinated with two mRNA vaccine doses or one Johnson & Johnson dose. The 116 fully vaccinated patients were considered to have a breakthrough infection while the other 164 were considered to have a non-breakthrough infection. The breakthrough and non-breakthrough groups were similar in terms of age, sex, race, ethnicity, smoking status, and type of rheumatic disease. Comorbidities were also similar, except obesity, which was more common in the non-breakthrough infection group (25%) than the breakthrough infection group (10%).

The researchers queried patients on their COVID-19 symptoms, how long symptoms lasted, treatments they received, and hospitalization details. COVID-19 symptoms assessed included fever, sore throat, new cough, nasal congestion/rhinorrhea, dyspnea, chest pain, rash, myalgia, fatigue/malaise, headache, nausea/vomiting, diarrhea, anosmia, dysgeusia, and joint pain.

Patients completed surveys about symptoms at 4 weeks and 3 months after infection. Long COVID, or PASC, was defined as any persistent symptom at the times assessed.

Vaccinated Patients Fared Better Across Outcomes

At 4 weeks after infection, 41% of fully vaccinated patients had at least one persistent symptom, compared with 54% of unvaccinated or partially vaccinated patients (P = .04). At 3 months after infection, 21% of fully vaccinated patients had at least one persistent symptom, compared with 41% of unvaccinated or partially vaccinated patients (P < .0001).

Vaccinated patients were half as likely to have long COVID at 4 weeks after infection (adjusted odds ratio [aOR], 0.49) and 90% less likely to have long COVID 3 months after infection (aOR, 0.1), after adjustment for age, sex, race, comorbidities, and use of any of four immune-suppressing medications (anti-CD20 monoclonal antibodies, methotrexate, mycophenolate, or glucocorticoids).

Fully vaccinated patients with breakthrough infections had an average 21 additional days without symptoms during follow-up, compared with unvaccinated and partially vaccinated patients (P = .04).

Reduced risk of long COVID did not change for vaccinated patients after sensitivity analyses for those who did not receive nirmatrelvir/ritonavir (Paxlovid) or monoclonal antibodies, those who didn’t receive any COVID-19-related treatment, those who completed their questionnaires within 6 months after infection, and those who were not hospitalized.

“One important message is that among those who did get PASC, the severity appears similar among those with and without a breakthrough infection,” Wallace said. “This highlights the need for ongoing research to improve recognition, diagnosis, and treatment of PASC.”

Many more breakthrough infections (72%) than non-breakthrough infections (2%) occurred during Omicron. The authors acknowledged that different variants might play a role in different long COVID risks but said such potential confounding is unlikely to fully explain the results.

Dr Naomi Patel

“Even with data suggesting that the Omicron variants may be intrinsically less severe, vaccination still has an impact on severity of infection, rates of hospitalization, and other outcomes and thus may play a role in the risk of PASC,” lead author Naomi Patel, MD, an instructor at Harvard Medical School, Boston, Massachusetts, and a rheumatologist at Massachusetts General Hospital, told Medscape Medical News. “A study evaluating the proportions with PASC by vaccination status during the time in which a single variant is predominant, such as the early Omicron era, could help to better assess the more isolated impact of vaccination on PASC.”

Calabrese said he is convinced that Omicron infections are less likely to result in more severe forms of acute COVID than pre-Omicron infections, and he suspects Omicron infections are also less likely to result in long COVID, although less evidence currently supports this hypothesis.

Hospitalization was more common in unvaccinated/partly vaccinated patients than in vaccinated patients (27% vs 5%; P = .001). Although pain and fatigue were lower in those with breakthrough infections, functional scores and health-related quality of life were similar in both groups.

Some symptoms significantly differed between vaccinated and unvaccinated/partly vaccinated groups, possibly due partly to different variants. Nasal congestion was more common (73%) in those with breakthrough infections than in those with non-breakthrough infections (46%; P < .0001). Those who were unvaccinated/partly vaccinated were significantly more likely to have loss of smell (46% vs 22%) or taste (45% vs 28%) or to have joint pain (11% vs 4%).

Treatment with nirmatrelvir/ritonavir was also more common in vaccinated patients (12%) than in unvaccinated/partly vaccinated patients (1%; P < .0001), as was treatment with monoclonal antibodies (34% vs 8%; P < .0001).

Dr Jeffrey Sparks

The study was limited by its low diversity and being at a single healthcare system, the authors said. Study coauthor Jeffrey A. Sparks, MD, MMSc, an assistant professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, told Medscape that the group is planning additional studies as their cohort grows, including “investigating the relationships between COVID-19 and specific rheumatic diseases and immunomodulating medications, expansion of autoimmunity and systemic inflammation, and lung damage among specific patient populations.”

Calabrese said it will be important for follow-up study of the symptomatic patients to “determine how many of these patients will fit the clinical picture of long COVID or long-haul phenotypes over the months and years ahead, including documenting exertional malaise and quality of life.

This study only assessed patients who received zero, one, or two doses of a vaccine, but many patients with rheumatic disease today will likely have received booster doses. However, Calabrese said it would be difficult to quantify whether a third, fourth, or fifth dose offers additional protection from long-term COVID complications after full vaccination or hybrid vaccination.

The research was funded by the Rheumatology Research Foundation, the National Institutes of Health, the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care. Wallace has received research support from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Zenas BioPharma, Horizon, Sanofi, Shionogi, Viela Bio, and Medpace. Sparks has received research support from Bristol-Myers Squibb and consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. Patel has received consulting fees from FVC Health. Calabrese has consulted for Genentech, Sanofi-Regeneron, AstraZeneca, and GlaxoSmithKline.

Ann Rheum Dis. Published online November 28, 2022. Full text.

Tara Haelle is a health/science journalist based in Dallas, Texas. Follow her at @tarahaelle.

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