Risk Factors for Repeat COVID-19 Among Patients With Rheumatic Diseases

Dr Jeffrey Sparks and research assistant Emily Kowalski share their findings from a study of the risk factors found among patient with systemic rheumatic diseases for repeat infections with COVID-19.

Jeffrey Sparks, MD, MMSc, is an associate professor of medicine at Harvard Medical School and rheumatologist at Brigham & Women's Hospital in Boston, Massachusetts. Emily Kowalski is a research assistant in the Division of Rheumatology, Inflammation, and Immunity at Brigham and Women's Hospital.

Any views and opinions expressed are those of the authors and or participants, and do not necessarily reflect the views policy or position of the Rheumatology and Arthritis Learning Network or HMP Global its employees and affiliates.

Welcome to this podcast from the Rheumatology and Arthritis Learning Network. I'm your host, Rebecca Mashaw, and today we're talking with Dr. Jeffrey Sparks, who's an associate professor of medicine at Brigham and Women's Hospital and Harvard Medical School in Boston, and Emily Kowalski, who is a research assistant at Brigham and Women's. They're going to be talking about a recent study they did on the risk factors and outcomes of repeat COVID-19 infections among patients with systemic autoimmune rheumatic diseases. I'm going to turn this over to the experts now and have Dr. Sparks take the lead.

Jeffrey Sparks:

Great. Thanks so much, Rebecca, for having us. We're very happy to highlight this study. As some of you may know, we have a research program related to COVID-19 outcomes among patients with systemic autoimmune rheumatic disease or ARDs. This has been a great collaboration with our colleagues at Mass General Hospital led by Dr. Zachary Wallace, and we're glad to highlight this recent paper about repeat COVID-19. That was co-led by Dr. Wallace and I and led by Emily Kowalski, one of the research assistants at our group. So Emily, maybe you could give us some background about what led us to investigate this particular topic.

Emily Kowalski:

Sure. We have been systemically identifying COVID-19 infections in patients with SARDS through physician referrals and positive COVID-19 tests within the hospital system. Since the start of the pandemic, we began noticing that the same patients were coming up on our lists time and time again. At first, we had hoped that early breakthrough cases following vaccination would be rare, but once we realized that many individuals were being infected following vaccination or even after infection, we decided to take a closer look at what, if anything, may be making these patients more susceptible to repeat. COVID-19 infection studies had been done in the general population and we decided that patients with SARDS needed their own investigation due to the immunosuppressive nature of many of their meds.

Jeffrey Sparks:

Yeah, I'll mention that this has been a nice program because we identify cases in real time and we're able to kind of notice trends as they're happening, and I think we started noticing repeat COVID-19 infections right around the omicron variant happened and we decided that there were enough cases to move forward probably shortly thereafter, and also gives you a feel for how long papers can take to actually get published. So a lot of this happened early in the Omicron wave, even though it was published pretty recently. So at the time, repeat COVID infections were just becoming a thing and now they are more the norm as opposed to a rare thing. So Emily, could you tell us more about the study design? How did we design this study?

Emily Kowalski:

Yeah, definitely. We conducted a case control study in the Mass General Brigham Healthcare system. All of the patients had a systemic rheumatic autoimmune disease and had at least one COVID-19 infection. We verified this by chart review because of these criteria. We did not include people with only osteoarthritis. Fibromyalgia, gout, or pseudogout cases had 2 COVID-19 infections separated by 60 days or more to ensure that these were 2 separate infections. Controls had exactly 1 COVID-19 infection by the end of the study period. The study period was from March 2020 through October 17, 2022. The final study population included 76 cases and 207 controls matched up to 1-to-3 on data first infection and duration between the date of first infection and date of second infection for index date to control for treatment and vaccine availability.

Jeffrey Sparks:

Yeah. I also mentioned that we debated other designs like a cohort study. One thing we realized is that calendar time is very important in COVID studies. So obviously things are very different between April 2020 and now. So what was available related to vaccines treatment, the virulence of the virus, people's immune status related to COVID? So we did decide that those were such important factors that we wanted to do a match case control study so that the cases and controls were really infected right at the very similar calendar time period. We also really wanted to make sure that the cases truly had a repeat covid infection and that the controls did not have a COVID infection. So we verified both of these by chart review. Emily, can you take us through some of the main findings?

Emily Kowalski:

Sure. Some of the main findings were that the most common SARDS in both groups were rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Most repeat infections took place after December 17th, 2021, which is when the omicron variant was the most prominent variant circulating in Boston. In the multivariable model, we found that risk factors for repeat COVID-19 infections included younger age with an odds ratio of 0.67 per 10 years; rituximab use with an odds ratio of 3.38; and methotrexate use with an odds ratio of 2.24. At first infection cases were younger than controls, less likely to have hypertension, and less likely to have been hospitalized.

Jeffrey Sparks:

Okay. Can you maybe tell us more about why you think the findings that we found, the younger age medications, rituximab, and methotrexate, why do you think these might've been associated with higher risk of repeat infection?

Emily Kowalski:

Yeah, definitely. We believe that the risk factor of young age can largely be attributed to the difficult-to-measure behavioral differences between the 2 groups. Younger patients may be more likely to work in person or participate in behaviors or activities that may put them in riskier settings, such as within large groups. As for the medications, our findings go to show just how immunosuppressive rituximab is. Even with similar rates of vaccinations between the groups, both rituximab and methotrexate are known to blunt vaccine response. It's also possible that they may blunt immunity to natural infection.

Jeffrey Sparks:

Yeah, and actually the age finding was particularly striking. Actually, I think people younger than 45 had over 7-fold increased odds compared to those who are 65 or older. And I think that is still holding up now that we are seeing some younger people who get really multiple infections, and this is something that was, I think, talked about a lot as repeat infections were first coming on. But another reason we did this study was to understand the severity of the repeat infection. So we found that 7% of those with repeat infections were hospitalized and there were no deaths. Can you tell us any more about the severity of the repeat infections?

Emily Kowalski:

Sure. We found that there were no deaths, which was really promising in the second round of hospitalizations. Patients who were hospitalized all had hybrid immunity by their second infection, meaning that they had immunity from both a natural initial infection and from at least 2 vaccines at the time of their second infection, that we did not have antibody results that would demonstrate whether any of these antibodies were circulating from vaccine or previous infection.

Jeffrey Sparks:

Yeah, we thought it was very reassuring that there were very few severe outcomes in that group. That's something we had worried about and we thought that might be something very specific to this population. So the fact that very few hospitalizations and that no deaths, I think is a really important take home. So we already mentioned that the study itself was done kind of early in the omicron era. We're now in February 2024. It's been about 4 years since the COVID pandemic started. Do you think that COVID is still a major concern and how did these findings impact patient's willingness to get vaccinated?

Emily Kowalski:

Sure. So it seems that rates have fallen off a little bit. Patients have not kept up with the same diligence of booster recommendations as they may have earlier in the pandemic. We believe that it's important to continue to be cautious and test, especially when we have effective treatments that can help minimize the symptoms of COVID-19. I would say that the concern is still there, but not as severe as it was when we did not have an effective way to treat the infection. However, it's difficult to predict how severely any patient may be affected as there are still many factors and variants that are frequently shifting.

Jeffrey Sparks:

Yeah, I would agree. Certainly the rituximab-treated patients remain a population that seemed to be at risk. Luckily, there's not as many severe outcomes overall even within rituximab-treated groups, but you found here a novel association of rituximab with repeat infection risk. Some of our other papers, we found that rituximab is associated with prolonged viral shedding and also increased risk for long COVID. So the jury's still out exactly what to do with these patients, but they still remain a patient population that has poor outcomes even if the severe outcomes are luckily less common. So maybe you can tell us about what our current and future plans are. Do we continue to track how these patients are doing and are we still finding covid infections?

Emily Kowalski:

Yes, we certainly are still finding COVID-19 infections. We still have patients who are being infected for the first time. As of now, we have about 3000 patients in our database, and we never know how the circumstances of the pandemic may change. So it's important that we keep collecting this data to help continue to inform patients, clinicians, and public officials. We've added a new method of identifying new cases, which includes reviewing prescriptions for Paxlovid prescribed by rheumatologists, which has been a fruitful method of identifying acute cases.

Jeffrey Sparks:

Yeah, I'll say that again. I think this has been a very successful project related to, even though it's a retrospective study, the data are collected in almost near real time. So we're trying to write papers that are really relevant to what patients and providers are experiencing now. And we've also shifted to prospective studies. We actually have 3 prospective studies ongoing, and one of them called HOMERheum, which is a collaboration with the positives team. Actually, we enroll rheumatic patients who are acutely infected within 5 days, and that's already generated some very important data related to how immune status affects viral shedding and evolution, as well as Paxlovid rebound risks. And we have a lot more plans in that database. We also have another study called RheumCARD that enrolls patients in the convalescent phase and we obtain surveys. So we've done some proteomic studies. We're planning on antibody profiling now.

And lastly, we have a study related to lung health in rheumatoid arthritis—patients who, as you know, are prone to having fibrotic lung disease, and we're wondering if COVID could be a trigger for fibrotic lung disease. So in that study, we're bringing patients back for chest CT scans, pulmonary function tests, and other measures of lung health. So there will be more COVID studies from our group ongoing, and we're also thinking to expand about, to look at outcomes of other viruses. This is certainly a problem that we will affect our patients as long as we're using immune suppressants. So thanks again for your attention. Any parting thoughts?

Emily Kowalski:

Thanks for having me on. This is a lot of fun, and thanks for highlighting our study.

Jeffrey Sparks:

Thanks.

Rebecca Mashaw:

Thank you both for joining us today to talk about this. This is very interesting and your plans for future studies are also very interesting, so we will no doubt be hearing from you again. I hope you'll come back and talk to us about what you find.

Again, you've been listening to this podcast with Dr. Jeffrey Sparks from Brigham and Women's Hospital in Boston, and researcher Emily Kowalski, looking at the impact of COVID-19 repeat infections and the risk of infections in patients with systemic autoimmune rheumatic diseases. Thanks very much for listening.

REFERENCE:

Kowalski EN, Wang X, Patel NJ, et al. Risk factors and outcomes for repeat COVID-19 infection among patients with systemic autoimmune rheumatic diseases: a case-control study. Semin Arthritis Rheum. 2023;63:152286