A new study by researchers from University of Birmingham-UK has found that SARS-CoV-2 infections can also trigger a variety of immune-mediated inflammatory diseases (IMIDS) especially type 1 diabetes mellitus, inflammatory bowel disease (IBD) and psoriasis.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2022.10.06.22280775v1
This was after adjustment for several important confounding factors and during a relatively short period of follow up. We also found that this association was specific to an increased incidence of T1DM, inflammatory bowel disease, and psoriasis in the SARS CoV-2 infected cohort compared to the unexposed cohort.
Comparison with Existing Literature
The relatively high incidence of psoriasis in the SARS CoV-2 infected cohort is supported by other reports from the literature which found that increased cases of psoriasis, and flares of existing disease, have been reported following COVID-19.14 Evidence regarding the development of IBD following COVID-19 is scarcer, although ulcerative colitis has been reported to develop post infection.14
Female sex was also an important risk factor for incidence of IMIDs in our study. This is in line with previous evidence that female sex is a risk factor for most IMIDs and interestingly aligns with the consistent observation that women are at a higher risk of developing Long COVID than men.37-39
All age groups older than 30 years had a relatively lower incidence of IMIDs than the 18- to 29-year-old group, although this was only statistically significant in the 40- to 49-year-old and 50- to 59-year-old groups.
The relationship between decreasing age and an increased risk of Long COVID has been found in another study, however, some studies do find an association between increasing age and Long COVID.39-41 This relationship may be due to the earlier age of diagnosis of T1DM, IBD and psoriasis, which made up the majority of outcome events in this study.42-44
Both smoking status and BMI were not significantly associated with the incidence of IMIDs, which conflicts with their presence as a known risk factor for both IMIDs in general and for Long COVID.28,37,40 However, the risk for developing IMIDs was significantly higher for overweight and obese patients with an increase of 4% and 18% respectively, compared to those with normal weight.
A significant increase in risk was also found for current and ex-smokers with a 21% and 18% respective increase when compared to never smokers. The lack of statistically significant associations may have been due to an insufficient sample size or the short follow up period to adequately assess these risk factors.
Strengths and Limitations
Data from over two million patients were included, which provided sufficient statistical power to assess for differences in the incidence of IMIDs between the exposed and unexposed cohorts over a relatively short follow-up period. This also allowed us to assess the relative incidence of eleven of the more common IMIDs across the two comparison groups. We included IMIDs in our outcome such as T1DM, that are likely to be well recorded in primary care records.
The use of primary care data meant that we were able to adjust for important demographic and clinical risk factors that are known to be associated with the incidence of IMIDs. Use of data from practices across a national database also improved the generalisability of our findings. The use of primary care data also meant that numerous demographic factors, such as age, sex and ethnicity, were recorded. This facilitated covariate adjustment and risk factor analysis.
The study had several limitations. We had missing data for ethnicity (21% missing), BMI (17%), and smoking status (7%), which we accounted for in our analyses using a missing category variable. We did not have access to data on socioeconomic status but partially accounted for this by matching patients in the unexposed and exposed cohorts on general practice, which would result in patients from both groups sharing their residential geography and social demography.
There is likely to be a degree of misclassification bias between the exposed and unexposed cohorts. There was little community testing for SARS CoV-2 infection in the first wave of the pandemic, which leaves open the possibility that some members of the unexposed cohort may have been infected but not diagnosed.
It is also likely that only a portion of the true number of diagnoses of IMIDs were detected during the study period with perhaps only the more severe cases being diagnosed. This is due to the relative inaccessibility of health services during the pandemic and the short period of follow-up in our study.
The study period encompassed three national lockdowns where healthcare appointments were reduced leading to a backlog of up to 300,000 patients waiting over a year for treatment.45,46 The short follow up period may have diluted the effect size and power of the study as IMIDs typically can take a prolonged period of time to be diagnosed after the beginning of immune dysregulation and thus the full scope of the potential impact of SARS CoV-2 infection is likely to have been underrepresented.47
However, there is also the possibility that patients experiencing COVID-19 may have accessed healthcare services more than those with no prior infection, and thus had more opportunities to be diagnosed with IMIDs.
Implications for Practice, Policy, and Research
Our findings provide epidemiological evidence that SARS CoV-2 infection is associated with an increased risk of a range of IMIDs, including T1DM, IBD, and psoriasis. This provides evidence that autoimmunity may be a potential mechanism that accounts for some of the longer-term symptoms and health impacts of a subgroup of those with Long COVID.
This is particularly of interest given the finding that women may be at increased risk of both IMIDs as well as Long COVID, that symptoms of Long COVID are diverse and often overlap with those of IMIDs, and that the symptoms of both IMIDs and Long COVID characteristically follow a relapsing remitting pattern over time.41
However, there is currently a scarcity of studies assessing the relationship between SARS CoV-2 infection and the incidence of IMIDs. Further epidemiological studies with a longer follow-up period are needed to confirm our findings, and to test for relevant autoantibodies in the serum of participants to correlate with symptoms and clinical findings.
These studies could also include other rarer IMIDs potentially associated with COVID-19 such as Guillain-Barre syndrome.15
Evidence suggests that those who have been vaccinated against COVID-19 are approximately half as likely to develop symptoms lasting over 28 days than unvaccinated individuals.48
It would be valuable to know if these differences in Long COVID incidence rates are also associated with differences in the incidence of IMIDs.
SARS CoV-2 infection was associated with an increased incidence of several IMIDs, including type 1 diabetes mellitus, inflammatory bowel disease, and psoriasis.
This finding lends support to the hypothesis that the long-term effects of COVID-19 or Long COVID may in part be related to increased autoimmunity. Further research is needed to replicate these findings in other populations and to sample autoantibody profiles in people with Long COVID as well as matched controls.