Variant connective tissue as a risk factor for Long COVID: a case-control study
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Objectives
This study explored the extent to which two measures of joint hypermobility, a marker of variant connective tissue, predict the development of Long COVID after COVID-19 infection, and whether the severity of initial COVID-19 symptoms impacts this relationship.
Design
Retrospective online survey. The survey was co-designed with Long COVID patients and carers.
Setting
Respondents were recruited from representative online panels in the U.S. and U.K. maintained by the data firm Dynata in early 2024.
Participants
After data cleaning, the final dataset comprised 1,816 respondents, 352 (19.4%) who reported Long COVID and 1,464 (80.6%) who did not.
Primary and secondary outcome measures
The primary outcome was self-reported Long COVID, defined as experiencing symptoms related to a COVID-19 infection at least three months after the infection began. Participants were also asked to indicate whether they experienced no, mild or severe initial symptoms during each COVID-19 infection and to respond to nine questions that assessed different aspects of hypermobility: the Hakim and Grahame 5-part questionnaire (5PQ) and four additional co-produced questions. The 5PQ was used to identify individuals with generalized joint hypermobility (GJH). All nine questions were used to develop a measure of extreme hypermobility, based on the top 10 th percentile of hypermobility among respondents in each of six groups sorted by age and gender.
Results
In separate binomial logistic regressions of the dataset controlling for sex assigned at birth, age, number of infections, and number of vaccine doses, both GJH (OR 1.29, 95% CI 1.00 to 1.65) and extreme hypermobility (OR 2.12, 95% CI 1.43 to 3.16) were found to be predictive of Long COVID. Hypermobility influences the odds of getting Long COVID through two pathways. First, both GJH and extreme hypermobility increase the risk that individuals with no or moderate initial symptoms from a COVID-19 infection experience Long COVID. Second, both GJH and extreme hypermobility are significant predictors of developing severe initial symptoms from (a) COVID-19 infection(s), which is independently associated with increased Long COVID risk. A mediation analysis confirmed that extreme hypermobility influences the odds of developing Long COVID in part by increasing the likelihood that individuals experience severe initial symptoms from (a) COVID infection(s).
Conclusions
Both GJH and extreme hypermobility are significant risk factors for Long COVID. People with extreme hypermobility are at particularly high risk of developing Long COVID after an initial COVID-19 infection. Further research is needed to replicate these findings with other datasets and clarify the pathophysiology that explains why people with hypermobility may be at greater risk of Long COVID.
