Variant connective tissue as a risk factor for long COVID: a case-control study of data from a retrospective online survey of adults in the USA and UK

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.

Methods

We recruited 1816 participants (352 (19.4%) reporting long COVID, 1464 (80,6%) not reporting long COVID) from the US and UK for a retrospective online survey. The primary outcome was self-reported long COVID, defined as experiencing symptoms related to a COVID-19 infection at least 3 months after infection. Secondary outcomes included severity of symptoms during each COVID-19 infection, generalised joint hypermobility (GJH), and the novel concept of 'extreme hypermobility'.

Results

In separate binomial logistic regressions 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. This likely occurs 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, 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.

Conclusions

Both GJH and extreme hypermobility are significant risk factors for long COVID. People with extreme hypermobility, as newly defined in this study, 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, clarify the pathophysiology that explains why people with hypermobility may be at greater risk of long COVID and assess the clinical significance of ‘extreme hypermobility’.