More common than we thought: Hypermobile Ehlers-Danlos Syndrome, comorbidity burden, and long COVID risk in a national cohort

Hypermobile Ehlers-Danlos Syndrome (hEDS) is a complex, underdiagnosed connective tissue disorder characterized by widespread symptoms affecting multiple organ systems. Recent clinical observations suggest that individuals with hEDS may be at increased risk for persistent symptoms following COVID-19, commonly referred to as Long COVID. Using data from over 19 million patients across the United States, we examined associations between hEDS, COVID-19 infection, Long COVID, and related chronic conditions. We identified just over 25,000 individuals with hEDS and estimated a prevalence of approximately 1 in 800, which is higher than previously recognized. Despite similar rates of COVID-19 infection between patients with hEDS and matched controls, patients with hEDS were nearly three times more likely to develop Long COVID. This risk was concentrated among patients with hEDS who also had overlapping conditions commonly seen in post-viral syndromes, including autonomic dysfunction (POTS), immune dysregulation (MCAS), and chronic fatigue (ME/CFS). Patients with hEDS also exhibited higher odds of having additional risk factors for severe or prolonged illness, including chronic lung and autoimmune conditions, depression, and cerebrovascular disease. A subgroup of patients received their hEDS diagnosis only after a COVID-19 or Long COVID diagnosis, and this subgroup was highly enriched for multimorbidity, particularly POTS and MCAS. These findings establish hEDS as more prevalent than previously recognized and identify a substantially elevated, comorbidity-driven risk of Long COVID in this population. Improved screening, earlier diagnosis, and integrated care pathways are urgently needed to support this complex and underserved patient group.