Understanding Comorbidities in Hypermobile Ehlers-Danlos Syndrome: Could a Viral Infection Lead to a Diagnosis?

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 23 million patients across the United States, we examined associations between hEDS, COVID-19 infection, Long COVID, and related chronic conditions. We identified nearly 30,000 individuals with hEDS and found that the estimated prevalence was approximately 1 in 800, higher than previously recognized. While rates of COVID-19 infection were similar between patients with hEDS and matched controls, those with hEDS were significantly more likely to develop Long COVID. This risk was especially elevated among patients with hEDS with overlapping conditions commonly seen in post-viral syndromes, including autonomic dysfunction, immune dysregulation, and chronic fatigue. Specifically, individuals with postural orthostatic tachycardia, mast cell-related symptoms, or chronic fatigue syndrome had the highest rates of Long COVID. Cumulative incidence analysis revealed that many patients received an hEDS diagnosis only after a COVID-19 infection, suggesting that viral illness may exacerbate or reveal previously unrecognized symptoms. 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. These findings highlight a previously unrecognized vulnerability in patients with hEDS and underscore the need for greater clinical awareness of their heightened risk for persistent post-COVID illness. Improved screening, earlier diagnosis, and integrated care pathways are urgently needed to support this complex and underserved patient population.