Clinical features and inflammatory signatures of patients with persistent gastrointestinal long COVID two years after severe SARS-CoV-2 infection

Persistent gastrointestinal (GI) symptoms are increasingly recognized as part of long COVID, yet their underlying mechanisms remain poorly defined. We conducted an exploratory case-series study of 80 adults hospitalized with severe COVID-19 in March-May 2020 in Manaus, Brazil. Two years post-infection, participants underwent structured clinical interviews and longitudinal cytokine analysis (IL-1β, IL-6, IL-8, IL-10, IL-12, and TNF-α). Overall, 30 participants reported ongoing GI symptoms (GI group) predominantly gastroesophageal reflux (63%), abdominal pain (43%), and diarrhea (37%). Compared with participants without GI symptoms (nGI group, n = 50), the GI group reported a higher burden of additional long COVID symptoms, including palpitations, headache, and arthralgia. They also exhibited distinct clinical and laboratory features, including lower baseline creatinine and ferritin levels and altered platelet indices. Although IL-6 levels were lower during the acute hospitalization phase, they became significantly elevated at four months post-infection (D120, p = 0.005), suggesting delayed inflammatory response. Ascendent biomarker analysis identified TNF-α as highly expressed in a large proportion of GI group. The findings suggest GI problems can persist two years after severe COVID-19, and long-term inflammatory dysregulation may underlie the pathogenesis of these GI manifestations in long COVID. Prolonged gastrointestinal surveillance in COVID-19 survivors is necessary.