Salivary cortisol in long COVID: a marker of broader stress system and circadian rhythm dysregulation

Introduction: Long COVID (LC) has been associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, although findings from blood cortisol measurements remain inconsistent. We hypothesized that LC patients exhibit a disrupted diurnal cortisol rhythm and that salivary cortisol (SC) profiling may provide a more accurate assessment of HPA activity. Methods: This prospective, single-center, case-control study was conducted at a Long COVID clinic in Rome between February 2023 and March 2024 and included 96 participants evaluated at least 28 days after confirmed SARS-CoV-2 infection. LC was defined as one or more new or persistent symptoms and classified as severe when four or more of the following were present: fatigue, cognitive impairment, exercise intolerance, dyspnea, arthralgia, or dysautonomia. SC was measured at 8:00 AM, 3:00 PM, and 11:00 PM. Results: The cohort (mean age 58.1 ± 14.8 years; 60% female; all White) included 83 LC patients (80% moderate, 20% severe) and 13 asymptomatic post-COVID (APC) individuals. Compared with healthy controls, both LC and APC groups showed reduced morning SC (p