SALIVARY CORTISOL IN LONG COVID: A MARKER OF BROADER STRESS SYSTEM AND CIRCADIAN RHYTHM DYSREGULATION

Marta Camici^1*Marta Franco²Lorenzo Talamanca³Manuela Petino⁴Jessica Paulicelli⁵Liliana Scarnecchia²Lucia Ciavarella²Tiziana Orzilli²Francesca Balducelli²Valentina Mazzotta⁵Ilaria Mastrorosa⁵Eleonora Cimini⁵Eleonora Tartaglia⁵Stefania Notari⁵Fabrizio Maggi⁵Enrico Girardi⁵Roberto Baldelli²Paolo Zuppi⁶Andrea Antinori⁵

• ¹National Institute for Infectious Diseases Lazzaro Spallanzani (IRCCS), Rome, Italy
• ²Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
• ³ETH Zurich Foundation, Zürich, Switzerland
• ⁴Azienda Sanitaria Locale Roma 1, Rome, Italy
• ⁵Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome, Italy
• ⁶Associazione dei Cavalieri Italiani del Sovrano Ordine di Malta, Rome, Italy

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. 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. 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<0.01), flattened diurnal variation, and elevated evening SC, indicating loss of the normal morning peak and nocturnal decline. Blood cortisol levels did not differ among groups, but LC patients had higher ACTH than APC (26 pg/mL vs 13 pg/mL; p<0.01), suggesting compensatory HPA activation. One LC patient (1.2%) was diagnosed with adrenal insufficiency. These exploratory findings suggest a disrupted circadian cortisol rhythm in individuals after COVID-19, with altered HPA axis dynamics that may be associated with disease severity.