While acute infection with COVID-19 is associated with significant morbidity and mortality, the post-acute sequelae of COVID-19 (PASC or “Long COVID”) affect over 50 % of individuals who have recovered from acute infection, even months later (Zeng et al., 2023). PASC is characterized by persistent, recurrent, or novel symptoms of COVID-19 that continue 30 or more days post-infection, without a definitive upper time limit (Thaweethai et al., 2023). There are a broad range of PASC symptoms, including, but not limited to, malaise, fatigue, neurocognitive symptoms, dizziness, chronic cough, gastrointestinal symptoms, palpitations, chest pain, autonomic dysfunction and loss of or change in smell or taste (Thaweethai et al., 2023). Neuropsychiatric problems are among the most prevalent PASC symptoms. Fatigue, depression, anxiety, post-traumatic stress, cognitive complaints (“brain fog”) and neuropsychological impairment occur in 20–50 % across studies (Ferrando et al., 2022; Giussani et al., 2024; Lynch et al., 2024; Muschel et al., 2024; Zeng et al., 2023). Generally, neuropsychiatric symptoms improve over time (Giussani et al., 2024; Lynch et al., 2024); however, many individuals experience persistent symptoms such as fatigue and neurocognitive difficulty, as well as impairment in social/occupational function and quality of life beyond 12 months after acute infection (Shahar et al., 2023; Thompson et al., 2023).

There are multiple sociodemographic and clinical factors which may predict or increase risk for the development of PASC, including older age, female gender, severity of acute COVID-19 illness, and number of medical comorbidities (e.g. obesity, diabetes) (Ferrando et al., 2022; Giussani et al., 2024; Lynch et al., 2024; Zeng et al., 2023). Nonetheless, the underlying biological mechanisms of PASC remain speculative. One comprehensive review of PASC cite multiple, probably overlapping, potential causes of PASC, including: persistence of SARS-Co-V2 reservoirs; peripheral and central nervous system immune system dysregulation; autoimmunity; disruption of gut microbiota; clotting and endothelial abnormalities; dysfunctional neurological signaling; and activation of latent viruses (e.g., Herpes Simplex-6, Epstein-Barr) (Davis et al., 2023).

Among potential immunological causes or markers of PASC are inflammatory cytokines, which were recognized early on to be key components of the so-called “cytokine storm” immune activation reaction during acute COVID-19. These inflammatory mediators include Interleukin-6 (IL-6), C-reactive protein (CRP), Tumor Necrosis Factor-alpha (TNF-α), and a host of others, which have been found in meta-analyses to be elevated in the acute stages of COVID-19 and to correlate with disease severity (Akbari et al., 2020) and with PASC (Lai et al., 2023). Inflammatory cytokines have also been presumed to play a causal role in the pathophysiology of the disease, leading to the utilization of immune modulating therapies. For example, tocilizumab, an IL-6 receptor antagonist, was used treat hospitalized COVID-19, and led to a lower 28-day all-cause mortality (Coomes and Haghbayan, 2020; WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al., 2021) patients. IL-6, CRP and TNF-α have also been investigated extensively in neuropsychiatric illness, particularly depression, anxiety and cognitive impairment, with a hypothesized bi-directional relationship between a pro-inflammatory state and neuropsychiatric dysfunction (Messay et al., 2012). Thus, these cytokines may serve as biological markers of neuropsychiatric symptoms of PASC.

The current study explored the cross-sectional prevalence and clinical correlates of elevated IL-6, CRP and TNF-α in a cohort of individuals recruited from the community and from a post-COVID recovery program approximately 6 months (mean = 183 days, SD = 137 days, range = 30–598 days) after acute infection. Participants were systematically assessed for sociodemographic characteristics, medical, psychiatric, and neuropsychological symptoms of PASC. We hypothesized that elevations in one or more of these pro-inflammatory cytokines would be associated with neuropsychiatric PASC symptoms as well as treatment-seeking for PASC, supporting their use as clinical markers and potential treatment targets.