Low IL-18: a hidden culprit of long COVID in patients with autoimmune disease

Emerging research from the RheumCARD study highlighted low concentrations of IL-18 as a significant risk factor for long COVID in patients with systemic autoimmune rheumatic diseases (SARDs). This points to a potential mechanism involving a blunted immune response in these patients, shifting the focus from hyperinflammation to immune dysregulation as a cause of long COVID.

Following the pandemic, long COVID or post-acute COVID-19 sequelae have emerged with substantial morbidity. The National Academy of Sciences, Engineering, and Medicine (NASEM) has recently defined long COVID as “an infection-associated chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems” [1].

The cause of long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is most likely multifactorial but may in part be driven by immune dysregulation. Therefore, patients with SARDs are probably at risk for long COVID due to underlying altered immunity. The RheumCARD study was a prospective study of individuals with prevalent SARDs with and without a history of COVID-19. The current analysis by Dr Jeffrey Sparks (Brigham and Women's Hospital, MA, USA) and colleagues aimed to explore whether the presence of circulating inflammatory cytokines after COVID-19 is associated with the occurrence of long COVID in patients with SARDs [2].

The authors measured 48 different circulating cytokines with a panel test (i.e. Olink Target 48 cytokine panel). Participants on DMARDs targeting specific cytokines were excluded. Included were 201 participants with SARD and a history of COVID-19, and 47 participants with SARD but no history of COVID-19. The cohort primarily consisted of women (81%), with a mean age of 56 years. The most common SARDs were inflammatory arthritis (60%) and connective tissue diseases (22%). 39% (79) of the participants with COVID-19 suffered from long COVID (defined in the study as symptoms persisting for ≥28 days) and were analysed for the primary outcome.

Lower IL-18 levels were significantly associated with a diagnosis of long COVID (199 pg/mL vs 221 pg/mL for those without; P=0.001) and a multivariable analysis confirmed this association. Additionally, lower levels of Colony Stimulating Factor (CSF) 2 and the chemokine CCL7, and higher levels of IL-2 were associated with long COVID. The robustness of these findings was confirmed across various subgroups, including those defined by disease activity and SARS-CoV-2 variants.

Thus, lower IL-18 levels were consistently seen in patients with long COVID and SARDs. This finding was robust across analyses and not explained by vaccination or viral variants. IL-18 induces cell-mediated immunity following infection, implicating a blunted immune response as a potential underlying mechanism for long COVID in patients with SARDs. These findings will need replication in the non-SARD population.

1. NASEM 2024. Washington, DC: The National Academies Press. DOI: 10.17226/27768.
2. Sparks JA, et al. Associations of circulating inflammatory cytokines with long COVID among patients with systemic autoimmune rheumatic diseases. POS0081, EULAR 2024 Congress, 12–15 June, Vienna, Austria.

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Posted on 29 July 2024