Effects of long COVID (LC) on innate immune responses and neuropsychiatric symptoms in children and young adults with autism spectrum disorders (ASD): Challenges in the diagnosis and management of LC in ASD patients.

Background Long-term sequelae of coronavirus disease-2019 (COVID-19) commonly referred to as long COVID (LC), cause marked and lasting changes on the immune system that result in variable clinical manifestations including neuropsychiatric symptoms. In the absence of reliable biomarkers for LC, timely diagnosis and management of LC are even more challenging in patients with pre-existing neuropsychiatric symptoms. This is the case for patients with autism spectrum disorders (ASD). In addition, patients with ASD often exhibit comorbidities associated with immune dysregulation, indicating that neuroinflammatory processes are common within this population. Methods In this study, we assessed behavioral changes in patients with ASD/LC (N = 50) through the use of validated questionnaires in comparison with changes in monocyte cytokine profiles. The controls included ASD/non-LC (N = 43), non-ASD/LC (N = 44), and normal control (N = 28) subjects. We evaluated monocyte cytokine profiles to assess how LC influences innate immunity, since we previously reported innate immune abnormalities in a portion of ASD subjects, and others have revealed the key role of monocytes in LC pathogenesis. Results We observed changes in symptoms of irritability, lethargy, and hyperactivity in both ASD/LC and non-ASD/LC patients. These ABC subscale scores were highly variable in the ASD/non-LC patients, which may be partly associated with pain and discomfort caused by underlying comorbid conditions. Compared with those in normal controls, monocyte cytokine profiles revealed increased production of inflammatory cytokines (TNF-α and IL-1ß) in both ASD/LC and non-ASD/LC patients, whereas highly variable results were detected in ASD/non-LC patients. However, our longitudinal studies in ASD/LC patients revealed increases in the production of TNFα and IL-1ß after LC, in addition to increased production of IL-12 and IL-23. Further analysis revealed that LC associated changes in monocyte cytokine profiles may be reflected in alterations in the serum levels of TGF-ß, IL-23, and kynurenine in LC patients. Conclusions Our results revealed that LC induced inflammatory skewed responses of monocytes, regardless of the ASD status. Our findings suggest that using immunomodulating agents targeting these abnormalities may improve behavioral symptoms in ASD/LC patients. If similar changes are found in ASD/non-LC subjects, they may also benefit from such measures.