Medical Condition

Long COVID underscores the lasting impact infections can have on brain health and systemic function. Progress will require a cross-disciplinary approach—integrating infectious disease, neurology, psychiatry, and immunology—with investment in biomarker development, precision medicine, and long-term translational research. With millions affected globally, it presents a major challenge to public health, clinical practice, and disability systems.

Long COVID, also known as Post-Acute Sequelae of SARS-CoV-2 infection (PASC), encompasses a heterogeneous group of symptoms that persist or emerge after the acute phase of COVID-19. It is typically defined by symptoms lasting beyond four weeks from the onset of infection and often persisting for several months (Nalbandian et al., 2021). Patients may present with a range of issues, most commonly fatigue, shortness of breath (dyspnea), chest pain, palpitations, sleep disturbances, cognitive impairment (often described as “brain fog”), and other neuropsychiatric symptoms. The clinical presentation is highly variable, and symptoms frequently fluctuate or relapse over time, often worsening with exertion or stress.

Prevalence estimates for Long COVID vary depending on the definition used and the population studied. Early self-reported studies suggested that 10–30% of infected individuals experienced lingering symptoms. However, more recent, controlled analyses indicate that functionally limiting symptoms persisting beyond 12 weeks occur in approximately 1–5% of all infected individuals, with higher rates observed among those hospitalized during acute infection (Lammi et al., 2025; Sudre et al., 2021).

Identified risk factors include female sex, middle age, pre-existing autoimmune conditions, and severity of the initial infection. Recent genomic studies also suggest roles for specific HLA haplotypes and interferon response pathways, though no single genetic marker has been definitively associated with Long COVID risk (Lammi et al., 2025; Proal & VanElzakker, 2021).

Neuropsychiatric symptoms are among the most common and debilitating features of Long COVID. These include cognitive dysfunction (“brain fog”), depression, anxiety, PTSD-like symptoms, irritability, and sleep disturbances. Symptoms may fluctuate over time and often significantly impair daily functioning and quality of life. While uncommon, a small number of case reports have described new-onset or worsening obsessive-compulsive symptoms following SARS-CoV-2 infection.

***internal note. For Long COVID, Pathogenesis and Mechanisms are combined****

The pathogenesis of Long COVID remains unclear. Proposed mechanisms include persistent viral antigens, immune dysregulation, sustained elevation of pro-inflammatory cytokines (e.g., IL-6, TNF-α), and autoantibody production against host targets. Some patients also show evidence of latent virus reactivation, particularly herpesviruses such as Epstein–Barr virus. Mitochondrial impairment has been reported and may contribute to symptoms such as fatigue, cognitive dysfunction, and post-exertional symptom exacerbation. Functional imaging studies in some patients have demonstrated hypometabolism in brain regions involved in attention, memory, and mood regulation.

There are currently no disease-specific or universally established treatments for Long COVID. Management is largely symptom-based, often involving rehabilitation, cognitive support, autonomic regulation, and mental health care. For patients with post-exertional symptom exacerbation, treatment typically includes pacing and activity management.

A range of anti-inflammatory and immunomodulatory therapies are under investigation (most notably in trials such as NIH’s RECOVER-VITAL), including antihistamines, corticosteroids, antivirals, and therapies targeting autoantibodies. Clinical trials are ongoing (e.g., NCT05595369, NCT05305780), but as yet no intervention has demonstrated definitive efficacy.

Long COVID is a complex, multisystem condition with a substantial neuroinflammatory and immunologic component. Its variable presentation and unclear pathogenesis pose ongoing diagnostic and therapeutic challenges. Mounting evidence points to immune dysregulation, viral persistence, and autonomic dysfunction as central contributors to symptoms such as fatigue, cognitive impairment, and post-exertional symptom exacerbation. Understanding these mechanisms is essential for developing targeted, evidence-based interventions.

Lammi, V., Delahaye, F., Porcu, E., et al. (2025). Genome-wide association study of long COVID identifies multiple genetic risk loci. Nature Genetics. https://doi.org/10.1038/s41588-025-02100-w

Patterson, B. K., Francisco, E. B., Yogendra, R., et al. (2022). Immune-based prediction of COVID-19 severity and chronicity decoded using machine learning. Frontiers in Immunology, 13, 843384. https://doi.org/10.3389/fimmu.2022.843384

Proal, A. D., & VanElzakker, M. B. (2021). Long COVID or post-acute sequelae of COVID-19 (PASC): An overview of biological factors that may contribute to persistent symptoms. Frontiers in Microbiology, 12, 698169. https://doi.org/10.3389/fmicb.2021.698169

Taquet, M., Geddes, J. R., Husain, M., Luciano, S., & Harrison, P. J. (2021). 6-month neurological and psychiatric outcomes in 236,379 survivors of COVID-19: A retrospective cohort study. The Lancet Psychiatry, 8(5), 416–427. https://doi.org/10.1016/S2215-0366(21)00084-5

Sudre, C. H., Murray, B., Varsavsky, T., et al. (2021). Attributes and predictors of long-COVID: Analysis of COVID cases and their symptoms collected by the COVID Symptoms Study App. Nature Medicine, 27(4), 626–631. https://doi.org/10.1038/s41591-021-01292-y

Nalbandian, A., Sehgal, K., Gupta, A., et al. (2021). Post-acute COVID-19 syndrome. Nature Medicine, 27(4), 601–615. https://doi.org/10.1038/s41591-021-01283-z

Yong, S. J. (2021). Persistent brainstem dysfunction in long-COVID: A hypothesis. ACS Chemical Neuroscience, 12(4), 573–580. https://doi.org/10.1021/acschemneuro.0c00793

World Health Organization Clinical Case Definition Working Group on Post-COVID-19 Condition. (2021, October 6). A clinical case definition of post COVID-19 condition by a Delphi consensus. World Health Organization. https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1

National Institutes of Health. (2024, June 25). NIH RECOVER-VITAL Trial: Nirmatrelvir/Ritonavir for the treatment of PASC (Long COVID). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05595369

National Institutes of Health. (2024, May 20). RECOVER-AUTONOMIC: Ivabradine for the treatment of autonomic dysfunction in PASC (Long COVID). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT06305780