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Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.Long COVID is an often debilitating illness of severe symptoms that can develop during or following COVID-19. In this Review, Davis, McCorkell, Vogel and Topol explore our knowledge of long COVID and highlight key findings, including potential mechanisms, the overlap with other conditions and potential treatments. They also discuss challenges and recommendations for long COVID research and care.

Increasing numbers of adults are living with the health-related consequences of Long COVID. The Episodic Disability Framework (EDF), derived from perspectives of adults living with HIV, characterizes the multi-dimensional and episodic nature of health-related challenges (disability) experienced by an individual. Our aim was to determine the applicability of the Episodic Disability Framework to conceptualize the health-related challenges experienced among adults living with Long COVID. We conducted a community-engaged qualitative descriptive study involving online semi-structured interviews. We recruited adults who self-identified as living with Long COVID via collaborator community organizations in Canada, Ireland, United Kingdom, and United States. We purposively recruited for diversity in age, gender identity, ethnicity, sexual orientation, and time since initial COVID-19 infection. We used a semi-structured interview guide informed by the EDF to explore experiences of disability living with Long COVID, specifically health-related challenges and how challenges were experienced over time. We conducted a group-based content analysis. Of the 40 participants, the median age was 39 years; and the majority were white (73%), women (63%), living with Long COVID for ≥ 1 year (83%). Consistent with the Episodic Disability Framework, disability was described as multi-dimensional and episodic, characterized by unpredictable periods of health and illness. Experiences of disability were consistent with the three main components of the Framework: A) dimensions of disability (physical, cognitive, mental-emotional health challenges, difficulties with day-to-day activities, challenges to social inclusion, uncertainty); B) contextual factors, extrinsic (social support; accessibility of environment and health services; stigma and epistemic injustice) and intrinsic (living strategies; personal attributes) that exacerbate or alleviate dimensions of disability; and C) triggers that initiate episodes of disability. The Episodic Disability Framework provides a way to conceptualize the multi-dimensional and episodic nature of disability experienced by adults living with Long COVID. The Framework provides guidance for future measurement of disability, and health and rehabilitation approaches to enhance practice, research, and policy in Long COVID.

IntroductionOur aim was to describe episodic nature of disability among adults living with Long COVID.MethodsWe conducted a community-engaged qualitative descriptive study involving online semistructured interviews and participant visual illustrations. We recruited participants via collaborator community organisations in Canada, Ireland, UK and USA.We recruited adults who self-identified as living with Long COVID with diversity in age, gender, race/ethnicity, sexual orientation and duration since initial COVID infection between December 2021 and May 2022. We used a semistructured interview guide to explore experiences of disability living with Long COVID, specifically health-related challenges and how they were experienced over time. We asked participants to draw their health trajectory and conducted a group-based content analysis.ResultsAmong the 40 participants, the median age was 39 years (IQR: 32–49); majority were women (63%), white (73%), heterosexual (75%) and living with Long COVID for ≥1 year (83%). Participants described their disability experiences as episodic in nature, characterised by fluctuations in presence and severity of health-related challenges (disability) that may occur both within a day and over the long-term living with Long COVID. They described living with ‘ups and downs’, ‘flare-ups’ and ‘peaks’ followed by ‘crashes’, ‘troughs’ and ‘valleys’, likened to a ‘yo-yo’, ‘rolling hills’ and ‘rollercoaster ride’ with ‘relapsing/remitting’, ‘waxing/waning’, ‘fluctuations’ in health. Drawn illustrations demonstrated variety of trajectories across health dimensions, some more episodic than others. Uncertainty intersected with the episodic nature of disability, characterised as unpredictability of episodes, their length, severity and triggers, and process of long-term trajectory, which had implications on broader health.ConclusionAmong this sample of adults living with Long COVID, experiences of disability were described as episodic, characterised by fluctuating health challenges, which may be unpredictable in nature. Results can help to better understand experiences of disability among adults living with Long COVID to inform healthcare and rehabilitation.

Long COVID is a debilitating condition consisting of prolonged neurological symptoms such as cognitive impairment ('brain fog') and sleep disturbance. Symptoms may be associated with ongoing neuroinflammation from the persistence of a viral reservoir, activation of other viruses, protracted macrophagic inflammatory memory or enduring viral Spike protein that stimulates proinflammatory cytokines via toll-like receptor (TLR) signalling. Bezisterim (NE3107) is an oral, blood-brain barrier-permeable, anti-inflammatory, insulin-sensitising dehydroepiandrosterone derivative that inhibits TLR-driven neuroinflammation and is being developed for neurodegenerative diseases in which TLR-driven inflammation contributes to cognitive decline. ADDRESS-LC (NCT06847191) is a phase 2, triple-blind, placebo-controlled, randomised proof-of-concept study to evaluate the efficacy and safety of bezisterim in adults with long COVID. This multicentre study will recruit 208 adults (aged 18-69 years) with symptoms of fatigue and neurocognitive impairment for at least 3 months following an index SARS-CoV-2 infection. Individuals who meet all eligibility criteria will be randomised 1:1 to receive bezisterim 20 mg or placebo two times per day for 12 weeks. Cognition, fatigue, sleep, post-exertional malaise, quality of life and burdensome symptoms will be evaluated via several assessments, including a bespoke Cogstate Cognition Battery, Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function Short Form (SF)-8a, PROMIS Fatigue SF-13a and Patient's Global Impression of Severity, among others. The protocol has been approved by an institutional review board prior to study initiation. The study is being conducted at multiple clinical research sites across the USA. A current list of participating study sites is publicly available through the ClinicalTrials.gov registration record (NCT06847191). The study protocol has received central institutional review board approval (Advarra #Pro00081088), and participating sites obtained the necessary approvals and agreements required for study conduct and data access in accordance with applicable regulations and Good Clinical Practice guidelines. Authorised representatives of the sponsor, regulatory authorities and ethics committees may access study-related records for monitoring, auditing and regulatory purposes consistent with participant informed consent. The study will disseminate results through academic publication and conference presentations. NCT06847191.

IntroductionAs the prevalence of Long COVID increases, there is a critical need for a comprehensive assessment of disability. Our aims are to: (1) characterise disability experiences among people living with Long COVID in Canada, UK, USA and Ireland; and (2) develop a patient-reported outcome measure to assess the presence, severity and episodic nature of disability with Long COVID.Methods and analysisIn phase 1, we will conduct semistructured interviews with adults living with Long COVID to explore experiences of disability (dimensions, uncertainty, trajectories, influencing contextual factors) and establish an episodic disability (ED) framework in the context of Long COVID (n~10 each country). Using the conceptual framework, we will establish the Long COVID Episodic Disability Questionnaire (EDQ). In phase 2, we will examine the validity (construct, structural) and reliability (internal consistency, test–retest) of the EDQ for use in Long COVID. We will electronically administer the EDQ and four health status criterion measures with adults living with Long COVID, and readminister the EDQ 1 week later (n~170 each country). We will use Rasch analysis to refine the EDQ, and confirm structural and cross-cultural validity. We will calculate Cronbach’s alphas (internal consistency reliability), and intraclass correlation coefficients (test–retest reliability), and examine correlations for hypotheses theorising relationships between EDQ and criterion measure scores (construct validity). Using phase 2 data, we will characterise the profile of disability using structural equation modelling techniques to examine relationships between dimensions of disability and the influence of intrinsic and extrinsic contextual factors. This research involves an academic–clinical–community partnership building on foundational work in ED measurement, Long COVID and rehabilitation.Ethics and disseminationThis study was approved by the University of Toronto Research Ethics Board. Knowledge translation will occur with community collaborators in the form of presentations and publications in open access peer-reviewed journals and presentations.

Introduction Long Covid and other infection‐associated chronic condition communities have been integral in advocating for patient engagement in all stages of research, from design and conduct, and implementation, through to interpretation and knowledge translation; nevertheless, the process varies across research teams. In this paper, we (1) describe our process undertaking a community‐engaged Long Covid research study; (2) evaluate our community‐engaged approach, highlighting strengths and limitations with our process; and (3) identify recommendations for engaging in community‐engaged patient‐oriented research in Long Covid. Methods Guided by the 4PI (Principles; Purpose; Presence; Process; Impact) Framework and Patient‐Led Research Scorecards, we describe our community‐engaged approach within the Long COVID and Episodic Disability Study, followed by an evaluation of our community engagement using a multistage consultation with members of the Long COVID and Episodic Disability Study team. We conducted an online group‐based discussion among persons with lived experiences and administered a web‐based Scorecard questionnaire rating the collaboration as it relates to four domains of patient burden, governance, integration into the research process, and organisation readiness to all members of the team, to assess strengths and limitations of our approach. Scores ranged from −2 (non‐collaboration) to +2 (ideal collaboration). Results Ten team members, five of whom were persons with lived experiences, completed the Scorecard questionnaire. Median Scorecard scores ranged from +1 to +2 for all domains. Five team members with lived experiences, representing four community support groups and organisations that participated in the community‐engagement discussion. We describe the practices and principles that enabled meaningful community engagement, with the strengths and limitations of our approach embedded throughout. Conclusion Our community‐engaged approach to the Long COVID and Episodic Disability Study enhanced the quality and relevance of the study to the community while highlighting areas to heighten meaningful engagement throughout. This study builds on foundational community‐based research principles of patient‐oriented research. Recommendations derived from our experiences may be used by other research teams conducting community‐engaged patient‐oriented research. Patient or Public Contribution The Long COVID and Episodic Disability Study is a community‐engaged research study involving 25 members, including 12 persons living with long Covid, 13 researchers and 5 clinicians (categories are not mutually exclusive), referred to as the Full Team. Persons with lived experiences possessed a range of professional and personal experiences spanning research, clinical, policy and private sector/business contexts; team members wore multiple hats and perspectives which collectively strengthened the diversity of expertise, perspectives and insights to the team and process. Engagement of people with lived experiences with Long Covid ensured that the study was fully co‐created with people living with Long Covid. During the development of the study proposal, community partners from organisations in Canada, Ireland, the United Kingdom and the United States, who were linked to larger networks of people living with Long Covid, were purposefully invited to join the study team. Several Long Covid community networks and organisations, represented by persons living with Long Covid, were involved in all stages of the research, including: COVID Long‐Haulers Support Group Canada (S.G.); Long COVID Advocacy Ireland (I.O., S.O. and R.S.); Long COVID Ireland (N.R. and R.S.); Long COVID Physio (D.A.B. and C.T.); Long Covid Support UK (M.O.H.); and Patient‐Led Research Collaborative (L.M., N.M. and H.W.). These representatives along with the Co‐PIs (K.K.O. and D.A.B.) and co‐ordinator (K.M.) comprised the Core Long COVID and Episodic Disability Community Collaborator Team (Core Team). Team members with lived experiences were provided yearly remuneration for their time and expertise dedicated to the study, either as an individual, or to the community organisation which they represented on the study according to their preference.

Background Prior case series suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) benefits some people with Long COVID, within and/or outside of the context of an acute reinfection. To the best of our knowledge, there have been no prior case series of people with Long COVID who have attempted longer courses of nirmatrelvir/ritonavir. Methods We documented a case series of 13 individuals with Long COVID who initiated extended courses (>5 days; range: 7.5–30 days) of oral nirmatrelvir/ritonavir outside ( n  = 11) of and within ( n  = 2) the context of an acute SARS-CoV-2 infection. Participants reported on symptoms and health experiences before, during, and after their use of nirmatrelvir/ritonavir. Results Among those who take an extended course of nirmatrelvir/ritonavir outside of the context of an acute infection, some experience a meaningful reduction in symptoms, although not all benefits persist. Others experience no effect on symptoms. One participant stopped early due to intense stomach pain. For the two participants who took an extended course of nirmatrelvir/ritonavir within the context of an acute reinfection, both report eventually returning to their pre-re-infection baseline. Conclusions Extended courses of nirmatrelvir/ritonavir may have meaningful benefits for some people with Long COVID but not others. We encourage researchers to study how and why nirmatrelvir/ritonavir benefits some and what course length is most effective, with the goal of informing clinical recommendations for using nirmatrelvir/ritonavir and/or other antivirals as a potential treatment for Long COVID. Plain language summary Long COVID is an infection-associated chronic condition in which symptoms persist more than 12 weeks after an acute COVID-19 infection. Prior reports suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) may help some people with Long COVID, but there have not yet been any reports of people with Long COVID trying extended courses of nirmatrelvir/ritonavir. Our patient-led study documents the experiences of 13 people with Long COVID who tried extended courses of Paxlovid; some were in the midst of a reinfection and others were not. Some participants reported meaningful benefits, although not all improvements lasted long-term. Others experienced no changes in symptoms. Our results suggest that extended courses of nirmatrelvir/ritonavir could be beneficial for some people with Long COVID. Cohen et al. report a patient-led case series of 13 individuals with Long COVID who initiated extended courses of Paxlovid outside of, or within the context of, an acute SARS-CoV-2 infection. Long courses of nirmatrelvir/ritonavir have meaningful benefits for some people with Long COVID but not all.

Background The symptomatic and immune responses to COVID-19 vaccination of people with Long COVID are poorly characterized. Methods In this prospective study, we evaluated changes in symptoms and immune responses after COVID-19 vaccination in 16 vaccine-naïve individuals with Long COVID. Surveys were administered before vaccination and at 2, 6, and 12 weeks after receiving the first vaccine dose of the primary series. Simultaneously, SARS-CoV-2-reactive TCR enrichment, SARS-CoV-2-specific antibody responses, antibody responses to other viral and self-antigens, and circulating cytokines were quantified before vaccination and at 6 and 12 weeks after vaccination. Results At 12 weeks post-vaccination, self-reported improved health is seen in 10 out of 16 participants, 3 have no change, and 3 have worse health although 2 report transient improvement after vaccination. One participant reporting worse health was hospitalized twice with chest pain (after each dose). Symptom outcomes are most associated with plasma biosignatures. Higher baseline sIL-6R is associated with symptom improvement, and stably elevated levels of IFN-β and CNTF are associated with no improvement. Significant elevation in SARS-CoV-2-specific TCRs and spike protein-specific IgG are observed at 6 and 12 weeks after vaccination. No changes in reactivities are observed against herpes viruses and self-antigens. Conclusions In this study of 16 people with Long COVID, vaccination is associated with increased SARS-CoV-2 spike protein-specific IgG and T cell expansion in most participants. Specific immune features are associated with symptom change after vaccination and most participants experience improved health or no change following vaccination. Plain language summary The impact of the COVID-19 vaccine on unvaccinated individuals suffering from Long COVID is uncertain. This study assessed the experience and biological markers of 16 unvaccinated participants with Long COVID. A total of 10 participants had improved health after vaccination, three reported worsening health, with one hospitalized twice with chest pain. Vaccination boosted the body’s immune responses against the virus that causes COVID-19. We identified biological markers that correlate with the changes in overall health after vaccination. Given that the study was small, more research is needed to confirm these results. Grady, Bhattacharjee and Silva et al. examine the effects of COVID-19 vaccination on 16 vaccine-naive individuals with Long COVID, finding that 10 reported improvements, 3 had no change, and 3 experienced worse overall health post-vaccination. Specific immune signatures correlate with these health changes following vaccination.

Long COVID represents the constellation of post-acute and long-term health effects caused by SARS-CoV-2 infection; it is a complex, multisystem disorder that can affect nearly every organ system and can be severely disabling. The cumulative global incidence of long COVID is around 400 million individuals, which is estimated to have an annual economic impact of approximately $1 trillion—equivalent to about 1% of the global economy. Several mechanistic pathways are implicated in long COVID, including viral persistence, immune dysregulation, mitochondrial dysfunction, complement dysregulation, endothelial inflammation and microbiome dysbiosis. Long COVID can have devastating impacts on individual lives and, due to its complexity and prevalence, it also has major ramifications for health systems and economies, even threatening progress toward achieving the Sustainable Development Goals. Addressing the challenge of long COVID requires an ambitious and coordinated—but so far absent—global research and policy response strategy. In this interdisciplinary review, we provide a synthesis of the state of scientific evidence on long COVID, assess the impacts of long COVID on human health, health systems, the economy and global health metrics, and provide a forward-looking research and policy roadmap. This Review outlines the current state of scientific evidence on long COVID, discusses its impacts on patients, health systems, economies and global health metrics, and proposes a forward-looking research and policy roadmap.