Background:Web-based surveys involving self-reported questionnaires are vulnerable to fraudulent responses. Advancements in artificial intelligence and bots have introduced additional challenges to preventing and identifying fraudulent responses to online questionnaires. Objective:This study aimed to describe our experiences with fraudulent responses, strategies for preventing and identifying fraudulent responses, lessons learned when conducting a web-based survey with adults living with Long COVID, and recommendations for web-based survey research. Methods:The Long COVID and Episodic Disability Study is an international community-engaged study among adults living with Long COVID in Canada, Ireland, the United Kingdom, and the United States. We conducted a longitudinal web-based survey, with online administration of a self-reported questionnaire at 2 timepoints (Time 1 and Time 2), 1 week apart. We recruited through Long COVID community groups using social media, emails, and word of mouth. The survey was disrupted by fraudulent responses, including bots. To defend data integrity, we implemented the following strategies: (1) pausing our initial launch (Wave 1), (2) developing and implementing screening criteria to identify fraudulent responses, and (3) relaunching the web-based survey (Wave 2) with revised recruitment strategies and questionnaire design to prevent and identify fraudulent responses. Results:We received 4663 responses for Time 1 and 1281 responses for Time 2, of which we retained 798 of 4663 (17%) responses and 629 of 1281 (49%) responses. Strategies for preventing fraudulent responses included enabling survey protection features in survey software, shutting down compromised survey links, avoiding recruitment via public social media groups, and removing mention of a financial incentive from recruitment materials. Strategies for identifying fraudulent responses included monitoring response completion times, start and end time stamps, geolocation, and screening for suspicious email address characteristics and duplicates. Conclusions:Our lessons learned fell into the following three areas: (1) survey-design and implementation to prevent and identify fraudulent and bot-generated responses, (2) recruitment strategies to mitigate the risk of disruption by bots, and (3) responding to disruptions caused by fraudulent and bot responses. We recommend the following tactics to prevent and mitigate the risks of fraudulent and bot responses when administering online web-based questionnaires: (1) review current literature and connect with researchers and Research Ethics Boards about strategies before launching, (2) invest in survey software with rigorous information security technology, (3) use bot-detection features available in survey software before launching, (4) design questionnaire items to identify bots and fraudulent actors, (5) tailor criteria for identifying fraudulent and bot responses to the characteristics of the target population, (6) avoid recruitment in public social media groups, (7) engage community leaders in tailored and targeted recruitment, (8) avoid advertising incentives, (9) shut down compromised links rapidly, (10) communicate with the Research Ethics Board about disruptions, and (11) combine automated and manual methods to identify potentially fraudulent responses on time.

Introduction 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.Methods and analysis 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.Ethics and dissemination 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.Trial registration number NCT06847191.

Background: Persons living with Long COVID experience a range of health-related challenges that may fluctuate over time, known as episodic disability. The Episodic Disability Questionnaire (EDQ) is a 35-item patient-reported outcome measure developed to assess presence, severity and episodic nature of disability across six dimensions: i) physical, ii) cognitive, iii) mental-emotional health, iv) difficulties with day-to-day activities, v) social inclusion, and vi) uncertainty about future health. Our aim was to assess the sensibility of the EDQ among adults living with Long COVID. Methodology: We conducted a two-phased sensibility assessment of the EDQ. In Phase 1, we assessed the face and content validity of the EDQ by mapping items from the EDQ onto the Episodic Disability Framework, which conceptualizes the health-related challenges living with Long COVID. Using the framework, we developed a 21-item Long COVID EDQ Supplement (LC-EDQ Supplement) for use in conjunction with the EDQ. In Phase 2, we conducted a cross-sectional measurement study involving adults living with Long COVID in Canada, Ireland, United Kingdom, and United States. We electronically administered the EDQ and LC-EDQ Supplement, followed by an 18-item sensibility questionnaire to assess face and content validity, ease of usage and format. Sensibility scores ranged from 1 (highly disagree) to 7 (highly agree). We considered the EDQ and the LC-EDQ Supplement sensible if median sensibility item scores were ≥5/7 for ≥80% of items and if none of the items had a median score of ≤3/7. Results: Of the 798 participants, most identified as female (82%), median age of 47 years (25th,75th percentile: 37, 56), and median of 2 years (1, 3) living with Long COVID. The EDQ and LC-EDQ Supplement met the criterion for sensibility as determined by sensibility item responses > 5/7 for 16/18 (89%) items on the sensibility questionnaire. Conclusions: The EDQ and LC-EDQ Supplement demonstrated sensibility among this sample of adults living with Long COVID. Results highlight the EDQ as a practical and feasible tool to assess the multi-dimensional and episodic nature of disability experienced among adults living with Long COVID.

BackgroundIncreasing 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.MethodsWe 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.ResultsOf 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.ConclusionsThe 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.

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.

Long COVID is a multisystem condition that negatively impacts daily function. Pacing is a self-management strategy to mitigate symptoms. Our aim was to describe experiences of pacing from the perspectives of adults living with Long COVID. We conducted a community-engaged qualitative descriptive study involving one-on-one online interviews with adults living with Long COVID from Canada, Ireland, United Kingdom, and United States to explore experiences of disability. We asked participants about strategies they used to deal with health challenges living with Long COVID. Interviews were audio recorded and transcribed verbatim. We analyzed data using group-based content analytical techniques. Among the 40 participants living with Long COVID, the majority were women (n = 25; 63

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. 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. 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. 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. 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.

Abstract Background Long COVID (LC) remains an urgent public health concern. The objective of this study was to explore recent patient perspectives of the COVID-19– or LC–related journey. Perceptions regarding symptoms and health status among patients diagnosed with LC are reported. Methods An online survey study was conducted in the United States by the Harris Poll (March 12-April 1, 2024) in 3090 adults aged ≥18 y who had COVID-19 or LC diagnosed in the previous 12 months. Non-demographic data were weighted by age, gender, race/ethnicity, region, education, marital status, household size, household income, and propensity to be online. Sampling precision was measured using a Bayesian credible interval. Statistical significance was determined by two-tailed t-test at the 95% (P< 0.05) confidence level. Results Of respondents, 2695 were diagnosed with COVID-19 and 445 were diagnosed with LC in the previous 12 months. Demographics were generally similar between groups (Table 1). A significantly greater proportion of LC patients (42%) self-described their current overall health as poor/fair vs those with COVID-19 alone (23%, P< 0.05; Table 2); LC patients also reported poorer physical and mental health. LC patients were significantly more likely to describe their initial LC symptoms as very/somewhat severe compared to the initial COVID-19 symptoms described by patients who did not develop LC (69% vs 44%, respectively; P< 0.05). Figure 1 shows self-reported COVID-19 or LC symptoms experienced within the first 3 days of feeling sick. LC patients waited over twice as long as those who did not develop LC to seek medical care following initial symptoms (8.0 vs 3.2 days, respectively; P< 0.05); Hispanic patients reported the longest wait times. Overall, 57% of respondents diagnosed with LC had experienced symptoms for ≥1 year. Fatigue and headache were reported as the most severe persistent symptoms (Figure 2). Conclusion COVID-19 and LC remain important areas of concern for the US population. Patients with recent LC reported greater initial LC symptom severity, a longer time to seeking medical care, and poorer overall, physical, and mental health compared with those who did not develop LC. Further analyses will explore perspectives related to healthcare access and differences by race/ethnicity. Disclosures Thomas F. Oppelt, PharmD, BCPS, Gilead Sciences, Inc: I am an employee of Gilead Sciences, Inc|Gilead Sciences, Inc: Stocks/Bonds (Public Company) Michael Caron, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Jamie Zagorski, MSN, FNP, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Rodney H. Taylor, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Chinonso Akano, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) LaKeisha Williams, PharmD, MSPH, Gilead Sciences, Inc.: Grant/Research Support Gary A. Puckrein, PhD, Dexcom: Grant/Research Support|Gilead Sciences, Inc.: Grant support for National Minority Quality Forum|National Minority Quality Forum: Employee

Web-based surveys involving self-reported questionnaires are vulnerable to fraudulent responses. Advancements in artificial intelligence (AI) and bots has introduced additional challenges to preventing and identifying fraudulent responses to online questionnaires. To describe our experiences with fraudulent responses, strategies for preventing and identifying fraudulent responses, lessons learned when conducting a web-based survey with adults living with Long COVID, and recommendations for web-based survey research. The Long COVID and Episodic Disability Study is an international community-engaged study among adults living with Long COVID in Canada, Ireland, United Kingdom (UK), and United States (US). We conducted a longitudinal web-based survey, with online administration of a self-reported questionnaire at two timepoints (Time One and Time Two), one week apart. We recruited through Long COVID community groups using social media, emails, and word of mouth. The survey was disrupted by fraudulent responses, including bots. To defend data integrity, we implemented the following strategies: a) pausing our initial launch (Wave One), b) developing and implementing screening criteria to identify fraudulent responses, and c) re-launching the web-based survey (Wave Two) with revised recruitment strategies and questionnaire design to prevent, and identify fraudulent responses. We received 4663 responses for Time One and 1281 responses for Time Two, of which we retained 798/4663 (17%) and 629/1281 (49%). Strategies for preventing fraudulent responses included enabling survey protection features in survey software, shutting down compromised survey links, avoiding recruitment via public social media groups, and removing mention of a financial incentive from recruitment materials. Strategies for identifying fraudulent responses included monitoring response completion times, start and end time stamps, geolocation, and screening for suspicious email address characteristics and duplicates. Our lessons learned fell into three areas: 1) survey-design and implementation to prevent and identify fraudulent and bot-generated responses; 2) recruitment strategies to mitigate risk of disruption by bots; and 3) responding to disruptions caused by fraudulent and bot responses. We recommend the following tactics to prevent and mitigate the risks of fraudulent and bot responses when administering online web-based questionnaires: a) review current literature and connect with researchers and Research Ethics Boards (REBs) about strategies prior to launching; b) invest in survey software with rigorous info-security technology; c) employ bot-detection features available in survey software prior to launching; d) design questionnaire items to identify bots and fraudulent actors; e) tailor criteria for identifying fraudulent and bot responses to the characteristics of the target population; f) avoid recruitment in public social media groups; g) engage community leaders in tailored and targeted recruitment; h) avoid advertising incentives; i) shut down compromised links rapidly; j) communicate with the REB about disruptions; and k) combine automated with manual methods to identify potentially fraudulent responses in a timely manner. n/a RR2-10.1136/bmjopen-2022-060826

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.

Introduction Long COVID is a multisystem condition that negatively impacts daily function. Pacing is a self-management strategy to mitigate symptoms. Our aim was to describe experiences of pacing from the perspectives of adults living with Long COVID. Methods We conducted a community-engaged qualitative descriptive study involving one-on-one online interviews with adults living with Long COVID from Canada, Ireland, United Kingdom, and United States to explore experiences of disability. We asked participants about strategies they used to deal with health challenges living with Long COVID. Interviews were audio recorded and transcribed verbatim. We analyzed data using group-based content analytical techniques. Results Among the 40 participants living with Long COVID, the majority were women (n=25; 63%), white (n=29;73%) and heterosexual (n=30;75%). The median age of participants was 39 years (25th, 75th percentile: 32, 49). Most participants (n=37;93%) used pacing to mitigate or prevent symptoms. Participant described experiences of pacing across five main areas: 1) using pacing as a living strategy (pacing to mitigate multidimensional health challenges; applying pacing to many types of activities; process of pacing experienced as a moving target; pacing experienced as a helpful strategy, but not a cure for Long COVID); 2) learning how to pace (acquiring knowledge about pacing; developing strategies and skills to support pacing); 3) encountering challenges with pacing (learning how to pace; experiencing inequitable access to pacing; experiencing stigma and judgement; undergoing psychological and emotional adjustment from beliefs of ‘fighting’ or ‘pushing through’ to balancing rest with activity; making sacrifices; and encountering unexpected obstacles); 4) experiencing consequences of not pacing; and 5) conceptualising and describing pacing using analogies or metaphors. Discussion Pacing is a challenging and complex strategy used to mitigate symptoms of Long COVID. Healthcare providers should work collaboratively with patients to further refine and implement this strategy, when appropriate. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Yes ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Toronto Health Sciences Research Ethics Board (protocol #41749). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All relevant data are within the manuscript and its Supporting Information files.

Background: COVID-19 reinfections are common worldwide. Long COVID is a serious infection-associated chronic condition and a major public health concern. Using a patient-centered approach, we characterized the association between reinfections and Long COVID. Methods: We developed and disseminated internationally a patient-centered online survey examining the outcomes of COVID-19 reinfections. The survey incorporated validated instruments on fatigue, post-exertional malaise, and physical function with questions about COVID-19 infection history, vaccination, and Long COVID symptoms, including symptoms related to immune and reproductive health. We tested whether the likelihood of Long COVID and related outcomes increases with COVID-19 infection numbers. Results: Here we show that reinfections increase the likelihood of reporting Long COVID, which increased 2.1-fold from one to two infections. Among 3,382 participants, 22% reported never having had COVID-19, 42% experienced it once, and 35% reported reinfections. Relative to those who did not report infections or experienced COVID-19 once, reinfections were associated with increased likelihood of severe fatigue, post-exertional malaise, decreased physical function, poorer immune health, symptom exacerbation before menstruation, and multiple other Long COVID symptoms. While vaccinations and boosters prior to infection are associated with lower likelihood of Long COVID, reinfections diminish their protective effect. The probability of reporting Long COVID remission is generally low (11.5%-6.5%). Conclusions: COVID-19 reinfections are associated with higher likelihood of Long COVID and related outcomes. These findings underscore the need for robust public health measures for COVID-19 infection prevention and the importance of considering reinfections in Long COVID research and clinical practice.

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.

Long COVID is a chronic and often disabling illness with long-term consequences. Although progress has been made in the clinical characterization of long COVID, no approved treatments exist and disconnects between patients and researchers threaten to hinder future progress. Incorporating patients as active collaborators in long COVID research can bridge the gap and accelerate progress toward treatments and cures.

Objectives. To document the prevalence of long COVID among a sample of survey respondents with long-term disabilities that existed before 2020 and to compare the prevalence among this group with that among the general population. Methods. We conducted a cross-sectional, descriptive study using data from the 2022 National Survey on Health and Disability (n = 2262) and comparative data for the general population from the federal Household Pulse Survey (HPS). Results. The prevalence of long COVID was higher among people with preexisting disabilities than in the general population (40.6% vs 18.9%). Conclusions. People with preexisting disabilities experienced and continue to experience increased exposure to COVID-19 and barriers to accessing health care, COVID-19 vaccines, and COVID-19 tests. These barriers, combined with long-standing health disparities in this population, may have contributed to the greater prevalence of long COVID among people with disabilities. Public Health Implications. The needs of people with disabilities must be centered in the response to the COVID-19 pandemic and future pandemics. (Am J Public Health. 2024;114(11):1261-1264. https://doi.org/10.2105/AJPH.2024.307794).

Long COVID is a debilitating, multisystemic illness following a SARS-CoV-2 infection whose duration may be indefinite. Over four years into the pandemic, little knowledge has been generated from clinical trials. We analyzed the information available on ClinicalTrials.gov, and found that the rigor and focus of trials vary widely, and that the majority test non-pharmacological interventions with insufficient evidence. We highlight promising trials underway, and encourage the proliferation of clinical trials for treating Long COVID and other infection-associated chronic conditions and illnesses (IACCIs). We recommend several guidelines for Long COVID trials: First, pharmaceutical trials with potentially curative, primary interventions should be prioritized, and both drug repurposing and new drug development should be pursued. Second, study designs should be both rigorous and accessible, e.g., triple-blinded randomized trials that can be conducted remotely, without participants needing to leave their homes. Third, studies should have multiple illness comparator cohorts for IACCIs such as Myalgic Encephalomyelitis (ME/CFS) and dysautonomia, and screen for the full spectrum of symptomatology and pathologies of these illnesses. Fourth, studies should consider inclusion/exclusion criteria with an eye towards equity and breadth of representation, including participants of all races, ethnicities, and genders most impacted by COVID-19, and including all levels of illness severity. Fifth, involving patient-researchers in all aspects of studies brings immensely valuable perspectives that will increase the impact of trials. We also encourage the development of efficient clinical trial designs including methods to study several therapies in parallel.

A growing number of working individuals have developed long COVID (LC) after COVID-19 infection. Economic analyses indicate that workers' LC symptoms contribute to workforce shortages. However, factors that affect return-to-work from perspectives of people with LC remain largely underexplored. This qualitative study of people with LC conducted by researchers living with LC aimed to identify participants' return-to-work experiences using Total Worker Health® and Episodic Disability frameworks. 10% of participants who participated in a mixed-method global internet survey, had LC symptoms >3 months, and responded in English were randomly selected for thematic analysis using NVivo12. 15% of responses were independently double-coded to identify coding discrepancies. Participants (N = 510) were predominately white and had at least a baccalaureate degree. Four primary work-related themes emerged: 1) strong desire and need to return to work motivated by sense of purpose and financial precarity; 2) diverse and episodic LC symptoms intersect with organization of work and home life; 3) pervasiveness of LC disbelief and stigma at work and in medical settings; and 4) support of medical providers is key to successful return-to-work. Participants described how fluctuation of symptoms, exacerbated by work-related tasks, made returning to work challenging. Participants’ ability to work was often predicated on job accommodations and support. Non-work factors were also essential, especially being able to receive an LC medical diagnosis (key to accessing leave and accommodations) and help at home to manage non-work activities. Many participants described barriers accessing these supports, illuminating stigma and disbelief in LC as a medical condition. Qualitative findings indicate needs for workplace accommodations tailored to fluctuating symptoms, continuously re-evaluated by workers and supervisors together. Reductions in medical barriers to access work accommodations is also critical since many medical providers remain unaware of LC, and workers may lack a positive COVID test result.

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.