Appendix A

Detailed Description of the Committee’s Approach and Study Methods

At the request of the Administration for Strategic Preparedness and Response (ASPR) and the Office of the Assistant Secretary for Health (OASH), the National Academies of Sciences, Engineering, and Medicine (National Academies) was asked to examine the definition for Long COVID. In response to this request, the National Academies convened the Standing Committee on Emerging Infectious Diseases and 21st Century Health Threats¹ to scope and better understand the issue. To respond to this new charge on Long COVID, the National Academies convened the Committee on Examining the Working Definition for Long COVID consisting of experts in the fields of health research and policy; research related to Long COVID and chronic multi-symptom illness; clinical practice and guidelines; infectious diseases; public health and epidemiology practice; social and behavioral health and decision science; patients and lived experience; and community engagement and health equity.

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¹ The Standing Committee on Emerging Infectious Diseases and 21st Century Health Threats was convened in March 2020 in response to the COVID-19 pandemic to help inform the federal government, and specifically ASPR, on critical science and policy issues related to emerging infectious diseases and other 21st century health threats. It comprises 27 members with expertise in emerging infectious diseases, public health, public health preparedness and response, biological sciences, clinical care and crisis standards of care, risk communications, epidemiology, regulatory issues, veterinary science, One Health, ethics, social science, and community engagement.

MULTI-PHASE EFFORT

This study was a multi-phase activity that began with the Standing Committee on Emerging Infectious Diseases and 21st Century Health Threats convening a series of scoping meetings to initiate information gathering and identify key issues, areas of expertise, and stakeholders to engage in the effort. In the next phase (Phase I), an ad hoc committee was appointed, the Committee on Examining the Working Definition for Long COVID. The committee conducted engagement activities and hosted a symposium. The committee also integrated and synthesized information from the engagement efforts and reviewed relevant literature and information gathered through the workshop. In Phase II, the committee was asked by the sponsor to produce a report to review additional evidence for definitions of Long COVID, consider efforts that have already been completed on this topic area, and put forth new definitions and related technical terms, with descriptions of the circumstances under which these new definitions and terminology should be adopted.

Scoping Phase

In the initial Scoping Phase of the study, the standing committee deliberated over a period of 2 months. The activities included three information-gathering scoping meetings to discuss the key issues and identify the areas of expertise and stakeholders to engage in this effort.

• The first scoping meeting featured a discussion on the request from OASH and ASPR, followed by a panel of federal and non-federal experts, including those with international perspectives and front-line community perspectives, examining lessons learned from other processes and experiences for developing disease definitions and diagnostic criteria. The meeting also featured a session where the standing committee took part in an initial stakeholder mapping activity.
• Building on the first scoping meeting, the second meeting featured a panel with experts, including those with lived experience, particularly focusing on lessons learned and best practices from engagement efforts for defining diseases and setting research priorities. The standing committee also had an opportunity to review and provide input on the first draft of the engagement plan focusing on the purpose, objectives, and the list of stakeholders.

• The final scoping meeting provided the standing committee with an opportunity to provide feedback and continue discussions on the revised engagement plan and the list of identified stakeholders.

Phase I and Phase II

In Phase I and Phase II, the committee used various engagement activities and evidence-building activities to gather, prioritize, synthesize, and evaluate evidence and information to help inform the refinement of Long COVID definitions and related terminology and put forth a report with recommendations. The detailed methodology for the engagement process and evidence review are described below. The committee also hosted an online Public Comment Portal (April 10–June 12, 2023) on the project website for the public to provide comments and submit resources about the current working definition.

ENGAGEMENT PROCESS

Engagement—of all those potentially affected by the definitions for Long COVID, including those with lived experience—was critical to ensuring that the right issues were addressed and to improve the transparency, accuracy, relevancy, usefulness, and acceptability of the definition. The committee worked with a consultant to engage patients and individuals across multiple sectors to solicit input from a wide variety of interested and affected stakeholders, including the general public, specific underserved communities, health professionals, government agencies, and relevant sectors of the economy.

The multi-perspective engagement process enabled the committee to solicit input from patients, caregivers, researchers, practitioners, health agencies, health policy and advocacy organizations, payors, and health industry businesses. A total of 1,315 participants were involved in engagement activities. Three key principles guided the engagement process:

• Commitment to inclusion to ensure that a wide set of perspectives were heard.
• Development of a fair and equitable process to ensure all participants had the information they needed to fully participate as well as accommodations necessary to enable their participation.
• Transparency in the process and in the documentation of findings from the engagement.

Two key engagement opportunities were hosted by the committee:

• Questionnaire (April 19–May 12, 2023): An online questionnaire was sent to interested and affected people and organizations. It was also publicly shared by invited participants. Respondents had the opportunity to provide specific feedback on key issues, concerns, and areas of improvement of the current working definition. The questionnaire was created using Qualtrics, and completed questionnaires were stored in Qualtrics’s secure servers online. The questionnaire contained 37 questions, none of which were required to be answered. Twenty-five questions were about Long COVID, and 11 were demographic questions.
• Virtual Focus Groups (April 26–May 8, 2023): Seven facilitated virtual focus groups were held with invited people and organizations to deepen the shared understanding of the concerns and areas of improvement of the current working definition. Seven facilitated virtual focus groups were held with invited individuals and organizations to explore concerns and areas for the improvement of the current Long COVID definitions:
  • Researchers (April 26): For those who conduct research and report results to the scientific or medical community.
  • Practitioners (April 28): For those who provide health care and for professional associations who provide clinical guidance.
  • Patients, Caregivers, and Patient Organizations (April 29): For those who are living with Long COVID or supporting someone affected and for groups who advocate on behalf of Long COVID patients.
  • Health Agencies (May 2): For those who lead or deliver programs that provide public health or community services.
  • Health Policy and Health Advocacy Organizations (May 4): For organizations that advance health care and health policy through data analysis, funding research, advocacy, supporting initiatives, or making recommendations.
  • Payors and Health Businesses (May 5): For businesses that provide health insurance as well as businesses that produce drugs, tests, devices, procedures, etc. related to Long COVID.
  • All Categories (May 8): For those unable to attend the session for their sector.

Each online focus group session was 2.5 hours long. Most of each session was spent in small group discussion to ensure that participants were able to share their views and hear from others. Key discussion questions for the focus groups were:

• How might you use a definition of Long COVID?
• What feedback do you have about the USG’s working definition, or other definitions, of Long COVID?
• What challenges might there be in using the current USG definition, or other definitions?
• What might address those challenges?
• What should the National Academies’ committee keep in mind to make sure the definition does not unintentionally make it harder for people with Long COVID to get health care, workplace support, or other things they need?
• What advice do you have for the National Academies’ committee charged with reviewing the USG’s definition of Long COVID?

Further details on the methodology and analysis, the description of who participated in the questionnaire and focus groups, and the results and findings can be found in the publicly available report What We Heard: Engagement Report on the Working Definition for Long COVID.² Findings from the engagement process were integrated throughout the committee’s report.

EVIDENCE REVIEW

Given the rapidly emerging scientific literature on Long COVID and the time constraints on the study, the committee conducted a scoping review that first identified recently published reviews (2020 through November 2023), including systematic, qualitative, and comprehensive scoping reviews. This scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was conducted with the help of a librarian and PICO Portal methodologists. This section describes in detail the scoping review methodology.

Importantly, the scoping review was supplemented with primary research. The primary research was identified through a secondary search, reference mining, forward citation searching, and committee suggestions.

Scoping Review Search Strategy

Literature was identified through a systematic search as well as “snowballing” and reference mining to identify additional published and pre-print articles. Electronic databases used for the literature search include PubMed, Embase, Medline, Cochrane Library, Google, Scopus, COVID-specific

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² What We Heard: Engagement Report on the Working Definition for Long COVID. Available on the study webpage https://www.nationalacademies.org/our-work/examining-the-working-definition-for-long-covid (accessed March 11, 2024).

databases including Lit COVID and the Centers for Disease Control and Prevention (CDC) COVID-19 Publications Database, and preprint databases. Literature was searched systematically and according to specific search criteria to identify signs, symptoms, and conditions experienced by individuals with Long COVID. The search was guided by the Population, Exposure, Comparator, Outcome (PECO) framework that supports the investigation of exposures with health outcomes. The PECO criteria for this review were:

• Population: Adults and children with ongoing symptomatic COVID-19 and Long COVID (i.e., post-acute sequelae of COVID-19, Post-COVID Conditions, Post-COVID-19 Syndrome).
• Exposure: Confirmed, probable, or suspected infection with SARS-CoV-2 or COVID-19 assessed by any diagnostic method or self-reported.
• Comparator: Any comparison.
• Outcomes:
  • Any health outcome (signs, symptoms, and conditions both patient-reported and clinical investigations).
  • Outcomes specific to adult versus pediatric populations.
  • Outcomes specific to other vulnerable populations.
  • Nature of health outcomes.
  • Clinical, laboratory, or other methods to assess health outcomes.
  • Onset of health outcomes following acute COVID-19 illness.
  • Short-term, long-term, and lifelong duration of health outcomes.
  • Impact of health outcomes on daily activities.
  • Common comorbid conditions (e.g., health conditions that commonly occur with Long COVID).
  • Severity of health outcomes.
  • Frequency of health outcomes.
  • Any symptoms, symptom constructs, clusters, or categories (e.g., autonomic manifestations, immune manifestations, fatigue, neurocognitive manifestations, neuroendocrine manifestations, post-exertional malaise, pain, etc.).
  • Disabilities and impairment.
  • Methods of assessment for health outcomes (e.g., clinical, imaging, questionnaire, etc.).

Studies were determined for inclusion in the review or exclusion, based on the criteria in Table A-1.

The initial search was conducted in May 2023, with subsequent, updated searches conducted in July 2023 and November 2023.

TABLE A-1 Inclusion and Exclusion Criteria

Scoping Review Screening

Results were collated and imported to the PICO Portal. After removing duplicates from the multiple databases, all titles and abstracts were with a single reviewer (National Academies staff). During title–abstract screening, all records were tagged according to characteristics of the study including methods (e.g., systematic review, narrative review, scoping review, meta-analysis) and health conditions and symptoms (e.g., systemic manifestations, neurologic, genetic and biological markers, etc.). For full-text screening, articles prioritized were tagged as systematic reviews and all health conditions. After screening those records, the remaining records were screened without prioritization. All eligibility criteria were applied equally to potentially eligible records. All full-text records were screened in duplicate with independent methodologists from PICO Portal, and a National Academies staff member resolved all discrepancies.

Scoping Review Quality Assessment

Following established protocols, all records included at full-text screening were assessed for their reliability. The reliability was assessed with two independent PICO Portal methodologists, and all discrepancies were resolved with a third, senior methodologist. Data were extracted only from studies that were considered to be “reliable.”

“Reliability” is an assessment of how transparent and reliable the methods used in a systematic review are for searching and synthesizing. There are many tools to assess the quality or risk of bias in systematic reviews, including Risk of Bias in Systematic Reviews (ROBIS), Assessment of Multiple Systematic Reviews (AMSTAR), Critical Appraisal Skills Checklist (CASP). These tools are valuable, but they are detailed and difficult to apply on a large scale. To aid their work and partnerships with clinical organizations and guideline development, Cochrane Eyes and Vision developed a method of assessing the presence of key elements to ascertain whether systematic reviews met the minimum criteria for being considered “reliable” enough to inform practice. This assessment takes common elements from the other, longer, tools and distills the minimum criteria to five questions, all of which must be answered yes for a systematic review to be reliable.

1. Does the systematic review provide the eligibility criteria for inclusion in the review?
2. Does the systematic review conduct a comprehensive search of the literature?
3. Does the systematic review assess the risk of bias/quality of the included studies using any relevant tool?
4. If there are quantitative analyses, are the methods (and the meta-analysis) appropriate?
5. Do the review’s conclusions align with the results that it actually found?

Explanation And Rational for Individual Items

Item 1 – This item is a simple “Yes” or “No” based on what has been reported in the paper or in an associated and accessible registry or protocol. If a systematic review does not report the criteria used to determine eligibility, it is not reproducible, and the reasons for including certain articles but not others cannot be determined.

Item 2 – This item requires some degree of consideration since a “comprehensive” search can be difficult to assess if one does not have expertise in searching. As a general rule of thumb, a search CAN be comprehensive if it meets the following minimum criteria: (1) searches at least two

Table A-2 Criteria for Assessing the Reliability of Systematic Reviews

bibliographic databases (note: for this assessment, PubMed/MEDLINE counts as a single database), (2) uses a combination of keywords and database-specific controlled vocabulary (e.g., MeSH, EMTREE, etc.), (3) uses at least one other additional source of studies (e.g., grey literature, conference/hand searching, references of included studies, asking experts in the field, government databases, etc.), and (4) does not inappropriately restrict the search based on time, language, etc. These are important aspects to consider in the search, but just because a review has all of these in the search does not mean that it is comprehensive. For example, a review can have a search strategy that uses keywords and controlled vocabulary that is poorly put together and does not capture all the relevant articles. An additional consideration is the number of records that are retrieved in the search. If the systematic reviewers are searching for multiple databases and only find less than a couple hundred records for title abstract screening, it is suspicious, and most likely the search is not comprehensive. Without a comprehensive search, a systematic review cannot make the basic claim that it has synthesized “all” the available evidence for a clinical question.

Item 3 – This item is also a simple “Yes” or “No” based on what the reviewers have reported about their methodology. It can be reported in the paper itself or in the registration or protocol. Systematic reviewers can use any method to assess the quality or risk of bias of the included studies; there are many different tools for the same study designs and many different study designs. This is critical for systematic reviews since a qualitative synthesis requires consideration of the respective qualities of the studies. If a study includes studies of different designs and different qualities but gives them all equal weight in informing conclusions, the overall conclusions will not be appropriate.

Item 4 – This item also needs some statistical and epidemiological consideration. If there is no meta-analysis, then it does not apply, and a review must meet the other four criteria to be considered reliable. If there is a meta-analysis, then the methodologist assessing reliability needs to consider the following:

• Is it fair to combine the studies given the clinical/methodological/statistical heterogeneity? THIS SHOULD BE “YES”: if they should not have combined them, then the analysis is inappropriate.
• Did they combine studies of different designs? THIS SHOULD BE “NO”: if they combined randomized controlled trials and observational designs (e.g., non-randomized trials, cohort studies, etc.), then the analysis is inappropriate UNLESS they did an individual participant data meta-analysis.
• Did they include any study arms in the analyses that were inappropriate (e.g., multiple intervention arms from the same trial with the same control arm in each comparison, so that the control subjects are double counted in a single analysis)? THIS SHOULD BE “NO”: if they have inappropriate arms in the analysis, it is inappropriate. NOTE: For this project, given that the overall objective is a scoping review of associations, most reviews will include multiple different study designs in meta-analyses for estimating prevalence and proportions. Where these analyses would typically be considered inappropriate in the context of clinical care and intervention reviews (e.g., meta-analyzing measures of association such as risk ratios and odds ratios), more lenient criteria were applied so that any meta-analyses that combined different study designs for proportions were accepted.

Item 5 – This item requires some consideration in terms of the review’s results and main conclusions/recommendations. The main consideration for this item is to check for any spinning of the results or any extrapolation that one thinks is inappropriate. For example, if the review did not assess harms

but the authors concluded that the intervention was “safe” or “well tolerated” or did not have any harms, that is inappropriate. Similarly, if there were meta-analyses or the majority of studies were finding no difference in effects for the intervention, but the reviewers concluded that there was evidence the intervention was effective or made any strong recommendations based on weak evidence, that was inappropriate. This is the one criterion that requires the most judgement on behalf of the assessor. Methodologists should make their best judgement in terms of whether they would make the same conclusion given the evidence that is presented in the review.

Scoping Review Data Extraction

Data were extracted from the reliable systematic reviews with one PICO Portal methodologist, and the data were verified by a second methodologist. Changes were checked by the verifier with a senior methodologist (PICO Portal and National Academies staff) during data cleaning to ensure accuracy and completeness of the data. Because of the study’s shortened timeline, this single extraction with verification was a revised approach from the originally intended double-independent extraction. Data extraction variables included standard elements such as research question, year of publication of earliest and latest published articles, primary article setting, article types, total number of studies in review, total number of study participants, population, etc. Data extraction variables also included elements specific to a Long COVID definition, including acute COVID-19 confirmation methods, time since acute COVID-19 symptom onset, acute COVID-19 symptom severity, populations hospitalized with acute COVID-19, Long COVID symptom duration and severity, description of Long COVID symptoms, comorbidities, frequency and time frame of health outcomes, impacts of health outcomes on daily activities, reinfection description, etc.

Scoping Review Results and Narrative Synthesis

After searching, a total of 1,590 records were imported for consideration in the review. These records were sourced from various databases, including 596 from Embase, 302 from NLM, 686 from MEDLINE, one from the Cochrane database, and five from other sources. Before screening, 47 records were removed as duplicates (n=46) or supplemental records (n=1). During the abstract screening phase, 1,543 records were assessed for eligibility with a single reviewer, excluding 702 as not relevant and an additional one as a duplicate. All 840 reports included at full-text screening were retrieved and screened, with priority given to those tagged as systematic reviews and/or meta-analyses. All full-text records were screened in duplicate with PICO Portal methodologists, and discrepancies were

resolved by National Academies Staff. Of these 840, 601 reports were excluded for various reasons: 575 were not systematic reviews, 28 did not include a population with Long COVID, 75 were excluded for other reasons, 21 focused on treatment rather than the review topic, and 2 more were excluded as duplicates. After the full-text review, 239 reports were deemed eligible and were included for reliability assessment. During reliability assessment/data extraction, one more article was removed because the scope did not fall within the question, and three more duplicates were identified (pre-prints for which the final publications were also included).

The reliability was of all 235 records was assessed according to five criteria, and 116 were judged to be reliable and continued with data extraction. The 116 included studies are listed below.

For the 119 studies deemed not reliable, 66 failed on a single criterion, 38 failed to meet two criteria, and 6 missed three criteria. The most common reason for being found not reliable was not having a risk of bias or quality assessment for the included studies (n=71), followed by not having a comprehensive search (n=65). These are also the most common reasons for unreliability in other fields and were expected for this set of reviews.

The committee reviewed the extracted data and synthesized the results narratively throughout the report where appropriate.

Included Reviews

1. Aiyegbusi, O. L., S. E. Hughes, G. Turner, S. C. Rivera, C. McMullan, J. S. Chandan, S. Haroon, G. Price, E. H. Davies, K. Nirantharakumar, E. Sapey, and M. J. Calvert. 2021. Symptoms, complications and management of long COVID: a review. Journal of the Royal Society of Medicine 114(9):428-442.
2. Akbari, A., A. Hadizadeh, M. Islampanah, E. Salavati Nik, S. L. Atkin, and A. Sahebkar. 2023. COVID-19, G protein-coupled receptor, and renin-angiotensin system autoantibodies: Systematic review and meta-analysis. Autoimmunity Reviews 22(9):103402.
3. Alkodaymi, M. S., O. A. Omrani, N. A. Fawzy, B. A. Shaar, R. Almamlouk, M. Riaz, M. Obeidat, Y, Obeidat, D. Gerberi, R. M. Taha, Z. Kashour, T. Kashour, E. F. Berbari, K. Alkattan, and I. M. Tleyjeh. 2022. Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: A systematic review and meta-analysis. Clinical Microbiology and Infection 28(5):657–666.
4. Almas, T., J. Malik, A. K. Alsubai, S. M. Jawad Zaidi, R. Iqbal, K. Khan, M. Ali, U. Ishaq, M. Alsufyani, S. Hadeed, R. Alsufyani, R. Ahmed, T. Thakur, H. Huang, M. Antony, I. Antony, A. Bhullar, F. Kotait, and L. Al-Ani. 2022. Post-acute COVID-19 syndrome and its prolonged effects: An updated systematic review. Annals of Medicine and Surgery 80:103995.
5. Ashton, R. E., B. E. Philips, and M. Faghy. 2023. The acute and chronic implications of the COVID-19 virus on the cardiovascular system in adults: A systematic review. Progress in Cardiovascular Diseases 76:31–37.

6. Badenoch, J. B., E. R. Rengasamy, C. Watson, K. Jansen, S. Chakraborty, R. D. Sundaram, D. Hafeez, E. Burchill, A. Saini, L. Thomas, B. Cross, C. K. Hunt, I. Conti, S. Ralovska, Z. Hussain, M. Butler, T. A. Pollak, I. Koychev, B. D. Michael, H. Holling, T. R. Nicholson, J. P. Rogers, and A G. Rooney. 2022. Persistent neuropsychiatric symptoms after COVID-19: A systematic review and meta-analysis. Brain Communications 4(1):fcab297.
7. Banerjee, M., R. Pal, and S. Dutta, S. 2022. Risk of incident diabetes post-COVID-19: A systematic review and meta-analysis. Primary Care Diabetes 16(4):591–593. https://doi.org/10.1016/j.pcd.2022.05.009.
8. Behnood, S. A., R. Shafran, S. D. Bennett, A. X. D. Zhang, L. L. O’Mahoney, T. J. Stephenson, S. N. Ladhani, B. L. De Stavola, R. M. Viner, and Swann, O. V. 2022. Persistent symptoms following SARS-CoV-2 infection amongst children and young people: A meta-analysis of controlled and uncontrolled studies. Journal of Infection 84(2):158–170.
9. Bertuccelli, M., L. Ciringione, M. Rubega, P. Bisiacchi, S. Masiero, and A. Del Felice. 2022. Cognitive impairment in people with previous COVID-19 infection: A scoping review. Cortex 154:212–230.
10. Bocchino, M., G. Rea, L Capitelli, R. Lieto, and D. Bruzzese. 2023. Chest CT lung abnormalities 1 year after COVID-19: A systematic review and meta-analysis. Radiology 308(1):e230535.
11. Bourmistrova, N. W., T. Solomon, P. Braude, R. Strawbridge, and B. Carter. 2022. Long-term effects of COVID-19 on mental health: A systematic review. Journal of Affective Disorders 299:118–125.
12. Cabrera Martimbianco, A. L., R. L. Pacheco, A. M. Bagattini, and R. Riera, R. 2021. Frequency, signs and symptoms, and criteria adopted for long COVID-19: A systematic review. International Journal of Clinical Practice 75(10):e14357.
13. Cares-Marambio, K., Y. Montenegro-Jiménez, R. Torres-Castro, R. Vera-Uribe, Y. Torralba, X. Alsina-Restoy, L. Vasconcello-Castillo, and J. Vilaró. 2021. Prevalence of potential respiratory symptoms in survivors of hospital admission after coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. Chronic Respiratory Disease 18:14799731211002240.
14. Ceban, F., S. Ling, L. M. W. Lui, Y. Lee, H. Gill, K. M. Teopiz, N. B. Rodrigues, M. Subramaniapillai, J. D. Di Vincenzo, B. Cao, K. Lin, R. B. Mansur, R. C. Ho, J. D. Rosenblat, K. W. Miskowiak, M. Vinberg, V. Maletic, and R. S. McIntyre. 2022. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain, Behavior, and Immunity 101:93–135.
15. Chen, C., S. R. Haupert, L. Zimmermann, X. Shi, L. G. Fritsche, and B. Mukherjee. 2021. Global prevalence of post-acute sequelae of COVID-19 (PASC) or long COVID: A meta-analysis and systematic review. medRxiv. https://doi.org/10.1101/2021.11.15.21266377.
16. Chinvararak, C., and T. Chalder. 2023. Prevalence of sleep disturbances in patients with long COVID assessed by standardised questionnaires and diagnostic criteria: A systematic review and meta-analysis. Journal of Psychosomatic Research 175:111535.
17. Choudhury, A., R. Tariq, A. Jena, E. K. Vesely, S. Singh, S. Khanna, and V. Sharma. 2022. Gastrointestinal manifestations of long COVID: A systematic review and meta-analysis. Therapeutic Advances in Gastroenterology Aug 19:15:17562848221118403.
18. Ciaffi, J., E. Vanni, L. Mancarella, V. Brusi, L. Lisi, F. Pignatti, S. Naldi, E. Assirelli, S. Neri, M. Reta, C. Faldini, and F. Ursini. 2023. Post-acute COVID-19 joint pain and new onset of rheumatic musculoskeletal diseases: A systematic review. Diagnostics 13(1):1850.

19. de Oliveira Almeida, K., I. G. Nogueira Alves, R. S. de Queiroz, M. R. de Castro, V. A. Gomes, F. C. Santos Fontoura, C. Brites, and M. G. Neto. 2023. A systematic review on physical function, activities of daily living and health-related quality of life in COVID-19 survivors. Chronic Illness 19(2):279–303.
20. Di Gennaro, F., A. Belati, O. Tulone, L. Diella, D. Fiore Bavaro, R. Bonica, V. Genna, L. Smith, M Trott, O. Bruyere, L. Mirarchi, C. Cusumano, L. J. Dominguez, A. Saracino, N. Veronese, and M. Barbagallo. 2022. Incidence of long COVID-19 in people with previous SARS-Cov2 infection: A systematic review and meta-analysis of 120,970 patients. Internal and Emergency Medicine 18(5):1573-1581.
21. Di Stefano, G., P. Falco, E. Galosi, G. Di Pietro, C. Leone, and A. Truini. 2023. A systematic review and meta-analysis of neuropathic pain associated with coronavirus disease 2019. European Journal of Pain (United Kingdom) 27(1):44–53.
22. Dirican, E., and T. Bal. 2022. COVID-19 disease severity to predict persistent symptoms: A systematic review and meta-analysis. Primary Health Care Research & Development 23:e69.
23. Du, M., Y. Ma, J. Deng, M. Liu, and J. Liu. 2022. Comparison of long COVID-19 caused by different SARS-CoV-2 strains: A systematic review and meta-analysis. International Journal of Environmental Research and Public Health 19(2):16010.
24. Durstenfeld, M. S., K. Sun, P. Tahir, M. J. Peluso, S. G. Deeks, M. A. Aras, D. J. Grandis, C. S. Long, A. Beatty, and P. Y. Hsue. 2022. Use of cardiopulmonary exercise testing to evaluate long COVID-19 symptoms in adults: A systematic review and meta-analysis. JAMA Network Open 5(1):e2236057.
25. Espin, E., C. Yang, C. P. Shannon, S. Assadian, D. He, and S. J. Tebbutt. 2023. Cellular and molecular biomarkers of long COVID: a scoping review. EBioMedicine 91:104552.
26. Espinoza, C., and D. Martella. 2023. Cognitive functions in COVID-19 survivors, approaches strategies, and impact on health systems: A qualitative systematic review. European Archives of Psychiatry and Clinical Neuroscience. https://doi.org/10.1007/s00406-023-01662-2 [Epub ahead of print].
27. Fernández-de-las-Peñas, C., M. Navarro-Santana, V. Gomez-Mayordomo, M. L. Cuadrado, D. Garcia-Azorin, L. Arendt-Nielsen, and G. Plaza-Manzano. 2021. Headache as an acute and post-COVID-19 symptom in COVID-19 survivors: A meta-analysis of the current literature. European Journal of Neurology 28(1):3820–3825.
28. Fernández-de-las-Peñas, C., D. Palacios-Cena, V. Gomez-Mayordomo, L. L. Florencio, M. L. Cuadrado, G. Plaza-Manzano, and M. Navarro-Santana. 2021. Prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: A systematic review and meta-analysis. European Journal of Internal Medicine 92:55–70.
29. Figueiredo, E. A. B., W. T. Silva, S. P. Tsopanoglou, D. F. M. Vitorino, L. F. L. Oliveira, K. L. S. Silva, H. D. H. Luz, M. R. Ávila, L. F. F. Oliveira, A. C. R. Lacerda, V. A. Mendonça, V. P. Lima, M. F. F. Mediano, P. H. S. Figueiredo, M. O. C. Rocha, and H. S. Costa. 2022. The health-related quality of life in patients with post-COVID-19 after hospitalization: A systematic review. Revista da Sociedade Brasileira de Medicina Tropical 55:e0741.
30. Franco, J. V. A., L. I. Garegnani, G. V. Oltra, M.-I. Metzendorf, L. F. Trivisonno, N. Sgarbossa, D. Ducks, K. Heldt, R. Mumm, B. Barnes, and C. Scheidt-Nave. 2022. Short and long-term wellbeing of children following SARS-CoV-2 infection: A systematic review. International Journal of Environmental Research and Public Health 19(2):14392.
31. Franco, J. V. A., L. I. Garegnani, G. V. Oltra, M. I. Metzendorf, L. F. Trivisonno, N. Sgarbossa, D. Ducks, K. Heldt, R. Mumm, B. Barnes, and C. Scheidt-Nave. 2022. Long-term health symptoms and sequelae following SARS-CoV-2 infection: An evidence map. International Journal of Environmental Research and Public Health 19(1):9915.

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PUBLIC AGENDAS

The committee held eight committee meetings from March 2023 to February 2024, and portions of four meetings were open to the public. Furthermore, the committee held a 2-day public symposium in June 2023. The agendas for these public sessions are included in this appendix.

1. The committee’s first meeting in March 2023 included a public session where the sponsors of the study provided their perspectives on the charge to the committee.
2. The committee’s second meeting in April 2023 included a public session where colleagues from the National Institutes of Health (NIH) and Centers for Disease Control and Prevention (CDC) provided additional background information and context for the study.

3. The May 2023 meeting included a public session where the committee heard from additional federal colleagues on ongoing efforts related to Long COVID and from researchers, practitioners, and patients about defining Long COVID.
4. Supplementing the evidence-building activities and the implementation of the engagement strategy, the committee convened a 2-day symposium in June 2023 to discuss potential considerations for refined Long COVID definitions and terminology, and for harmonizing efforts for patient engagement, clinical care, research, and surveillance across the federal government and relevant stakeholders. The committee heard from dozens of experts and examined the evidence supporting different elements of a Long COVID definition. The committee also explored emerging evidence, gaps, and key considerations for updating and modifying the definition in the future and considered how the definition might need to be adapted for different purposes, including but not limited to clinical research, epidemiologic and surveillance, policy, and advocacy and education.
5. The January 2024 meeting included a public session where the committee engaged with additional experts to learn about relevant research and implementation considerations.

MEETING 1 AGENDA

Friday, March 31, 2023

Purpose

• Hold an open session to hear from sponsoring agencies on their perspectives of the statement of task.

OPEN SESSION

Sponsor Briefing: Discussion of the Committee’s Charge

MEETING 2 AGENDA

Friday, April 14, 2023

Purpose

• Hold an open session to hear from federal agencies on ongoing efforts to define Long COVID.

OPEN SESSION

MEETING 3 AGENDA

Friday, May 12, 2023

Purpose

• Hold an open session to hear from federal, state, and local agencies on ongoing efforts on Long COVID.
• Hear perspectives from researchers, practitioners, and patients about defining Long COVID.

OPEN SESSION

SESSION Information Gathering to Inform Effort to Define Long COVID

PUBLIC SYMPOSIUM AGENDA (DAY 1)

Thursday, June 22, 2023

Purpose

• Discuss the approaches employed by the committee to solicit broad feedback about the U.S. government working definition for Long COVID.
• Examine the evidence supporting different elements of a Long COVID definition.
• Based on the evidence and stakeholder input, discuss the necessary elements of a definition for Long COVID.
• Explore emerging evidence, gaps, and key considerations for updating and modifying the definition in the future.
• Understand industry and payer perspectives on the definition for Long COVID, and consider how the definition might need to be adapted for different purposes, including but not limited to clinical research, epidemiologic and surveillance, policy, and advocacy and education.

SESSION I DAY 1 OPENING SESSION

SESSION II PLENARY SESSION: LESSONS LEARNED FROM INFECTION-ASSOCIATED CHRONIC CONDITIONS

SESSION III IMPACTS OF LONG COVID ON OVERALL WELL-BEING

SESSION IV RESEARCH ON THE CLINICAL MANIFESTATIONS, EPIDEMIOLOGIC CHARACTERISTICS, AND UNDERLYING MECHANISMS OF LONG COVID

SESSION V DAY 1 CLOSING REMARKS

PUBLIC SYMPOSIUM AGENDA (DAY 2)

Friday, June 23, 2023

SESSION VI WELCOME TO DAY 2

SESSION VII LESS STUDIED LONG COVID SYMPTOMS AND EVIDENCE GAPS

SESSION VIII MULTI-SECTORAL PERSPECTIVE ON THE DEFINTION FOR LONG COVID

SESSION IX DAY 2 CLOSING REMARKS

MEETING 7 AGENDA

Thursday, January 18, 2024

Purpose

• Hear from experts about additional perspectives on defining Long COVID and implementation considerations for Long COVID definitions.

SESSION I WELCOME AND INTRODUCTIONS