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. 2023 Jun 23;18(6):e0286297.
doi: 10.1371/journal.pone.0286297. eCollection 2023.

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design

Leora I Horwitz  1 , Tanayott Thaweethai  2 , Shari B Brosnahan  3 , Mine S Cicek  4 , Megan L Fitzgerald  5 , Jason D Goldman  6 , Rachel Hess  7 , S L Hodder  8 , Vanessa L Jacoby  9 , Michael R Jordan  10 , Jerry A Krishnan  11 , Adeyinka O Laiyemo  12 , Torri D Metz  13 , Lauren Nichols  14 , Rachel E Patzer  15 , Anisha Sekar  5 , Nora G Singer  16 , Lauren E Stiles  17 , Barbara S Taylor  18 , Shifa Ahmed  2 , Heather A Algren  19 , Khamal Anglin  20 , Lisa Aponte-Soto  21 , Hassan Ashktorab  12 , Ingrid V Bassett  22 , Brahmchetna Bedi  23 , Nahid Bhadelia  24 , Christian Bime  25 , Marie-Abele C Bind  2 , Lora J Black  26 , Andra L Blomkalns  27 , Hassan Brim  28 , Mario Castro  29 , James Chan  2 , Alexander W Charney  30 , Benjamin K Chen  31 , Li Qing Chen  32 , Peter Chen  33 , David Chestek  34 , Lori B Chibnik  35 , Dominic C Chow  36 , Helen Y Chu  37 , Rebecca G Clifton  38 , Shelby Collins  23 , Maged M Costantine  39 , Sushma K Cribbs  23 , Steven G Deeks  40 , John D Dickinson  41 , Sarah E Donohue  42 , Matthew S Durstenfeld  43 , Ivette F Emery  44 , Kristine M Erlandson  45 , Julio C Facelli  46 , Rachael Farah-Abraham  47 , Aloke V Finn  48 , Melinda S Fischer  18 , Valerie J Flaherman  49 , Judes Fleurimont  50 , Vivian Fonseca  51 , Emily J Gallagher  52 , Jennifer C Gander  53 , Maria Laura Gennaro  54 , Kelly S Gibson  55 , Minjoung Go  56 , Steven N Goodman  57 , Joey P Granger  58 , Frank L Greenway  59 , John W Hafner  60 , Jenny E Han  61 , Michelle S Harkins  62 , Kristine S P Hauser  63 , James R Heath  64 , Carla R Hernandez  65 , On Ho  66 , Matthew K Hoffman  67 , Susan E Hoover  26 , Carol R Horowitz  68 , Harvey Hsu  69 , Priscilla Y Hsue  40 , Brenna L Hughes  70 , Prasanna Jagannathan  56 , Judith A James  71 , Janice John  72 , Sarah Jolley  73 , S E Judd  74 , Joy J Juskowich  75 , Diane G Kanjilal  76 , Elizabeth W Karlson  77 , Stuart D Katz  78 , J Daniel Kelly  40 , Sara W Kelly  79 , Arthur Y Kim  76 , John P Kirwan  80 , Kenneth S Knox  69 , Andre Kumar  56 , Michelle F Lamendola-Essel  78 , Margaret Lanca  81 , Joyce K Lee-Lannotti  82 , R Craig Lefebvre  83 , Bruce D Levy  84 , Janet Y Lin  34 , Brian P Logarbo Jr  85 , Jennifer K Logue  86 , Michele T Longo  87 , Carlos A Luciano  88 , Karen Lutrick  89 , Shahdi K Malakooti  90 , Gail Mallett  91 , Gabrielle Maranga  1 , Jai G Marathe  92 , Vincent C Marconi  93 , Gailen D Marshall  94 , Christopher F Martin  47 , Jeffrey N Martin  95 , Heidi T May  96 , Grace A McComsey  97 , Dylan McDonald  37 , Hector Mendez-Figueroa  98 , Lucio Miele  99 , Murray A Mittleman  100 , Sindhu Mohandas  101 , Christian Mouchati  90 , Janet M Mullington  102 , Girish N Nadkarni  103 , Erica R Nahin  78 , Robert B Neuman  104 , Lisa T Newman  105 , Amber Nguyen  2 , Janko Z Nikolich  106 , Igho Ofotokun  47 , Princess U Ogbogu  107 , Anna Palatnik  108 , Kristy T S Palomares  109 , Tanyalak Parimon  33 , Samuel Parry  110 , Sairam Parthasarathy  25 , Thomas F Patterson  111 , Ann Pearman  90 , Michael J Peluso  112 , Priscilla Pemu  113 , Christian M Pettker  114 , Beth A Plunkett  115 , Kristen Pogreba-Brown  116 , Athena Poppas  117 , J Zachary Porterfield  118 , John G Quigley  119 , Davin K Quinn  120 , Hengameh Raissy  121 , Candida J Rebello  122 , Uma M Reddy  123 , Rebecca Reece  75 , Harrison T Reeder  2 , Franz P Rischard  124 , Johana M Rosas  78 , Clifford J Rosen  44 , Nadine G Rouphael  23 , Dwight J Rouse  125 , Adam M Ruff  29 , Christina Saint Jean  1 , Grecio J Sandoval  38 , Jorge L Santana  126 , Shannon M Schlater  127 , Frank C Sciurba  128 , Caitlin Selvaggi  2 , Sudha Seshadri  129 , Howard D Sesso  130 , Dimpy P Shah  131 , Eyal Shemesh  132 , Zaki A Sherif  133 , Daniel J Shinnick  2 , Hyagriv N Simhan  134 , Upinder Singh  135 , Amber Sowles  13 , Vignesh Subbian  136 , Jun Sun  11 , Mehul S Suthar  137 , Larissa J Teunis  138 , John M Thorp Jr  139 , Amberly Ticotsky  72 , Alan T N Tita  140 , Robin Tragus  141 , Katherine R Tuttle  142 , Alfredo E Urdaneta  27 , P J Utz  135 , Timothy M VanWagoner  143 , Andrew Vasey  41 , Suzanne D Vernon  144 , Crystal Vidal  1 , Tiffany Walker  23 , Honorine D Ward  145 , David E Warren  146 , Ryan M Weeks  147 , Steven J Weiner  38 , Jordan C Weyer  148 , Jennifer L Wheeler  148 , Sidney W Whiteheart  149 , Zanthia Wiley  47 , Natasha J Williams  150 , Juan P Wisnivesky  103 , John C Wood  151 , Lynn M Yee  152 , Natalie M Young  19 , Sokratis N Zisis  97 , Andrea S Foulkes  2
Affiliations

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design

Leora I Horwitz et al. PLoS One. .

Abstract

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.

Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.

Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.

Registration: NCT05172024.

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: Helen Chu reported consulting for Merck, GSK, Pfizer, Ellume, Janssen, Vindico CME, and the Bill and Melinda Gates Foundation, and receiving research support from Gates Ventures, Ellume, and Sanofi Pasteur. She also serves as a co-investigator on studies funded by Pfizer, Novavax, and GSK. Maged Costantine reported receiving grant support for work not related to RECOVER work/publications from Baxter International and Siemens Healthcare and personal consulting fees not related to this paper from Progenity, Quidel Ortho, and Siemens Healthcare. Kristine Erlandson reported research funding from Gilead Sciences and consulting payments from Gilead Sciences, Merck, and ViiV Pharmaceuticals, all paid to the University of Colorado. Emily Gallagher reported consulting for Novartis, Flare Therapeutics and Seagen. Edward Gardner reported research support (clinical trials) from Gilead Sciences, ViiV Healthcare, and Cepheid. Jason Goldman reported research support from Gilead, Eli Lilly and Regeneron; grants from Gilead, Merck (BARDA); personal fees for consulting from Gilead, Eli Lilly; and non-financial support from Adaptive Biotechnologies and Labcorp/Monogram Biosciences outside the submitted work. Timothy Heinrich reported grant support from Merck Inc. and consulting fees from Roche. Rachel Hess reported serving as Data Safety Monitoring Board member for Astellas Pharmaceuticals unrelated to the current work. Leora Horwitz reported being a member of the National Academy of Medicine Committee on the Long-Term Health Effects Stemming from COVID-19 and Implications for the Social Security Administration. Priscilla Hsue reported receiving honoraria from Gilead and Merck unrelated to study topic, receiving study drug from Regeneron unrelated to study topic, and receiving a research grant from Novartis. Judith James reported OMRF has licensed her IP to Progentec Biosciences, has received grant support from Progentec Biosciences, and serves on Advisory Committees to Glaxo Smith Klein, Merck and Novartis. Arthur Kim reports providing educational materials to Clinical Care Options and UpToDate and serving on a Data Safety Monitoring board for Kintor Pharmaceuticals, Ltd. Bruce Levy reported serving as a consultant for AstraZeneca, Entrinsic Biosciences, Gossamer Bio and Nocion Therapeutics and receiving research support from Amgen, Genentech, GlaxoSmithKline, Pieris Pharmaceuticals, SRA and Sanofi unrelated to the current work. Vincent Marconi reported receiving grants from NIH during the conduct of the study and grants from NIH, Veteran Affairs, and Centers for Disease Control and Prevention; grants, personal fees, nonfinancial support, and other from Lilly and Gilead; grants and personal fees from ViiV; and nonfinancial support from Bayer outside the submitted work. Grace McComsey reported serving as consultant for Merck, Gilead, ViiV, Janssen and have received research support from Pfizer, Vanda, Genentech, Roche, Redhill and Cognivue. Torri Metz reported being a site PI and a participant in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She also reported being a site PI for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Janet Mullington reported support for investigator-initiated research by "Open Medicine Foundation and the Patient-Led Research Collaborative" Princess Ogbogu reported research support from Astrazeneca, GSK, Blueprint medical; advisory board for Astrazeneca, GSK, Sanofi, Kalvista; and consulting for Astrazeneca, GSK Sairam Parthasarathy reported research funding to Institution from Sergey Brin foundation of COVID and Long-COVID research. Michael Peluso reported consulting fees from Gilead Sciences and AstraZeneca, and service on data safety monitoring board for American Gene Technologies. Sean Quigley reported service on speaker Board for Servier, Alnylam, Agios; service on advisory board for Recordati, Alexion. Franz Rischard reported research support from NIH/NHLBI, United Therapeutics, Acceleron/Merck, Janssen, Insmed, Aerovate, and Bayer; and consulting/advisory compensation from Acceleron and Bayer. Nadine Rouphael reported being a consultant for ICON and EMMES as a safety consultant for clinical trials; service on the advisory boards for Moderna; funds to institution from Sanofi, Lilly, Merck, Quidel and Pfizer. PJ Utz reported stock ownership of Gilead and PI of biomarker studies for Pfizer STOP-PASC paxlovid trial Juan Wisnivesky received receiving consulting honorarium from Sanofi, Banook, Prospero, PPD and Atea and research grants from Sanofi, Regeneron, Axella, and Arnold Consultants.

Figures

Fig 1
Fig 1. Schedule of assessments.
See this image and copyright information in PMC

Update of

  • Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.
    Gross R, Thaweethai T, Rosenzweig EB, Chan J, Chibnik LB, Cicek MS, Elliott AJ, Flaherman VJ, Foulkes AS, Witvliet MG, Gallagher R, Gennaro ML, Jernigan TL, Karlson EW, Katz SD, Kinser PA, Kleinman LC, Lamendola-Essel MF, Milner JD, Mohandas S, Mudumbi PC, Newburger JW, Rhee KE, Salisbury AL, Snowden JN, Stein CR, Stockwell MS, Tantisira KG, Thomason ME, Truong DT, Warburton D, Wood JC, Ahmed S, Akerlundh A, Alshawabkeh AN, Anderson BR, Aschner JL, Atz AM, Aupperle RL, Baker FC, Balaraman V, Banerjee D, Barch DM, Baskin-Sommers A, Bhuiyan S, Bind MC, Bogie AL, Buchbinder NC, Bueler E, Bükülmez H, Casey BJ, Chang L, Clark DB, Clifton RG, Clouser KN, Cottrell L, Cowan K, D'Sa V, Dapretto M, Dasgupta S, Dehority W, Dummer KB, Elias MD, Esquenazi-Karonika S, Evans DN, Faustino EVS, Fiks AG, Forsha D, Foxe JJ, Friedman NP, Fry G, Gaur S, Gee DG, Gray KM, Harahsheh AS, Heath AC, Heitzeg MM, Hester CM, Hill S, Hobart-Porter L, Hong TKF, Horowitz CR, Hsia DS, Huentelman M, Hummel KD, Iacono WG, Irby K, Jacobus J, Jacoby VL, Jone PN, Kaelber DC, Kasmarcak TJ, Kluko MJ, Kosut JS, Laird AR, Landeo-Gutierrez J, Lang SM, Larson CL, Lim PPC, Lisdahl KM, McCrindle BW, McCulloh RJ, Mendelsohn AL,… See abstract for full author list ➔ Gross R, et al. medRxiv [Preprint]. 2023 May 12:2023.04.27.23289228. doi: 10.1101/2023.04.27.23289228. medRxiv. 2023. Update in: PLoS One. 2023 Jun 23;18(6):e0286297. doi: 10.1371/journal.pone.0286297. PMID: 37214806 Free PMC article. Updated. Preprint.

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