{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T01:17:06Z","timestamp":1790471826302,"version":"4.1.0"},"reference-count":82,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T00:00:00Z","timestamp":1588118400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>There are currently no proven or approved treatments for coronavirus disease 2019 (COVID\u201019). Early anecdotal reports and limited\u00a0in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID\u201019 are treated with these agents and more evidence accumulates, there continues to be no high\u2010quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac\u00a0side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto\u2010immune conditions, and provided a component in the original rationale for their use in\u00a0patients with COVID\u201019, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID\u201019. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside\/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID\u201019, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or\u00a0detract from the use of these agents\u00a0for the treatment of COVID\u201019 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case\u2010by\u2010case basis after rigorous consideration of the risks and benefits of this therapeutic approach.<\/jats:p>","DOI":"10.1096\/fj.202000919","type":"journal-article","created":{"date-parts":[[2020,4,30]],"date-time":"2020-04-30T02:10:04Z","timestamp":1588212604000},"page":"6027-6037","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":114,"title":["Rethinking the role of hydroxychloroquine in the treatment of COVID\u201019"],"prefix":"10.1096","volume":"34","author":[{"given":"Eric A.","family":"Meyerowitz","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augustin G. L.","family":"Vannier","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) Boston MA USA"},{"name":"Vaccine and Immunotherapy Center (VIC) MGH and HMS Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan G. N.","family":"Friesen","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) Boston MA USA"},{"name":"Vaccine and Immunotherapy Center (VIC) MGH and HMS Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Schoenfeld","sequence":"additional","affiliation":[{"name":"Division of Allergy, Immunology and Rheumatology MGH and HMS Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Gelfand","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) Boston MA USA"},{"name":"Vaccine and Immunotherapy Center (VIC) MGH and HMS Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael V.","family":"Callahan","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) Boston MA USA"},{"name":"Vaccine and Immunotherapy Center (VIC) MGH and HMS Boston MA USA"},{"name":"Special Advisor to the Assistant Secretary of Public Health Preparedness and Response U.S Dept of Health and Human Services Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur Y.","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick M.","family":"Reeves","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) Boston MA USA"},{"name":"Vaccine and Immunotherapy Center (VIC) MGH and HMS Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Poznansky","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) Boston MA USA"},{"name":"Vaccine and Immunotherapy Center (VIC) MGH and HMS Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,29]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2002032"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0822-7"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30243-7"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.3201\/eid2606.200233"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.2648"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30566-3"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.7326\/M20-0504"},{"key":"e_1_2_13_9_1","article-title":"COVID\u201019 illness in native and immunosuppressed states. A clinical\u2010therapeutic staging proposal","author":"Siddiqi HK","year":"2020","journal-title":"J. Hear Lung Transplant"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.1585"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.1017"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14768"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-015-0239-y"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(03)00806-5"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-4-39"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.08.085"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-2-69"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-020518-115759"},{"key":"e_1_2_13_19_1","article-title":"SARS\u2010CoV\u20102 invades host cells via a novel route: CD147\u2010spike protein","author":"Wang K","year":"2020","journal-title":"bioRxiv"},{"key":"e_1_2_13_20_1","article-title":"Gene expression and in situ protein profiling of candidate SARS\u2010CoV\u20102 receptors in human airway epithelial cells and lung tissue","author":"Aguiar JA","year":"2020","journal-title":"bioRxiv"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2020.02.026"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0194868"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03011-14"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0282-0"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.3109\/03009747409115809"},{"key":"e_1_2_13_26_1","first-page":"6","article-title":"Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS\u2010CoV\u20102 infection in vitro","volume":"6","author":"Liu J","year":"2020","journal-title":"Cell Discov"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1989.tb03439.x"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00339-08"},{"key":"e_1_2_13_29_1","volume-title":"Plaquenil \u00ae Hydroxychloroquine Sulfate Tablets, Usp Description","author":"FDA\/CDER","year":"2017"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.10307"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.150379"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/15.3.235"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.245639"},{"key":"e_1_2_13_34_1","article-title":"Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide\u2010spread use for COVID\u201019: a multinational, network cohort and self\u2010controlled case series study","author":"Lane JCE","year":"2020","journal-title":"medRxiv"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.5582\/bst.2020.01047"},{"key":"e_1_2_13_36_1","first-page":"E019","article-title":"Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia","volume":"43","author":"Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for Chloroquine in the Treatment of Novel Coronavirus Pneumonia","year":"2020","journal-title":"Zhonghua Jie He He Hu Xi Za Zhi"},{"key":"e_1_2_13_37_1","article-title":"A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease\u201019 (COVID\u201019)","volume":"49","author":"Chen J","year":"2020","journal-title":"J Zhejiang Univ (Med Sci)"},{"key":"e_1_2_13_38_1","article-title":"Hydroxychloroquine and azithromycin as a treatment of COVID\u201019: results of an open\u2010label non\u2010randomized clinical trial","volume":"105949","author":"Gautret P","year":"2020","journal-title":"Int J Antimicrobial Agent"},{"key":"e_1_2_13_39_1","article-title":",(ISAC). Official Statement from International Society of Antimicrobial Chemotherapy (ISAC) on: Hydroxychloroquine and azithromycin as a treatment of COVID\u201019: results of an open\u2010label non\u2010randomized clinical trial (Gautret P et al. PMID 32205204)","author":"Voss A","year":"2020","journal-title":"Statement IJAA Pap"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmaid.2020.101663"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.medmal.2020.03.006"},{"key":"e_1_2_13_42_1","article-title":"Efficacy of hydroxychloroquine in patients with COVID\u201019: results of a randomized clinical trial","author":"Chen Z","year":"2020","journal-title":"medRxiv"},{"key":"e_1_2_13_43_1","first-page":"1","article-title":"No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID\u201019 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial","author":"Mahevas M","year":"2020","journal-title":"medRxiv"},{"key":"e_1_2_13_44_1","article-title":"Hydroxychloroquine in patients with COVID\u201019: an open\u2010label, randomized, controlled trial","author":"Tang W","year":"2020","journal-title":"medRxiv"},{"key":"e_1_2_13_45_1","article-title":"Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS\u2010CoV\u20102) infection: Preliminary safety results of a randomized, double\u2010blinded, phase IIb cl","author":"Borba MGS","year":"2020","journal-title":"medRxiv"},{"key":"e_1_2_13_46_1","first-page":"19","article-title":"Use of hydroxychloroquine and chloroquine during the COVID\u201019 pandemic: what every clinician should know","author":"Yazdany J","year":"2020","journal-title":"Ann Intern Med"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(11)70065-2"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kei282"},{"key":"e_1_2_13_49_1","first-page":"7","article-title":"Functional exhaustion of antiviral lymphocytes in COVID\u201019 patients","author":"Zheng M","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21072657"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0819-2"},{"key":"e_1_2_13_52_1","article-title":"COVID\u201019: immunopathology and its implications for therapy","volume":"2019","author":"Cao X","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0401-3"},{"key":"e_1_2_13_54_1","article-title":"Restoration of leukomonocyte counts is associated with viral clearance in COVID\u201019 hospitalized patients","author":"Chen X","year":"2020","journal-title":"medRxiv"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.21568"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kem076"},{"key":"e_1_2_13_57_1","first-page":"387","article-title":"The risk of hospitalized infection in patients with rheumatoid arthritis","volume":"35","author":"Smitten AL","year":"2008","journal-title":"J Rheumatol"},{"key":"e_1_2_13_58_1","doi-asserted-by":"publisher","DOI":"10.1111\/1756-185X.13725"},{"key":"e_1_2_13_59_1","article-title":"Immune responses and pathogenesis of SARS\u2010CoV\u20102 during an outbreak in Iran: comparison with SARS and MERS","author":"Rokni M","year":"2020","journal-title":"Rev Med Virol"},{"key":"e_1_2_13_60_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000240"},{"key":"e_1_2_13_61_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402793"},{"key":"e_1_2_13_62_1","article-title":"SARS\u2010CoV\u20102 sensitive to type I interferon pretreatment","author":"Lokugamage KG","year":"2020","journal-title":"bioRxiv"},{"key":"e_1_2_13_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2014.08.004"},{"key":"e_1_2_13_64_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.9.5048"},{"key":"e_1_2_13_65_1","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/art.38221","article-title":"Effectiveness of chloroquine and inflammatory cytokine response in patients with early persistent musculoskeletal pain and arthritis following chikungunya virus infection","volume":"66","author":"Chopra A","year":"2014","journal-title":"Arthritis Rheum"},{"key":"e_1_2_13_66_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.170737"},{"key":"e_1_2_13_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.04.105"},{"key":"e_1_2_13_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0372-x"},{"key":"e_1_2_13_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.06.065"},{"key":"e_1_2_13_70_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20051106"},{"key":"e_1_2_13_71_1","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00166-08"},{"key":"e_1_2_13_72_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111139"},{"key":"e_1_2_13_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02935502"},{"key":"e_1_2_13_74_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ker427"},{"key":"e_1_2_13_75_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aap8029"},{"key":"e_1_2_13_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.10.087"},{"key":"e_1_2_13_77_1","article-title":"Molecular mechanism for antibody\u2010dependent enhancement of coronavirus entry","volume":"94","author":"Wan Y","year":"2020","journal-title":"J Virol"},{"key":"e_1_2_13_78_1","doi-asserted-by":"publisher","DOI":"10.1080\/00034983.1985.11811963"},{"key":"e_1_2_13_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(83)90005-6"},{"key":"e_1_2_13_80_1","doi-asserted-by":"publisher","DOI":"10.1249\/00005768-199407000-00008"},{"key":"e_1_2_13_81_1","doi-asserted-by":"publisher","DOI":"10.1086\/513984"},{"key":"e_1_2_13_82_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-3-39"},{"key":"e_1_2_13_83_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa237"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1096%2Ffj.202000919","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202000919","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202000919","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202000919","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T23:01:55Z","timestamp":1761692515000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202000919"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,29]]},"references-count":82,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,5]]}},"alternative-id":["10.1096\/fj.202000919"],"URL":"https:\/\/doi.org\/10.1096\/fj.202000919","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,29]]},"assertion":[{"value":"2020-04-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}