key: cord-254817-e1niin4m authors: Solomon, Daniel H.; Bucala, Richard; Kaplan, Mariana J.; Nigrovic, Peter A. title: The “Infodemic” of COVID‐19 date: 2020-08-02 journal: Arthritis Rheumatol DOI: 10.1002/art.41468 sha: doc_id: 254817 cord_uid: e1niin4m Some in the medical publishing world have observed an “infodemic” occurring alongside the pandemic. One might define an infodemic as a contagious disease infecting our information culture. As the Editors of A&R, tasked with conducting, reviewing, reporting, and translating science to the rheumatic disease community, we agree with this diagnosis. Herein, we reflect on how the pandemic has impacted A&R, the medical publishing world, and how we may best engage our community to navigate current challenges. This article is protected by copyright. All rights reserved Some in the medical publishing world have observed an "infodemic" occurring alongside the pandemic. One might define an infodemic as a contagious disease infecting our information culture. As the Editors of A&R, tasked with conducting, reviewing, reporting, and translating science to the rheumatic disease community, we agree with this diagnosis. Herein, we reflect on how the pandemic has impacted A&R, the medical publishing world, and how we may best engage our community to navigate current challenges. Two "front page" rheumatology examples and how their stories progressed demonstrate the infodemic: hydroxychloroquine and the cytokine storm. Hydroxychloroquine, a drug that has both anti-microbial and immunomodulatory properties, was widely touted as a cure or preventative treatment for COVID-19. As rheumatologists know too well, the resulting demand for hydroxychloroquine squeezed supply, impacting our patients who have benefitted from the drug for decades. The rationale behind the hydroxychloroquine excitement was limited to in vitro activity against SARS-CoV-2, together with a small uncontrolled study (1, 2) . When people are dying, doctors need to act upon the best data available, even when those data are weak. Small case series led to larger observational studies, with comparator patients who did not receive hydroxychloroquine (3) . Randomized controlled trials (RCTs) were begun to put the hypotheses to the test. However, as the observational studies grew in size and rigor, the results became less encouraging (4); not surprisingly, RCT results matched the negative observational studies (5). The cytokine storm remains a more complex story. Infection with any pathogen elicits an immune response, sometimes resulting in more harm than good. The "storm" metaphor is appropriate when inflammation becomes self-sustaining, driven primarily by cytokines and other immune signals rather than by the original trigger. Many reviews examined whether severe COVID-19 represented a vicious circle of this kind, including one in the pages of A&R that explicitly highlighted both what we know and what we don't (6) . Immunosuppression helps some patients with COVID-19, as shown most clearly by the RECOVERY trial that found dexamethasone to reduce mortality in patients This article is protected by copyright. All rights reserved requiring respiratory support (7) . Blockade of the cytokines IL-6 and IL-1 has been supported at the case series level, although hydroxychloroquine illustrates the potential pitfalls of uncontrolled observational data in a disease that has a variable and unpredictable course. Multisystem Do these syndromes reflect cytokine storm? Many distinct conditions fall under this umbrella term (6) . At the core of most cytokine storms is a macrophage-lymphocyte amplification loop, wherein activated macrophages stimulate lymphocytes that in turn elaborate macrophage-activating cytokines, in the absence of adequate counter-regulatory signals. Whether SARS-CoV-2 triggers such a loop remains uncertain. Elevation of ferritin, D-dimer, the interferon  marker CXCL9, and the T cell activation product soluble CD25 suggest such a possibility, but the levels observed typically do not approach those seen in more archetypical cytokine storms (8) . Further work will be required to define whether SARS-CoV-2 initiates a different kind of cytokine storm, or whether these inflammatory markers simply reflect the immune response elicited by the virus directly and through the endothelial injury it produces. Three questions raised by these examples shine a light on the infodemic: 1) Did the scientific process during this phase of the COVID-19 pandemic progress in an appropriate manner? 2) Was the science reviewed using appropriate methods? And, 3) how should the information arising from these studies be effectively managed and communicated? This article is protected by copyright. All rights reserved Few activities, including science, are best conducted as a "sprint." However, the COVID-19 pandemic killed so many people that speed was necessary. Gathering all the usual supportive databiomarkers, pharmacodynamics, safety in the target population -was compressed or neglected, albeit with the best of intentions, in the effort to re-purpose rheumatic disease drugs for COVID-19. The hydroxychloroquine and anti-cytokine scientific stories have some differences in this respect, but many similarities. Hydroxychloroquine has known effects on malaria as well as several less common pathogens. A small literature suggested that it might have activity against SARS-CoV-2, but no clinical studies had been conducted. As an approved drug with a relatively good safety profile, clinicians watching patients die of COVID-19 were understandably eager to grasp at this straw. From these early uncontrolled experiences, observational studies were conducted with mostly negative results and trials were organized (5) . The trials showed no benefit, possible risk, and most have been shut down. The cytokine storm story has yet to play out. Enthusiasm for IL-6 blockade continues, perhaps at a slightly diminished pitch because of the early closure of several trials for futility, although others remain in progress or have shown promising results (9) . Randomized studies of IL-1 blockade and other immunomodulators are in progress. Notably, there is now evidence that dexamethasone may save lives, supporting the general principle that immunosuppression could be a viable approach to severe SARS-CoV-2-related illness. In MIS-C, physicians will need to act on the basis of immunological principles together with experience gathered in the clinic. The ACR guidance recommend consideration of IVIG, corticosteroids, and in severe cases the IL-1 blocker anakinra This article is protected by copyright. All rights reserved The review of science has an orthodoxy that at first blush seems unfit for a pandemic. It is by necessity deliberate, with a role for editors, peer reviewers, discussion and revision. The key questions -is the submitted science innovative, rigorous, and well presented -take time to answer. Why should these questions and processes slow science during a pandemic? We suggest that it is for the same reason as the imperative for speed: because so many lives are at stake. Many authors of COVID-19 papers can offer how the traditional review process did not work for them. It was too slow, too picky, and may have hindered progress. All of these criticisms are fair and to some extent true. Like many journals, A&R was overwhelmed with COVID-19 submissions. Nevertheless, A&R responded, and COVID-19 papers (82 papers through July 27, 2020) have had a first decision in an average of 7 days. Our reviewers, often themselves overextended by the exigencies of COVID-19, stepped up to answer our call for quick but thorough reviews. Accepted papers have gone on-line almost immediately and free of charge. The rush to publish in the COVID era has had some unfortunate consequences. While retractions will always be a part of scientific publishing, a few high-profile retractions of COVID-19 papers (10, 11) has left the public unsure as to what to believe, reducing their confidence in the medical profession. Disputes between authors of COVID-19 papers have spilled into the lay press, allowing the public to see that human foibles affect us all. Perhaps the most difficult aspect of the infodemic is how to effectively present the peer-reviewed science to the public. A&R has a historic tradition of peer review and publishing that has served rheumatology well, but much less expertise at messaging the science to the lay public. Some might suggest that this is not the journal's role, but during the pandemic are we not all responsible for the information being put out in the media? A&R offers press releases for many of our articles, and for This article is protected by copyright. All rights reserved almost all regarding COVID-19. We will help put journalists in touch with authors. As many know, we have worked to make the science in all of the ACR journals more accessible through social media, including encouraging authors to create a video describing the science that is hosted on the journal website. We have not attempted to directly communicate with patients or the public at large. Should A&R or the ACR make public communication a greater part of our agenda? During COVID-19, communication with the public has been a major difficulty. Most of the problems have been with inconsistencies in simple messages -"wear a mask", "get tested if you display any symptoms", "do not drink chlorine bleach" (no, chlorine is not the same as hydroxychloroquine). Some of the communication problems have been with complex scientific issues: Does hydroxychloroquine work to prevent or treat COVID-19? Are NSAIDs dangerous to people with COVID-19? Should DMARDs be discontinued to prevent an infection or during a known infection? These are questions with evolving answers that have been the focus of ongoing studies. Good public health messaging without adequate data is fraught. Should the journal add to the cacophony of COVID-19 communication? A&R has stuck with the fundamentals that we do well: review, edit, and publish science. We work to make our reviewing responsive to the needs of the community, finding relevant experts who give constructive feedback in a timely manner. Editing and publishing have been appropriately sped up. However, we will continue to maintain our high standards. We have been reminded over the last few months that science is an imperfect process, but that with careful attention to accumulating data, it becomes a self-correcting one. As A&R's editorial board enters a new era, we welcome the input of our readers as we continue to work toward the benefit of the community of patients and physicians we serve. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial On the Alert for Cytokine Storm: Immunopathology in COVID-19 Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report Clinical and immunological features of severe and moderate coronavirus disease 2019 Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized COVID-19 Patients: Survival and Clinical Outcomes Retraction: Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19 This article is protected by copyright. All rights reserved Mehra MR, Ruschitzka F, Patel AN. Retraction-Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020;395(10240):1820.