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      Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

      research-article
      , M.D., , M.D., , M.D., , M.S., , , , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , Ph.D., , Ph.D., , , M.D., , B.I.T., , , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.S., , M.D., , M.D., , M.D., , M.S., , M.D., , , , , , , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , Ph.D., , M.D., , Ph.D., , M.D. *
      The New England Journal of Medicine
      Massachusetts Medical Society
      Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_6Keyword part (keyword): Viral Infections , 18, Infectious Disease, Keyword part (code): 18_6Keyword part (keyword): Viral Infections, 18_6, Viral Infections

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          Abstract

          Background

          Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness.

          Methods

          We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible.

          Results

          A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed.

          Conclusions

          Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163.)

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          Most cited references17

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          Is Open Access

          OpenSAFELY: factors associated with COVID-19 death in 17 million patients

          COVID-19 has rapidly impacted on mortality worldwide. 1 There is unprecedented urgency to understand who is most at risk of severe outcomes, requiring new approaches for timely analysis of large datasets. Working on behalf of NHS England we created OpenSAFELY: a secure health analytics platform covering 40% of all patients in England, holding patient data within the existing data centre of a major primary care electronic health records vendor. Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19 related deaths. COVID-19 related death was associated with: being male (hazard ratio 1.59, 95%CI 1.53-1.65); older age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions. Compared to people with white ethnicity, black and South Asian people were at higher risk even after adjustment for other factors (HR 1.48, 1.29-1.69 and 1.45, 1.32-1.58 respectively). We have quantified a range of clinical risk factors for COVID-19 related death in the largest cohort study conducted by any country to date. OpenSAFELY is rapidly adding further patients’ records; we will update and extend results regularly.
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            A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

            Abstract Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao 2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao 2) to the fraction of inspired oxygen (Fio 2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. Results A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir–ritonavir group, and 100 to the standard-care group. Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir–ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. Conclusions In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.)
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              • Article: not found

              Efficacy of Tocilizumab in Patients Hospitalized with Covid-19

              Abstract Background The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. Methods We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. Results We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P=0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P=0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P=0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. Conclusions Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.)
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                Author and article information

                Journal
                N Engl J Med
                N Engl J Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                06 January 2021
                : NEJMoa2033700
                Affiliations
                From Fundación INFANT (R. Libster, S.C., A.B., I.E., M.T.C., C.W., D.A.P., S.E., A.F., G.O., S.S.A., C.S.Y., J.D.L., S.J.B., S.L., F.N., F.P.P.), iTrials (R. Libster, G.P.M., D.W., S.C., A.B., V.B., S.S.A., F.P.P.), Swiss Medical Group (D.W., J.L., F.E., J.M.), National Scientific and Technical Research Council (M.T.C., D.A.P., S.E.), Hospital Dr. Carlos Bocalandro (A.R., G. Lescano), Centro Gallego (P.C.), Instituto de Efectividad Clínica y Sanitaria (M.B., A.C., R.R., L.G., E.B.), Hospital Simplemente Evita (V.F.V.), CEMIC (R.V.), Fundación Hematológica Sarmiento (F. Alvez), Hospital Municipal San Isidro, (R. Larrea), Sanatorio Anchorena Recoleta (M.S.), Sanatorio Sagrado Corazón, Obra Social de los Empleados de Comercio y Actividades Civiles (G. Leberzstein), Ministerio de Salud de la Provincia de Buenos Aires (A.D., N.K.), Sanatorio Finochietto (M.G.), Programa de Atención Médica Integral (E.P.), Hospital Militar Central (G.P.M., V.B., C.W., N.I., A.H., M.L.O., C.E., A.N., I.N., J.A., R.L.C., G.C., S.R., F.D., D.A., S.P.A.), and Hospital San Juan de Dios (Y.R.) — all in Buenos Aires; the University of Oklahoma, Norman (G.O.); and the United Nations Development Program–United Nations Population Fund–United Nations Children’s Fund–World Health Organization–World Bank Special Program of Research, Development, and Research Training in Human Reproduction, Department of Sexual and Reproductive Health and Research, World Health Organization, Geneva (F. Althabe).
                Author notes
                Address reprint requests to Dr. Polack at Fundación INFANT, Gavilan 94, Buenos Aires (1406), Argentina, or at fpolack@ 123456infant.org.ar .
                [*]

                The Fundación INFANT–COVID-19 Group members are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org.

                Drs. Libster and Pérez Marc contributed equally to this article.

                Article
                NJ202101063840704
                10.1056/NEJMoa2033700
                7793608
                33406353
                28b552f2-e52c-45e4-a610-69e14edd7740
                Copyright © 2021 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

                History
                Funding
                Funded by: Bill and Melinda Gates Foundation, FundRef http://dx.doi.org/10.13039/100000865;
                Funded by: The Fundacion INFANT Pandemic Fund, FundRef ;
                Categories
                Original Article
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                2021-01-06T17:00:00-05:00
                2021
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                06
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