To the Editor In the Covid-19 Convalescent Plasma in Outpatients (C3PO) trial,1 Korley et al., members of the Strategies to Innovate Emergency Care Clinical Trials Network (SIREN), administered convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19. It is unclear why the authors selected 1 week instead of a shorter time frame, since it has been shown that the 30-day and 60-day mortality benefits of convalescent plasma have been observed when it is administered within 3 days after diagnosis and that the benefit dissipates after this point.2,3 The aim of their trial was to determine whether convalescent plasma prevents progression to severe Covid-19. However, severe Covid-19 was not defined, and the authors instead assessed disease progression, which relies on surrogate measures, including hospital admission for any reason. This is a confusing outcome for a subgroup of patients who were at high risk for disease progression and were therefore likely to require hospital admission. David Fisher, M.Sc.Stephen Malnick, M.A., M.Sc.Kaplan Medical Center, Rehovot, Israel [email protected] No potential conflict of interest relevant to this letter was reported. This letter was published on October 13, 2021, at NEJM.org.3 References1. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early convalescent plasma for high-risk outpatients with Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2103784.2. Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. August 12, 2020 (https://www.medrxiv.org/content/10.1101/2020.08.12.20169359v1). preprint.3. Salazar E, Christensen PA, Graviss EA, et al. Significantly decreased mortality in a large cohort of coronavirus disease 2019 (COVID-19) patients transfused early with convalescent plasma containing high-titer anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein IgG. Am J Pathol 2021;191:90-107.To the Editor Korley et al. reported the results of a randomized trial in which the early administration of convalescent plasma was intended to prevent disease progression in high-risk patients with Covid-19. Some limitations of the trial could have been discussed. First, the definition of “high risk” was broad, as indicated by the low 30-day case fatality rate in the entire study population of 1.2% (6 of 511 patients) and the low median age of 54 years, which is not representative of a high-risk population. Second, high-risk, immunodeficient patients — especially those with actively treated cancer1 or hematologic cancer2 — were underrepresented (constituting 4 of the 511 patients [0.8%] in the study population), and the type of immunosuppression (present in 50 of 511 patients [9.7%]) was not described. Third, although neutralizing antibody titers were obtained before intervention, as an exploratory end point of the trial, these titers were not reported, and the importance of convalescent plasma in immunodeficient patients who are unable to mount a timely humoral response was not discussed.3,4 We are uncertain whether the trial participants needed antibodies in the first place. Eduard Schulz, M.D., Ph.D.Medical University of Graz, Graz, Austria [email protected] No potential conflict of interest relevant to this letter was reported. This letter was published on October 13, 2021, at NEJM.org.4 References1. Grivas P, Khaki AR, Wise-Draper TM, et al. Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium. Ann Oncol 2021;32:787-800.2. Vijenthira A, Gong IY, Fox TA, et al. Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients. Blood 2020;136:2881-2892.3. Hatzl S, Posch F, Sareban N, et al. Convalescent plasma therapy and mortality in COVID-19 patients admitted to the ICU: a prospective observational study. Ann Intensive Care 2021;11:73-73.4. Hueso T, Pouderoux C, Péré H, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood 2020;136:2290-2295.Response The authors reply: We acknowledge the limitations of our study raised by Fisher and Malnick and by Schulz. In response to Fisher and Malnick, we chose to include patients within 1 week after Covid-19 symptom onset in order to target a time period during which endogenous antibodies to SARS-CoV-2 are less likely to be present1 and Covid-19 symptoms, which typically appear in the second week of illness, are not common.2 Observational data suggesting an association between better outcomes and treatment with convalescent plasma within 3 days after symptom onset are intriguing, but we did not observe differential treatment effects in the 246 patients who were enrolled within 3 days after symptom onset (see Fig. 2 in our article, available at NEJM.org). Second, we chose a primary outcome of progression of Covid-19 from an illness that did not require hospital admission to any illness that did require unscheduled medical attention or to death without hospitalization. This outcome is patient-centered, is relevant to health care utilization, and was designed to prevent the failure to notice any of the protean effects of Covid-19. The components of this primary outcome in our population were predominately symptoms related to a viral illness (see Fig. S4 and Table S4 in the Supplementary Appendix of the article, available at NEJM.org). Prespecified secondary outcomes included ratings on an eight-category ordinal scale of illness (see Fig. 3 in the article). In response to Schulz, we used risk factors for severe Covid-19 illness as defined by the Centers for Disease Control and Prevention. Severe illness included but was not limited to death.3 These patient characteristics do imply a risk for hospitalization, as evidenced by the 158 of 511 patients (30.9%) who reached the primary outcome — a rate much higher than the rates in other trials involving outpatients with Covid-19.4 We agree that more study is required regarding the treatment of immunodeficient patients, including those with cancer. There remain many questions regarding dosing, pharmacokinetics, and patient selection that cannot be addressed in a single trial investigating the use of convalescent plasma in one particular outpatient population with Covid-19. Finally, we are in the process of analyzing both baseline and subsequent antibody levels in the trial participants over 30 days. We hope that the trajectories of the antibody responses in individual patients will provide insight into disease progression and will help in the design of future studies. Frederick K. Korley, M.D., Ph.D.University of Michigan, Ann Arbor, MIValerie Durkalski-Mauldin, Ph.D.Medical University of South Carolina, Charleston, SCClifton W. Callaway, M.D., Ph.D.University of Pittsburgh, Pittsburgh, PA [email protected] Since publication of their article, the authors report no further potential conflict of interest. This letter was published on October 13, 2021, at NEJM.org.4 References1. Li L, Liang Y, Hu F, et al. Molecular and serological characterization of SARS-CoV-2 infection among COVID-19 patients. Virology 2020;551:26-35.2. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-1069.3. Centers for Disease Control and Prevention. Underlying medical conditions associated with high risk for severe COVID-19: information for healthcare providers. May 2021 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html).4. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med 2021;384:238-251.