Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial
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Abstract
Hyperimmune plasma from Covid-19 convalescent is a potential treatment for severe Covid-19. We conducted a multicenter one arm proof of concept interventional study. Patients with Covid-19 disease with moderate-to-severe Acute Respiratory Distress Syndrome, elevated C-reactive Protein and need for mechanical ventilation and/or CPAP were enrolled. One to three 250-300 ml unit of hyperimmune plasma (neutralizing antibodies titer ≥1:160) were administered. Primary outcome was 7-days hospital mortality. Secondary outcomes were PaO2/FiO2, laboratory and radiologic changes, as well as weaning from mechanical ventilation and safety. The study observed 46 patients from March, 25 to April, 21 2020. Patients were aged 63, 61% male, of them, 30 were on CPAP and 7 intubated. PaO2/FiO2 was 128 (SD 47). Bilateral infiltrates on chest X-ray was present in 36 patients (84%). Symptoms and ARDS duration were 14 (SD 7) and 6 days (SD 3). Three patients (6.5%) died within 7 days as compared to an expected 15% from the National Statistics and 30% from a small concurrent cohort of 23 patients. The upper one-sided 90%CI was 13.9%, allowing to reject the null hypothesis of a 15% mortality. PaO2/FiO2 increased by 112 units (95%CI 82 to142) in survivors, the chest radiogram severity decreased in 23% (95%CI 5% to 42%); CRP, Ferritin and LDH decreased by 60, 36 and 20% respectively. Weaning from CPAP was obtained in 26/30 patients and 3/7 were extubated. Five serious adverse events occurred in 4 patients (2 likely, 2 possible treatment related). In conclusion, Hyperimmune plasma in Covid-19 shows promising benefits, to be confirmed in a randomized controlled trial. This proof of concept study could open to future developments including hyperimmune plasma banking, development of standardized pharmaceutical products and monoclonal antibodies.
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SciScore for 10.1101/2020.05.26.20113373: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: It has been approved by the local Ethical Committee on March 17th, 2020 (Number n. 20200027967). Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Selection of convalescent donors and hyperimmune plasma: Male adults or female with no previous pregnancy COVID-19 recovered subjects, with 2 consecutive negative naso-pharyngeal swabs performed 7 to 30 days before, were recruited from the hospital records; their suitability was assessed according to the current Italian guidelines and transfusion law21,22. Table 2: Resources
Software and Algorithms Sentences Resources Data were included into a database in REDCap … SciScore for 10.1101/2020.05.26.20113373: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: It has been approved by the local Ethical Committee on March 17th, 2020 (Number n. 20200027967). Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Selection of convalescent donors and hyperimmune plasma: Male adults or female with no previous pregnancy COVID-19 recovered subjects, with 2 consecutive negative naso-pharyngeal swabs performed 7 to 30 days before, were recruited from the hospital records; their suitability was assessed according to the current Italian guidelines and transfusion law21,22. Table 2: Resources
Software and Algorithms Sentences Resources Data were included into a database in REDCap hosted at the Fondazione IRCCS Policlinico San Matteo in Pavia and monitored remotely for missingness. REDCapsuggested: (REDCap, RRID:SCR_003445)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This study has some limitations, first of all the lack of a randomized control arm; it was however designed as a proof of concept study to verify the potential efficacy and safety of the administration of hyperimmune plasma in severely compromised Covid-19 patients and inform the design of a rigorous controlled randomized trial. However, the mortality was shown to be decreased by the treatment, both when compared to the mortality in Italy at the time of the design of hospitalized patients and to the mortality in our concurrent and similar observational cohort. Second, it was designed at the very beginning of the pandemic in Italy, and the patients were included under the pressure of medical emergency to provide them with an effective treatment at very short term. For this reason, some information was not planned to be collected, such as, but not only, the levels of D-dimer or other markers of inflammation, and long-term outcome. In conclusion, we were able to show a promising benefit of hyperimmune plasma in Covid-19 patients, both through a reduction of mortality, an increase in the respiratory function and a decrease in the inflammatory indices. This is a proof of concept study, thus these findings should not be overinterpreted. Nevertheless, they pave the way to future developments including the rigorous demonstration of hyperimmune plasma efficacy in a randomized clinical trial, the need for hyperimmune plasma banking to anticipate a potential second wave of the pandemic,...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04321421 Completed Hyperimmune Plasma for Critical Patients With COVID-19 Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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