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COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials
Levine AC, Fukuta Y, Huaman MA, Ou J, Meisenberg BR, Patel B, Paxton JH, Hanley DF, Rijnders BJ, Gharbharan A, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2023
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Editor's Choice
Abstract
BACKGROUND Outpatient monoclonal antibodies are no longer effective and antiviral treatments for COVID-19 disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma is promising, clinical trials among outpatients have shown mixed results. METHODS We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching MEDLINE, Embase, MedRxiv, World Health Organization, Cochrane Library, and Web of Science from January 2020 to September 2022. RESULTS Five included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14,580 in diverse assays. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 COVID-19 convalescent plasma treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving COVID-19 convalescent plasma with antibody titers below the median titer. CONCLUSIONS Among outpatients with COVID-19, treatment with COVID-19 convalescent plasma reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher.
PICO Summary
Population
Adult COVID-19 outpatients (5 studies, n= 2,620).
Intervention
Intravenous COVID-19 convalescent plasma (CCP) transfusion (n= 1,305).
Comparison
Non-convalescent plasma or normal saline (n= 1,315).
Outcome
The virus neutralizing antibody dilutional titre levels ranged from 8 to 14,580 in diverse assays. 160 (12.2%) of 1,315 control patients were hospitalized, versus 111 (8.5%) of 1,305 COVID-19 convalescent plasma treated patients, yielding a 3.7% (95% CI: 1.3% - 6.0%) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titre with a 7.6% absolute risk reduction (95% CI: 4.0% - 11.1%) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving COVID-19 convalescent plasma with antibody titres below the median titre.
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Outpatient convalescent plasma therapy for high-risk patients with early COVID-19. A randomized placebo-controlled trial
Gharbharan A, Jordans C, Zwaginga L, Papageorgiou G, van Geloven N, van Wijngaarden P, den Hollander J, Karim F, van Leeuwen-Segarceanu E, Soetekouw R, et al
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2022
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Editor's Choice
Abstract
OBJECTIVES The potential benefit of convalescent plasma (CP) therapy for COVID-19 is highest when given early after symptom onset. Our objective was to determine the effectiveness of CP in improving the disease course of COVID-19 in high-risk outpatients. METHODS A multicentre double blind randomized trial was conducted comparing 300mL of CP with non-CP. Patients were 50 years or older, symptomatic for <8 days, had PCR or antigen-test confirmed COVID-19 and at least 1 risk factor for severe COVID-19. The primary endpoint was the highest score on a 5-point ordinal scale ranging from fully recovered (score=1) or not (2) on day 7, over hospital admission (3), ICU admission (4) and death (5) in the 28 days following randomization. Secondary endpoints were hospital admission, symptom duration and viral RNA excretion. RESULTS After enrolment of 421 patients and the transfusion of 416, recruitment was discontinued when the countrywide vaccination uptake in those aged >50 years was 80%. Patients had a median age of 60, symptoms for 5 days and 207 of 416 received CP. During the 28 days of follow-up, 28 patients were hospitalized and 2 died. The odds ratio (OR) for an improved disease severity score with CP was 0.86 (95%credible interval 0.59-1.22). The OR was 0.58 (95%confidence interval 0.33-1.02) for patients with ≤5 days of symptoms. The hazard ratio for hospital admission was 0.61 (95%confidence interval 0.28-1.34). No difference was found in viral RNA excretion nor in the duration of symptoms. CONCLUSIONS In patients with early COVID-19, CP did not improve the 5-point disease severity score. CLINICAL REGISTRY NUMBER NCT04589949.
PICO Summary
Population
High-risk outpatients with early COVID-19 (n= 416).
Intervention
Convalescent plasma (CP), (n= 207).
Comparison
Regular plasma (non-CP, n= 209).
Outcome
Patients had a median age of 60 years old, and symptoms for 5 days. During the 28 days of follow-up, 28 patients were hospitalized and two died. The odds ratio (OR) for an improved disease severity score with CP was 0.86 (95% credible interval: 0.59-1.22). The OR was 0.58 (95% confidence interval: 0.33-1.02) for patients with ≤5 days of symptoms. The hazard ratio for hospital admission was 0.61 (95% confidence interval: 0.28-1.34). No difference was found in viral RNA excretion nor in the duration of symptoms.
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Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients
Millat-Martinez P, Gharbharan A, Alemany A, Rokx C, Geurtsvankessel C, Papageourgiou G, van Geloven N, Jordans C, Groeneveld G, Swaneveld F, et al
Nature communications. 2022;13(1):2583
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Editor's Choice
Abstract
Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of recruitment target was achieved. A Bayesian-adaptive individual patient data meta-analysis was implemented. Outpatients aged ≥50 years and symptomatic for ≤7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with ≤5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution. TRIAL REGISTRATION Clinicaltrials.gov NCT04621123 and NCT04589949. REGISTRATION NCT04621123 and NCT04589949 on https://www. CLINICALTRIALS gov.
PICO Summary
Population
COVID-19 outpatients enrolled in two multicenter trials: COnV-ert and CoV-Early (n= 797).
Intervention
Convalescent plasma (n= 390).
Comparison
Placebo (n= 392).
Outcome
Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of convalescent plasma for improved disease severity scale was 0.936; OR for hospitalization or death was 0.919. The convalescent plasma effect on hospital admission or death was largest in patients with ≤5 days of symptoms (OR 0.658). Convalescent plasma did not decrease the time to full symptom resolution.
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Expected individual benefit of prophylactic platelet transfusions in hemato-oncology patients based on bleeding risks
Cornelissen LL, Caram-Deelder C, Fustolo-Gunnink SF, Groenwold RHH, Stanworth SJ, Zwaginga JJ, van der Bom JG
Transfusion. 2021
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Editor's Choice
Abstract
BACKGROUND Prophylactic platelet transfusions prevent bleeding in hemato-oncology patients, but it is unclear how any benefit varies between patients. Our aim was to assess if patients with different baseline risks for bleeding benefit differently from a prophylactic platelet transfusion strategy. STUDY DESIGN AND METHODS Using the data from the randomized controlled TOPPS trial (Trial of Platelet Prophylaxis), we developed a prediction model for World Health Organization grades 2, 3, and 4 bleeding risk (defined as at least one bleeding episode in a 30 days period) and grouped patients in four risk-quartiles based on this predicted baseline risk. Predictors in the model were baseline platelet count, age, diagnosis, disease modifying treatment, disease status, previous stem cell transplantation, and the randomization arm. RESULTS The model had a c-statistic of 0.58 (95% confidence interval [CI] 0.54-0.64). There was little variation in predicted risks (quartiles 46%, 47%, and 51%), but prophylactic platelet transfusions gave a risk reduction in all risk quartiles. The absolute risk difference (ARD) was 3.4% (CI -12.2 to 18.9) in the lowest risk quartile (quartile 1), 7.4% (95% CI -8.4 to 23.3) in quartile 2, 6.8% (95% CI -9.1 to 22.9) in quartile 3, and 12.8% (CI -3.1 to 28.7) in the highest risk quartile (quartile 4). CONCLUSION In our study, generally accepted bleeding risk predictors had limited predictive power (expressed by the low c-statistic), and, given the wide confidence intervals of predicted ARD, could not aid in identifying subgroups of patients who might benefit more (or less) from prophylactic platelet transfusion.
PICO Summary
Population
Haemato-oncology patients enrolled in the TOPPS trial (n= 600).
Intervention
Platelet transfusions based on a threshold of 10 × 10 9/L (Prophylactic arm, n= 299).
Comparison
Platelet transfusions in case of active bleeding (Therapeutic arm, n= 301).
Outcome
47% of patients (279) developed at least one WHO grade 2, 3, or 4 bleeding during 30-day follow-up. The model had a c-statistic of 0.58. There was little variation in predicted risks (quartiles 46%, 47%, and 51%), but prophylactic platelet transfusions gave a risk reduction in all risk quartiles. The absolute risk difference was 3.4% in the lowest risk quartile (quartile 1), 7.4% in quartile 2, 6.8% in quartile 3, and 12.8% in the highest risk quartile (quartile 4).