Convalescent Plasma Treatment in Patients with Covid-19: A Systematic Review and Meta-Analysis

Convalescent plasma is a suggested treatment for Coronavirus disease 2019 (Covid-19), but its efficacy is uncertain. We aimed to evaluate whether the use of convalescent plasma is associated with improved clinical outcomes in patients with Covid-19.In this systematic review and meta-analysis, we searched randomized controlled trials investigating the use of convalescent plasma in patients with Covid-19 in Medline, Embase, Web of Science, Cochrane Library, and medRxiv from inception to October 17th, 2021. Two reviewers independently extracted the data. The primary efficacy outcome was all-cause mortality. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. This study was registered with PROSPERO, CRD42021284861. Of the 8874 studies identified in the initial search, sixteen trials comprising 16 317 patients with Covid-19 were included. In the overall population, the all-cause mortality was 23.8% (2025 of 8524) with convalescent plasma and 24.4% (1903 of 7769) with standard of care (risk ratio (RR) 0.97, 95% CI 0.90-1.04) (high-certainty evidence). All-cause mortality did not differ in the subgroups of noncritically ill (21.7% [1288 of 5929] vs. 22.4% [1320 of 5882]) and critically ill (36.9% [518 of 1404] vs. 36.4% [455 of 1247]) patients with Covid-19. The use of convalescent plasma in patients who tested negative for anti-SARS-CoV-2 antibodies at baseline was not associated with significantly improved survival (RR 0.94, 95% CI 0.87-1.02). In the overall study population, initiation of mechanical ventilation (RR 0.97, 95% CI 0.88-1.07), time to clinical improvement (HR 1.09, 95% CI 0.91-1.30), and time to discharge (HR 0.95, 95% CI 0.89-1.02) were similar between the two groups. In patients with Covid-19, treatment with convalescent plasma, as compared with control, was not associated with lower all-cause mortality or improved disease progression, irrespective of disease severity and baseline antibody status. Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42021284861).

Forrest plot depicting the hazard ratio for the time to hospital discharge between convalescent plasma and control. 15

Appendix Tables
Appendix Table 1    (1) in-hospital survival (2) 28-day survival (3) 90-day survival (4) respiratory support-free days (5) cardiovascular support-free days (6) progression to invasive mechanical ventilation, ECMO or death (8) ICU length of stay (9) hospital length of stay (10) WHO ordinal scale score at day 14 (11) venous thromboembolic events at 90 days (12) serious adverse events not reported (1) adult patients (2) admitted to hospital with acute illness due to confirmed Covid-19 (1) death is deemed to be imminent and inevitable during the next 24 hours AND one or more of the patients, substitute decision maker or attending physician are not committed to full active treatment (2) patient is expected to be discharged from hospital today or tomorrow (3) more than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to suspected or proven pandemic infection (4)  (1) time to intubation or death (2) ventilator-free days by day 30 (3) in-hospital death by day 90 (4) time to in-hospital death (5) death by day 30 (6) length of stay in critical care and hospital (7) need for extracorporeal membrane oxygenation (8) need for renal replacement therapy (9) convalescent plasma-associated adverse events (10) (2) infiltrates on chest imaging (3) oxygen saturation less than or equal to 94% on room air or requirement for supplemental oxygen, IMV, or ECMO (1) receipt of any antiviral agent with possible activity against SARS-CoV-2 within 24 hours of randomization (2)  (1) contraindication to transfusion or history of prior reactions to transfusion blood products (2) receipt of pooled (polyclonal) immunoglobulin or any intravenous polyclonal immunoglobulin in past 30 days (3) female subjects with positive pregnancy test, breastfeeding, or planning to become pregnant/breastfeed during the study period (4) in the treating physician's opinion, the patient is unable to tolerate a 450-550 mL infusion of plasma over up to 8 hours (4 hours max per unit) (5) unable to be randomized within 14 days of admission to Stony Brook Hospital n.a. (1) C-reactive protein (2) procalcitonin (3) lactate dehydrogenase (4) troponin (5) ferritin (6) D-Dimer (7) brain natriuretic peptide (8) lactate changes (9) 28-day mortality rate not reported

RECOVERY
(1) signed informed consent (2) aged at least 21 years (3) COVID-19 diagnosis based on PCR testing (5) hypoxia (oxygen saturation of less than or equal 92% on air, or PO2 < 60 mmHg arterial blood gas, or arterial partial pressure of oxygen/fraction of inspired oxygen of 300 or less and the patient requiring oxygen therapy (6) pneumonia confirmed by chest imaging.
(1) Patients with mild disease not requiring oxygen therapy (2) Patients with a normal CXR or CT scan (3) (2) time (in days) to discharge from the hospital (3) time to discharge from the ICU (4) time to improvement in at least two categories on the ordinal scale (5) time to death (6) time to full functional recovery not reported (1) hospitalized adults (2) positve RT-PCR assay of a respiratory tract sample (3) radiologically confirmed pneumonia (4) no previous directives rejecting advanced life support (5) at least one of the following severity criteria: oxygen saturation <93% while they were at rest and breathing ambient air, a ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2) below 300 mm Hg (PaO2:FiO2), or a Sequential Organ Failure Assessment (SOFA) or modified SOFA score of two or more points above baseline status (1) pregnant or lactating (2)  (1) 75 years of age or older or between 65 and 74 years of age with at least one coexisting condition (hypertension or diabetes for which the patient was currently receiving pharmacologic treatment, obesity, chronic renal failure, cardiovascular disease, and COPD) (2) at the time of screening for SARS-CoV-2 by RT-PCR assay, eligible patients had had at least one of each sign or symptom in the following two categories for less than 48 hours: a temperature of at least 37.5°C, unexplained sweating, or chills; and dry cough, dyspnea, fatigue, myalgia, anorexia, sore throat, dysgeusia, anosmia, or rhinorrhea. (1) time to symptom resolution (2) change in oxygen requirement after plasma transfusion (3) total duration of respiratory support during hospital admission (4) postenrolment duration of respiratory support until day 28 or discharge (5) proportion of participants requiring invasive or non-invasive ventilation (6) sequential organ failure assessment score over days 0, 3, and 7 (7) conversion to a negative result for SARS-CoV-2 RNA on days 3 and 7 (8) levels of biomarkers (9)requirement of vasopressor support (1) frequency of minor and serious adverse event within six hours of convalescent plasma transfusion (1) moderate illness with either a partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air (2) availability of a matched donor for convalescent plasma at the point of enrolment (1) pregnant and lactating women (2) known hypersensitivity to blood products (3) recipients of immunoglobulin in the past 30 days (4) conditions precluding infusion of blood products (5) participants in any other clinical trials (6) critically ill patients with PaO2/ FiO2 <200 mm Hg or shock (requiring vasopressors to maintain a mean arterial pressure (MAP) of ≥65 mm Hg or MAP of <65 mm Hg).

n.a.
ChiCTR China open-label, multicenter RCT time to clinical improvement within a 28-day period (1) 28-day mortality (2) duration of hospitalization (3) conversion of nasopharyngeal swab viral PCR results from positive at baseline to negative at follow-up assessed at 24, 48, and 72 hours not reported (1) signed informed consent (2) aged at least 18 years (3) COVID-19 diagnosis based on polymerase chain reaction (PCR) testing (4) positive PCR result within 72 hours prior to randomization (5) pneumonia confirmed by chest imaging (6) clinical symptoms meeting the definitions of severe or lifethreatening COVID-19 (7) acceptance of random group assignment (8) hospital admission (9) willingness to participate in all necessary research studies and be able to complete the study follow-up (10) no participation in other clinical trials during the study period (1) pregnancy or lactation (2) immunoglobulin allergy (3) IgA deficiency (4) preexisting comorbidity that could increase the risk of thrombosis (5) life expectancy less than 24 hours (6) disseminated intravascular coagulation (7)  (1) SARS-CoV-2 infection confirmed by PCR (bronchoalveolar lavage, sputum, nasal and/or pharyngeal swap) (2) age ≥ 18 years and ≤ 75 years (3) severe disease defined by at least one of the following: a) respiratory rate ≥ 30 breaths / minute under ambient air; b) requirement of any type of ventilation support; or c) needs treatment on ICU (4) written informed consent by patient or representative (1) accompanying diseases other than COVID-19 with an expected survival time of less than 12 months (2) previous treatment with any SARS-CoV-2-convalescent plasma (3) in the opinion of the clinical team, progression to death is imminent and inevitable within the next 48 hours, irrespective of the provision of treatment (4) Interval > 72 hours since start of mechanical ventilation (5) not considered eligible for extracorporeal oxygenation support (6) chronic obstructive lung disease, stage 4 (7) lung fibrosis with usual interstitial pneumonia pattern in CT and severe emphysema (8) chronic heart failure NYHA ≥ 3 and/or pre-existing reduction of left ventricular ejection fraction to ≤ 30% (9) shock of any type requiring ≥ 0.5 μg/kg/min noradrenaline (or equivalent) or requiring more than two types of vasopressor medication for more than 8 hours (10) liver cirrhosis Child C (11) liver failure: bilirubin > 5 x upper limit of normal (ULN) and elevation of ALT /AST (at least one >10 x ULN); (12) any history of adverse reactions to plasma proteins (13) known deficiency of immunoglobulin A (14) pregnancy (15)  (1) SARS-CoV-2 infection (positive by real-time PCR assay) patient (2) severe COVID-19 (respiratory rate (RR) 30/min, oxygen saturation level less than 93% in resting state, the partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) 300 mmHg, lung infiltrates >50% within 24 to 48 hours]) (1) failure to obtain informed consent (2) patients less than 18 years or more than 65 years of age (3) co-morbid conditions (cardiopulmonary disease-structural or valvular heart disease, coronary artery disease, COPD, chronic liver disease, chronic kidney disease) (4) multi-organ failure or on mechanical ventilation (5) pregnant females (6) HIV (7) viral hepatitis (8) cancer (9) (3) proportion of patients in categories 5, 6 or 7 at day 29 (4) mortality at days 15 and 29 (5) duration of hospital stay (6) number of days alive and free from oxygen support (7) number of days alive and free from MV not reported (1) hospitalized for laboratory-confirmed SARS-CoV-2 infection (RT-PCR) with either radiographic evidence of pulmonary infiltrates or clinical evidence plus SpO2 94% on room air (2) within 12 days from the onset of symptoms (fever or cough) (1) excluded if already on mechanical ventilation (invasive or non-invasive) or high flow oxygen devices ≤ 12 d Abbreviations: ECMO extracorporeal membrane oxygenation, ICU intensive care unit, MV mechanical ventilation, NIV non-invasive ventilation, RCT randomized controlled trial Appendix