Convalescent plasma is a clutch at straws in COVID-19 management! A systematic review and meta-analysis.

In the absence of definitive therapy for coronavirus disease (COVID-19), convalescent plasma therapy (CPT) may be a critical therapeutic option. This review was conducted to evaluate the impact of CPT in COVID-19 patients based on the publications reported to date. A robust screening of electronic databases was conducted up to 10th July 2020. Randomized controlled trials (RCTs), cohort studies, and case series with a control group evaluating the effectiveness and safety of CPT in patients with COVID-19 are included for the meta-analyses. Our search retrieved seven studies, including two RCTs and five cohort studies, with a total of 5444 patients. In patients with COVID-19, the use of CPT reduces mortality (odd's ratio [OR] 0.44; 95% CI, 0.25-0.77), increases viral clearance (OR, 11.29; 95% CI, 4.9-25.9) and improves clinically (OR, 2.06; 95% CI, 0.8 to 4.9). However, the evidence is of low quality (mortality reduction, and viral clearance), and very low quality (clinical improvement). CPT may be beneficial for reducing mortality, viral shedding and improving clinical conditions in COVID-19 patients. However, further randomized control trials (RCT) are required to substantiate the safety margin, initiation, optimal dosage, titre and duration of CPT.

INTRODUCTION

Convalescent Plasma Transfusion (CPT) has been traditionally tried during large‐scale epidemics in patients with viral infections whose critical condition is refractory to supportive care. It is obtained from a recently recovered person from a viral illness and is expected to have the maximum levels of polyclonal antibodies directed against the virus. Both passive immunity (reduction in viremia) and active immunity (host immune response) have been postulated for providing an immediate promising treatment option during the evaluation of existing drugs and developing new definitive therapies.The effectiveness of CPT has been tested ever since the Spanish Influenza pandemic in 1915‐1917, severe acute respiratory syndrome (SARS) in 2003, influenza A (H1N1) in 2009, avian influenza A (H5N1), and even in Ebola.

Recently, the US Food and Drug Administration has approved the use of CPT for patients with coronavirus disease (COVID‐19) under the emergency investigational new drug category and not for routine clinical use.

The absence of a definitive therapeutic modality for COVID‐19 has made CPT most relevant in the current grievous scenario. However, the clinical data for the studies involving COVID‐19, are still scarce. Thus, the aim of our study is to systematically analyze the current evidence on efficacy and safety of convalescent plasma therapy in COVID‐19 patients for decision‐making to prevent and control this pandemic. This study is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA‐P) guidelines.

METHODS

Search strategy

This systematic search was conducted with the major electronic databases (PubMed and Medline), Google Scholar (https://scholar.google.com), and preprint platforms MedRxiv (https://www.medrxiv.org) from 1st January2020 to 10th July 2020, independently by two researchers (SS and PK). The following terminologies: (“COVID‐19”) OR (“SARS‐CoV‐2”) AND (“plasma” OR “convalescent plasma”) were searched for.

Inclusion and exclusion criteria

We included randomized controlled trials (RCT), controlled clinical trials, prospective and retrospective comparative cohort studies, case‐control studies; cross‐sectional studies, and case series with a control group on steroid therapy for COVID‐19 patients. Our primary outcome of interest was mortality, and secondary outcomes included improvement in clinical conditions and clearance of viral shedding.We excluded articles written in languages other than English, absence of essential data, and without retrievable full text (PRISMA flow diagram). ,

Study selection

The available literature was screened independently after the removal of duplications by two researchers (SS and KDS). We screened all the abstracts primarily to exclude irrelevant articles. Finally, full‐texts of the potentially eligible studies were screened for inclusion. Disagreements involved consultation with a third researcher (PK).

Data extraction

Two researchers (SS and KDS) extracted the data independently from all included studies with the use of pre‐conceived data extraction sheet. The extracted information contained details of the intervention and control groups, mortality, clinical improvement, and viral clearance. The number of events along with the total number of patients per group was extracted for dichotomous data. Studies with missing or unusable data are reported in findings descriptively.

Risk of bias assessment

Two researchers (SS and PK) assessed the potential bias in each selected study independently. The third researcher (KDs) was consulted for resolving any difference of opinion.

The RoB 2.0 tool, was used for RCTs, which includes five domains: “randomization process”, “deviations from intended interventions”, “missing outcome data”, “measurement of the outcome”, and “selection of the reported result”. We used the Risk Of Bias In Non‐randomized Studies—of Interventions (ROBINS‐I) tool for assessing the risk of bias in non‐randomized studies. It comprises seven domains: “bias due to confounding”, “selection of participants, classification of interventions”, “deviations from intended interventions”, “missing data”, “measurement of outcomes”, and “selection of the reported result”. Each domain is graded as “Low”, “Moderate”, “Serious”, and “Critical”.

Quality of the evidence

Two experienced researchers (PK and KDS) evaluated the quality of evidence by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. , It has five downgrading factors (study limitations, consistency of effect, imprecision, indirectness, and publication bias) and three upgrading factors (large magnitude of the effect, dose‐response relation, and plausible confounders or biases). The quality of evidence of each outcome is classified as “High”, “Moderate”, “Low” or “Very low”. , , , , , ,

Data synthesis

Review manager version 5.4 was used for conducting the meta‐analysis. The Odd's ratio (OR) with 95% confidence intervals (CIs) was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Statistical heterogeneity was assessed with the I2 statistic, >50% indicating substantial heterogeneity. A funnel plot was used to assess publication bias.

The present study was not registered for rapid decision making in the context of the ongoing public health emergency.

RESULTS

Basic characteristics

We included 7 studies (2 RCTs and 5 cohort studies) out of 679 identified publications in this rapid review, after satisfying the inclusion criteria (Figure 1 and Table 1). The risk of bias was low in one of the included RCTs and another one had some concerns (Figure 2A). Out of the other five studies, four studies were associated with a moderate degree of bias (Figure 2B).

Figure 1

PRISMA‐2009 flow diagram

Table 1

Characteristics of included studies

SN	Studies (Year)	Type of study (centre)	No of patients	Patient condition	Time of administration	Dosage of CPT	Antibody titer	Concomitant therapy	Author's conclusion
1	Chen et al 24	Retrospective Observational, MC	29	Severely ill	19 d (IQR, 14‐20)	200‐500 mL (4‐5 mL/kg)	>1:160	Not specified	Significant improvement in clinical outcomes in comparison to the untreated cases
2	Duan et al 25	Pilot prospective cohort with a historical control group, SC	20	Severely ill	16.5 d (IQR, 11‐19)	200 mL	>1:640	antiviral therapy, steroids and supportive care as appropriate	CPT shows a potential therapeutic effect and low risk in the treatment of severe COVID‐19 patients
3	Gharbharan et al  26	Open‐label RCT, MC	86	Mild‐ moderately ill	9 d (IQR, 7‐13)	300 mL	1:640 (IQR, 1:320‐1:1280)	Chloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, anakinra as appropriate	No statistically significant differences in mortality (OR, 0.95, CI, 0.20‐4.67; P = .95) or improvement in the day‐15 disease severity (OR, 1.30; CI, 0.52‐3.32; P = .58) was observed when the study was suspended
4	Joyner et al 27	Observational CT, MC	5000	Critically ill	Not specified	200‐500 mL	Not specified	Not specified	Seven‐day mortality rate = 14.9%
5	Li et al 28	Open label RCT, MC	103	Critically ill	27 d (IQR, 22‐39)	4‐13 mL/kg 200 mL (IQR, 200‐300)	>1:640	antivirals, steroids, immunoglobulin, antibiotics and Chinese herbal medicines, as appropriate	In severe or life‐threatening COVID‐19 patients, in addition to standard treatment, CPT did not result in a statistically significant improvement in time to clinical improvement within 28 d. Interpretation is limited by early termination of the trial
6	Liu et al 29	Case controlled study, SC	185	Moderate‐ critically ill	4 d (IQR, 1‐7)	2 units. Each unit of 250 mL	>1:320	antivirals, anti‐biotics, steroid and immunoglobulins as appropriate	Plasma recipients also demonstrated improved survival, compared to control patients
7	Zeng et al 30	Retrospective observational study, MC	21	Critically ill	21.5 d (IQR, 17.8‐23)	300 mL (IQR, 200‐600)	Not specified	antivirals, steroid and immunoglobulins as appropriate	CPT can discontinue the viral shedding and contribute longer survival duration in COVID‐19 patients with respiratory failure, although it cannot reduce the mortality in critically end‐stage patients

Abbreviations: CPT, convalescent plasma transfusion; IQR, interquartile range; MC, multi‐center; OR, odds ratio; RCT, randomized controlled trial; SC, single center.

Figure 2

A, ROB2 tool assessment for the included RCTs. B, ROBINS‐I assessment for the included non‐randomized cohort studies

Meta‐analysis

Mortality was assessed in seven articles (two RCTs and five cohort studies) with a total of 5444 patients. The use of CPT reduced the risk of mortality almost by half in COVID‐19 (OR, 0.44; 95% CI, 0.25 to 0.77; I 2 = 0), which is statistically significant (Figure 3).

Figure 3

The efficacy of convalescent plasma therapy on mortality in COVID‐19 patients

Five studies with a total of 259 patients assessed the clinical improvement in COVID‐19. The majority of the COVID‐19 patients who received CPT showed clinical improvement than that in patients who received no CPT (OR, 2.06; 95% CI, 0.8 to 4.9; I 2 = 44%) (Figure 4A). However, the finding is not statistically significant.

Figure 4

A, The impact of convalescent plasma therapy on clinical improvement in COVID‐19 patients. B, The effect of convalescent plasma therapy on viral clearance in COVID‐19 patients

The incidence of viral clearance was assessed in two studies with a total of 144 patients. It is found that the use of CPT helps in viral clearance (OR, 11.29; 95% CI, 4.9 to 25.9; I 2 = 0%) significantly (Figures 4B).

Apart from mild heterogeneity among studies on assessing clinical improvement (I 2 = 44), the overall findings are homogenous. In view of the high homogeneity, the overall effect seems to be conclusive.

Quality of evidence

The quality of evidence on the impact of CPT on mortality and viral clearance in COVID‐19 is of low quality, and that of clinical improvement is of very low quality (Table 2).

Table 2

GRADE evidence profile of COVID‐19 studies

Out come	No. of participants			Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Quality of evidence (Grade)	Relative effect
	Total no.	Intervention	Control
Mortality	5444	5169	285	Yes	No	No	No	None	Low ⊕⊕⊝⊝	OR 0.44 (95% CI, 0.25 to 0.77)
Clinical improvement	259	130	129	Yes	No	No	Yes	None	Very low ⊕⊝⊝⊝	OR 2.06 (95% CI, 0.8 to 4.9)
Viral Clearance	144	68	76	Yes	No	No	No	None	Low ⊕⊕⊝⊝	OR 11.29 (95% CI, 4.9 to 25.9)

Abbreviations: CI, confidence interval; COVID‐19, coronavirus disease 2019; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; MD, mean difference; OR, odds ratio.

Publication bias

We assessed publication bias for the studies on COVID‐19 mortality. The funnel plot indicates a publication bias is likely in view of smaller studies with a large effect (Figure S1).

DISCUSSION

We have identified low‐quality evidence with variability that the convalescent plasma therapy is associated with around 44% reduction in the mortality in COVID‐19 patients.

A similar systematic review and meta‐analysis on severe acute respiratory syndrome (SARS), reported that the CPT is beneficial for reducing the mortality (OR, 0.25; 95% CI, 0.14 to 0.45; I 2 = 0%) in comparison to placebo or no therapy.

Another recent systematic review on CPT in COVID‐19 patients reported about a potential reduction in mortality but was unable to provide any opinion regarding the efficacy of CPT in COVID‐19 due to paucity in quantitative synthesis.

The present study has identified that very low‐quality evidence regarding improvement in clinical conditions and low‐quality evidence for viral clearance are associated with CPT.

A recent systematic review on the efficacy of CPT for the management of COVID‐19 also reported a significant decrease in viral loads and improvement in clinical symptoms within 3 to 26 days post‐transfusion. Rajendran et al also reported similar findings in their systematic review.

Another meta‐analysis on the efficacy and safety of convalescent plasma have found uninformative results regarding complete recovery (OR, 1.04; 95% CI, 0.69 to 1.64), length of stay (mean difference, 1.62; 95% CI, –3.82 to 0.58) and reduction in viral load on day 3 (RR, 1.07; 95% CI, 0.58 to 1.8), and day 7 (RR, 1.32; 95% CI, 0.97 to 1.81). However, the quality of evidence was very low due to the presence of high level of indirectness.

Salazar et al reported out of 25 critically ill patients, who received CPT on the 7th post‐transfusion day, 9 patients improved, while 13 remained static, and 3 deteriorated, and on the 14th post‐transfusion day 19 patients had a better clinical status, as per 6 points WHO ordinal scale.

The studies have shown significant variation regarding the timing of initiation, dosage and neutralizing antibody titer, and concomitant therapy.

However, a dilemma exists on finding a concrete conclusion about the favorable outcome being due to CP therapy alone based on the given evidence and not due to natural disease progression or concomitant therapies.

Adverse events

The overall incidence of serious adverse events was very low. None of the patients, who received CPT in two studies, Gharbharan et al (n = 43) and Zeng et al (n = 6) showed any adverse event. Joyner et al reported the incidence of serious adverse events after CPT was low (<1%) in 5,000 patients. They reported about transfusion‐associated circulatory overload (TACO) (n = 7), transfusion‐related lung injury (TRALI) (n = 11) and severe allergic reactions (n = 3). Dua et al reported about rashes in one patient out of 10 patients, who received CPT. Another study reported about TRALI in one patient and rashes in one patient out of 52 patients.

Strengths and limitations

Our study is one of the first comprehensive and systematic reviews of the effectiveness and safety of convalescent plasma therapy for patients with COVID‐19 using data from COVID‐19 studies and may be considered at the moment as the best evidence for decision‐making.

Although in the current scenario, CPT is an effective therapeutic option in addition to current antiviral, antimicrobial agents, a wide range of variation regarding selection of the donor, clinical stage of the recipient, initiation time, antibody titer, volume, dose and duration of CPT is noted across the available studies so far. We could not conduct subgroup analyses due to lack of data. We also acknowledge the procedure is yet to be standardized, and information in this regard is still evolving.

CONCLUSION

CPT may be an effective therapeutic option, until the availability of therapeutic and/or prophylactic agents for COVID‐19, with some early promising evidence on safety, viral clearance, and reduction in mortality. However, large multi‐center clinical trials are the need of the hour for establishing a stronger quality of evidence along with the optimal doses, titer, and initiation time point for CPT for effective use.

Summary statement

Impact of convalescent plasma therapy in COVID‐19 management:

↓ Mortality (OR, 0.44; 95% CI, 0.25 to 0.77).

↑ Viral clearance (OR, 11.29; 95% CI, 4.9 to 25.9).

↑ Clinical‐improvement (OR, 2.06; 95% CI, 0.8 to 4.9).

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interests.

AUTHOR CONTRIBUTIONS

SS: conceptualization search strategy study selection, data extraction, risk of bias assessment, and drafted the manuscript; KDS: study selection, data extraction, risk of bias assessment, quality of the evidence assessment, data synthesis, and editing; PK: conceptualization, search strategy, study selection, risk of bias assessment, quality of the evidence assessment, and editing.

Supplementary information

Click here for additional data file.

Supplementary information

Click here for additional data file.