key: cord-0716472-uwydmd8p
authors: Wang, Ying; Huo, Pengfei; Dai, Rulin; Lv, Xin; Yuan, Shaofei; Zhang, Yang; Guo, Yiming; Li, Rui; Yu, Qian; Zhu, Kun
title: Convalescent plasma may be a possible treatment for COVID-19: A systematic review
date: 2020-12-05
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2020.107262
sha: b1f153e8a4e136c07f5fd11880de16c1d1e9722b
doc_id: 716472
cord_uid: uwydmd8p

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has spread globally. Therapeutic options including antivirals, anti-inflammatory compounds, and vaccines are still under study. Convalescent plasma(CP) immunotherapy was an effective method for fighting against similar viral infections such as SARS-CoV, and MERS-CoV. In the epidemic of COVID-19, a large number of literatures reported the application of CP. However, there is controversy over the efficacy of CP therapy for COVID-19. This systematic review was designed to evaluate the existing evidence and experience related to CP immunotherapy for COVID-19. METHODS: A literature search was conducted on Pubmed, Cochrane Library, Clinical Key, Wanfang Database; China National Knowledge Infrastructure(CNKI) were used to search for the proper keywords such as SARS-CoV-2, COVID-19, plasma, serum, immunoglobulins, blood transfusion, convalescent, novel coronavirus, immune and the related words for publications published until 15.10.2020. Other available resources were also used to identify relevant articles. The present systematic review was performed based on PRISMA protocol. Data extraction and risk of bias assessments were performed by two reviewers. RESULTS: Based on the inclusions and exclusions criteria, 45 articles were included in the final review. First, meta-analysis results of RCTs showed that, there were no statistically significant differences between CP transfusion and the control group in terms of reducing mortality(OR 0.79, 95% CI 0.52–1.19, I(2) = 28%) and improving clinical symptoms(OR 1.21, 95%CI 0.68–2.16; I(2) = 0%). The results of controlled NRSIs showed that CP therapy may reduce mortality in COVID-19 patients(RR 0.59, 95% CI 0.53–0.66, I(2) = 0%). Second, limited safety data suggested that CP is a well-tolerated therapy with a low incidence of adverse events. But, due to lack of safety data for the control group, it is really not easy to determine whether CP transfusion has an impact on moderate to serious AEs. Thirdly, for children, pregnant, elderly, tumor and immunocompromised patients, CP may be a well-tolerated therapy, if the disease cannot be controlled and continues to progress. Studies were commonly of low or very low quality. CONCLUSIONS: Although the results of limited RCTs showed that CP cannot significantly reduce mortality, some non-RCTs and case report(series) have found that CP may help patients improve clinical symptoms, clear the virus, and reduce mortality, especially for patients with COVID-19 within ten days of illness. We speculate that CP may be a possible treatment option. High-quality studies are needed for establishing stronger quality of evidence and pharmacists should also be actively involved in the CP treatment process and provide close pharmaceutical care.

The coronavirus disease 2019(COVID- 19) , an outbreak caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), continues to spread, and as per the World Health Organization(WHO) data on November 10, 2020, it has reported cumulative numbers to over 49.7 million confirmed cases and over 1.2 million deaths [1] . The case fatality rate in COVID-19 may be as high as 2.3% overall and from 10% to 40% among severely affected individuals [2] . Very few effective antivirals treatments exist [3] , although hundreds of registered clinical trials are still ongoing, including several phase III vaccine trials [4] . In addition, we have to face an extremely challenge that some drugs are not widely available across the world [5] . Therefore, affordable, effective, and available therapies are in need. Over the past two decades, convalescent Plasma(CP) therapy was successfully used in the treatment of severe acute respiratory syndrome(SARS), middle east respiratory syndrome(MERS), avian influenza A(H5N1), and 2009 H1N1 pandemic [6] [7] [8] [9] . Since the virological and clinical characteristics share similarity among SARS, MERS, and COVID-19 [10] . Given the absence of effective drugs, CP therapy may be one of a few promising treatments for COVID-19 [11] . The experiences of CP therapy are gradually enriched with the increasing number of patients. However, there is controversy over the efficacy of convalescent plasma therapy for COVID-19. Some recent systematic reviews on the efficacy of CP therapy for the COVID-19 patients reported a potential reduction in mortality and significant improvement in clinical symptoms, whether in addition to antiviral drugs or not [12, 13] . Another systematic review and meta-analysis found that whether CP decreases mortality (hazard ratio(HR) 0.64, 95% CI 0. 33-1.25 ) and improvement of clinical symptoms at seven days (RCT: risk ratio(RR) 0.98, 95% CI 0. 30-3.19 ) were very uncertain [14] . Hence, we conducted this study to systematically analyze the latest evidence of the effect and safety of CP therapy in COVID-19 patients.

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15] (Table S1 ). The study protocol was registered with the National Institute for Health Research international prospective register of systematic reviews [16] .

The study population of interest was patients who are diagnosed with COVID-19. The intervention of interest was CP, convalescent serum or hyperimmune immunoglobulin. Comparator treatments included placebo, sham therapy, or no intervention; studies with no comparator group were also included. Outcome measures were derived from the protocol research questions to ascertain the clinical effectiveness of therapy. Any other outcome associated with the intervention.

Studies will be included if the cases considered are positive for COVID- 19 , and have been diagnosed using any established protocol for case confirmation. Systematic reviews, meta-analyses, randomized clinical trials(RCTs), quasi-experimental studies, cohort studies, case series, case reports, clinical guidelines, protocols for clinical trials, any other grey literature will be included. Languages will include Chinese and English.

The following study types will not be included: studies without an available full text, posters, commentaries, opinion articles, and in vitro studies.

Pubmed, Cochrane Library, Clinical Key, Wanfang Database; China National Knowledge Infrastructure(CNKI) were used to search for the proper keywords such as SARS-CoV-2, COVID-19, plasma, serum, immunoglobulins, blood transfusion, convalescent, novel coronavirus, immune and the related words for publications published until 15.10.2020 . The search strategies are available in the supplementary data (Table S2) . Following the removal of duplicate entries, a three-stage screening process was followed to identify eligible records through the sequential examination of each title, abstract, and full text. Two reviewers(Y.W and K.Z) screened each record, with provision for arbitration from a third reviewer(Q.Y).

The studies retrieved during the searches will be screened against the eligibility criteria, and those meeting the criteria will be selected for inclusion. Data will then be extracted from the eligible studies using a template by two independent authors(Y.W and K.Z) and validated by a third(Q.Y). The following information will be extracted: authors and country of the study, study design, number of participants, patients condition, time of administration, titers and dosages of CP, concomitant therapy, conclusion of authors, adverse events(AEs) and other results. The review will be constantly updated during the pandemic.

Two researchers (Y.W and RL.D) assessed the potential bias in each selected study independently. The third researcher (X.L) was consulted for resolving any difference of opinion.

The 'Risk of Bias' 2.0 tool [17] was used to assess the randomized clinical trials, which includes five domains: 'randomization process', 'deviations from intended interventions', 'missing outcome data', 'measurement of the outcome', and 'selection of the reported results'. The 'Risk of Bias In Non-randomized studies-of Interventions (ROBINS-I)' [18] tool was applied to assess the risk of bias in controlled nonrandomized studies of interventions(NRSIs). It comprises of seven domains: 'bias due to confounding', 'selection of participants, classification of intervention', 'deviations from intended interventions', 'missing data', 'measurement of outcomes' and 'selection of the reported results'. Each domain is judged as 'low', 'moderate', 'serious' and 'critical'. The 'Risk of bias' assessment criteria tool for observational studies provided by Cochrane Childhood Cancer [19] was used to assessed the methodological quality and risk of bias for included non-controlled NRSIs. It comprises of following domains: 'Unrepresentative study group (selection bias)', 'Incomplete outcome assessment/follow-up (attrition bias)', 'Outcome assessors unblinded to investigated determinant (detection bias)', 'Important prognostic factors or follow-up not taken adequately into account (confounding)', 'Poorly defined study group (reporting bias)', 'Poorly defined follow-up (reporting bias)', 'Poorly defined outcome (reporting bias)', 'Poorly defined risk estimates (analyses)'. For every criterion, risk of bias judgements are 'high', 'unclear' or 'low'.

The National Institute for Health and Care Excellence's Quality Assessment for Case Series will be used to evaluate the quality of case series. The total score is 8 points, in which a score of 4-8 is high quality, and a score less than 4 is low quality.

Two researchers (Y.W and R.L) assessed the quality of evidence by using the 'Grading of Recommendations Assessment, Development and Evaluation (GRADE)' tool [20] . We used 'GRADEpro GDT' software to create a 'Summary of findings' table, as suggested in the Cochrane Handbook for Systematic Reviews of Interventions. The quality of evidence of each outcome is classified as 'high', 'moderate', 'low' or 'very low'.

The Review Manager version 5.3 software was used for analyses. One researcher (Y.W) would have entered the data into the software, and a second researcher (K.Z) would have checked the data for accuracy. For dichotomous outcomes, the number of events and total number of participants in two groups were recorded. Fixed-effects model was used if the result of the Q test was not significant (p＞0.1) or I 2 ＜50%. The different types of studies were analyzed separately (such as RCTs and controlled NRSIs). If we could not perform a meta-analysis, we had planned to comment on the results from all studies. The odd's ratio(OR) and the RR with 95% confidence intervals(CIs) was assessed for RCTs and controlled NRSIs respectively. A Chi 2 test with a significance level at P ≤ 0.1 was used to assess heterogeneity of treatment effects between trials. The I 2 statistic was used to quantify possible heterogeneity (I 2 statistic: 30-60% may represent moderate heterogeneity, 75-100% considerable heterogeneity). If heterogeneity had been above 80%, we would explore potential causes through sensitivity and subgroup analyses. If we had not found a reason for heterogeneity, we would not have conducted a meta-analysis. Subgroup analyses will be performed, if appropriate based on the data retrieved.

Because of insufficient evidence available from RCTs, we also included controlled NRSIs, non-controlled NRSIs and case reports(series). The search process yielded 5645 records. Following removing duplicates and screening of titles and abstracts, we evaluated 153 articles in full text. Among these, we found 45 relevant articles (4RCTs, 11 controlled NRSIs, 7 non-controlled NRSIs and 23 case reports) . Extracted details are presented in Table 1 (RCTs, controlled NRSIs, and non-controlled NRSIs) and table 2(case report(series)). A flow chart summarizing the inclusion and exclusion criteria of the searched studies is presented in Fig. 1 .

The included 45 studies were identified and critically evaluated, which included 44,068 participants in this review, of whom 22,260 received CP. The patients included in the study had a wide range of age distribution, ranged from 4 to 100 years old. The patients' conditions were variable, two RCTs [21, 24] and three controlled NRSIs [26, 28, 33] included moderate to severely ill patients, one RCT included less-severe patients, and the clinical symptoms of patients in the 6 controlled NRSIs met the definitions of severe or life-threatening disease [29, 31, 32, 37, 41, 42] . One RCT [22] and 4 controlled NRSIs [27, 34, 35, 40] evaluated CP therapy in critically ill individuals.

We assessed the methodological quality and risk of bias for RCTs, controlled NRSIs and non-controlled NRSIs for different outcomes (such as mortality, clinical improvement, and safety) respectively, the results were summarized in Figs. 2a, 2b and 2c. Some studies reported only one or two of mortality, clinical improvement, or safety outcomes, and we assess the risk of bias for the results reported in the study. For example, bias in measurement of outcomes was not applicable for clinical improvement for Ralph Rogers, because they did not report this outcome.

The methodological quality evaluation results of the 2 researchers on the included case reports(series) showed that the quality was low to medium (Table 3) .

Mortality outcomes were reported in 21 of the included 22 controlled studies and non-controlled NRSIs [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] 42] . The mortality outcome was evaluated from controlled studies: 4RCTs and 11NRSIs(Figs. 3a and 3b). Compared to the control group, the results of RCTs showed that the use of CP transfusion may reduce the mortality rate (OR 0.79, 95% CI 0.52-1.19, I 2 = 28%), but there was no significant difference between the two groups (Fig. 3a) . The results of controlled NRSIs showed similar findings (RR 0.59, 95% CI 0.53-0.66, I 2 = 0%), but there is statistically Fig. 2c . Risk of bias summary for non-controlled NRSIs. significant (Fig. 3b) . Evidence suggests that CP may have effect on reducing mortality in patients, but it is uncertain whether there is a statistical difference between CP and or not.

However, by far the largest study of CP transfusion -Expanded Access Program(EAP), which resulted in widespread use of CP to treat COVID-19 in the U.S.A. The authors reported 7 and 30-day mortality in 35, 322 severe to critical hospitalized adults transfused with CP was 3706 (10.49%) and 8652(24.49%) respectively [36] . The case fatality rate in COVID-19 may be as high as 2.3% overall and from 10% to 40% among severely affected individuals [2] . Although the EAP program was designed to evaluate the safety of CP, overall data suggest that patients with severe to critical conditions who use CP have a lower mortality rate [36].

For most viral illnesses, viremia peaks in the first week of infection [66] . Studies have shown that viral loads are highly correlated with disease severity and progression [67, 68] . In theory, the patient is at greater risk of virus-related damage. At this time, if CP is transfused, the patients may benefit more [69, 70] . In this systematic review, 11 controlled studies reported the time from symptom onset (or hospitalization) to transfusion, and the treatment time point was different.

For the median time of patients from symptoms onset (or hospitalization) to transfusion, there was 6 studies reported less than 10 days, 4 studies reported 10-20 days, and only one study reported exceed 30 days. Meta-analysis was conducted for studies in which the time from symptom onset(or hospitalization) to transfusion was less than 10 days for RCTs and controlled NRSIs respectively. Compared to the control group, the results of RCTs showed that the use of CP transfusion may be reduce the mortality of patients, if the treatment time point was within 10 days(OR 0.4, 95%CI 0.14-1.11; I 2 = 0%). But there was no significant difference between the two groups (Fig. 4a) . Similar results were found in controlled NRSIs (RR 0.54, 95%CI 0.39-0.76; I 2 = 0%), but there is statistically significant (Fig. 4b) .

In this study, the clinical improvement was assessed by WHO 8-point disease severity scale (5-6 score) and/or oxygen status improvement. There are only two RCTs reported improvement of clinical symptoms and 8 controlled NRSIs reported clinical improvement or discharged outcomes at 14-30 days. However, due to the high heterogeneity of results from controlled NRSIs (I 2 = 82%), we abandoned the analysis. The clinical improvement outcome was evaluated from 2RCTs (Fig. 5) . Compared to the control group, the results of RCTs showed that the use of CP transfusion may be beneficial to the improvement of patients' clinical symptoms (OR 1.21, 95%CI 0.68-2.16; I 2 = 0%).But there was no significant difference between the two groups (Fig. 5 ).

The safety data in the controlled studies was insufficient, we included non-controlled NRSIs to list information on adverse reactions. Due to the lack of safety outcomes data for the control group, we did not conduct a meta-analysis, but provided information in table 1 and 2. In the included studies, the reporting of safety results and the follow-up period were different. Only one RCT reported AEs and serious AEs in the control group, and none of the other controlled studies reported safety data for the control group. Meanwhile, it is difficult to determine whether some (serious) AEs were related with CP transfusion, or due to underlying disease or other combination treatment, or above. 21 studies (43,990 participants) assessed AEs and/or serious AEs for 22,182 of its participants. 15 studies (1371 recipients) reported no serious AEs and 7 studies (541 recipients) reported 33 patients seemed major or non-severe reactions possibly attributed to CP transfusion. The majority of AEs were allergic, fever, rash, or respiratory events.

The EAP study reported on serious AEs within the 4 h and an additional 7 days after transfusion respectively [38] . There were 141 serious AEs within 4 h and 1247 serious AEs within 7 days after transfusion. These were mainly allergic or respiratory, thrombotic or thromboembolic and cardiac events. There were 78 non-mortality events occurring within 4 h after CP transfusion, of which 36 reports of transfusionassociated circulatory overload (TACO), 21 reports of transfusionrelated acute lung injury (TRALI), and 21 reports of severe allergic transfusion reaction. There were 63 deaths occurring within 4 h of CP transfusion, of which 10 were possibly related to transfusion. Of these serious AEs reported within 7 days post-transfusion, only 38 thromboembolic or thrombotic events, 457 sustained hypotensive events, and 80 cardiac events were judged to be related to the plasma transfusion.

Combined with the included evidence, convalescent plasma therapy may be a well-tolerated therapy with a low incidence of AEs. However, because of the lack of safety data for the control group, it is really not easy to determine whether CP transfusion has an impact on AEs.

In vivo studies showed that the effects of neutralizing antibodies in CP were not only limited to viral clearance, but also included acceleration of infected cell clearance, and have been considered essential in protecting against viral diseases [71, 72] . The efficacy of this therapy has been associated with the titer of neutralizing antibodies in CP [73] . We found that the antibody titers of CP were significantly different in the included literatures. In addition, the detection methods and evaluation indexes of antibody titer were also different. All the four included RCTs reported titers, but the values were different. Among them, the titers in CP were greater than 1:80 in 2 RCTs [21, 23] and a subgroup in 1 RCT [24] . However, due to the lack of subsets of data with titer greater than 1:80, we were unable to carry out meta-analysis. Similar trends were pronounced in controlled NRSIs. Only eight controlled NRSIs reported donors' CP titers, and the titers varied in scope, unit, and assay. We were also unable to perform a meta-analysis on titers.

However, there is not a standard transfusion dose of CP. The dosage range of CP commonly used in clinical practice is between 200 and 500 ml, with single or double regimen doses (Tables 1 and 2 ). We think that the optimal dose cannot be determined due to the different titers.

Currently, there are not sufficiently randomized controlled trials for the treatment of COVID-19. Case reports and case series are the available clinical evidence particularly for the passive immunity transfer namely convalescent immune plasma therapy, especially among special groups.

Pregnant women, especially at the end of pregnancy, maybe more susceptible to COVID-19, probably due to changes in the immune system and physical stature [54] . A pregnant woman with COVID-19 received CP treatment six days after delivery, and her clinical course improved, particularly during the second week [54] . The other pregnant was extubated and her oxygen requirements were gradually decreased after receiving CP [49] . A pregnant woman with COVID-19 developed severe ARDS, after 8 days of CP treatment, continuous renal replacement therapy and extra-corporeal membrane oxygenation were removed [46] .

Treating transplant recipients with COVID-19 can be challenging given the need for ongoing immunosuppressive medications in these patients, such as kidney transplantation, bone marrow transplantation or stem cell transplantation. Çınar et al reported an immunocompromised patient due to myelodysplastic syndrome, and attacked by SARS-CoV-2 leading to COVID-19 syndrome, which was successfully managed via the administration of double CP transfusion [50] . Naeem S et al and Jiang J et al reported 4 cases of renal transplantation patients undergoing immunotherapy, two of them were 65 and 70 years old, they were discharged and the use of plasma was helpful for SARS-CoV-2 clearance and her recovery [59, 63] . Karataş A et al reported a 61-year-old man with a history of mixed cellularity classical Hodgkin lymphoma, autologous stem cell transplantation (6 months ago) [58] . On After the CP transfusion, his fever resolved after 3 days and he was discharged from the hospital on the 78th day of hospitalization. But unfortunately, a week later, his sensor released and follow-up RT-PCR test was found to be positive. In patients with hematological malignancies or immunosuppression such as ASCT may lead to prolonged viral shedding [58] .

As everyone known, the patient had an older age and coexisting chronic diseases, which were associated with severe clinical symptoms and poor prognosis. A male centenarian with cough and dyspnea for 2 months was diagnosed with COVID-19. Without effective treatments and with the increased risks of antiviral therapy for the elderly, this patient was given CP. The viral load and clinical symptoms improved after CP transfusion [48] .

Few cases of severe and often fatal COVID-19 have been reported although the infection is mild in the large majority in children. Figlerowicz M et al reported the first case of CP transfusion in a child with COVID-19-associated severe aplastic anemia. Three weeks after CP treatment, although her hematologic parameters did not improve significantly, the results of sars-cov-2 RNA in 7 nasopharyngeal swabs were negative [56] . Shankar R et al reported the case of a 4-year-old girl with severe COVID-19 associated pneumonia who presented to us as febrile neutropenia. She is the frst in a child with underlying malignancy [62] . The use of CP along with steroids and intravenous immunoglobulin showed dramatic results in this child and she recovered without the need for any specific treatment.

According to the findings of the present studies, clinical symptoms, laboratory results, and viral load were significantly improved in pregnant women, children, elderly, and immunocompromised COVID-19 patients after CP transfusion. No serious adverse reactions occurred during and after CP infusion.

The quality of evidence on the impact of CP transfusion on mortality in COVID-19 was of low and very low quality for RCTs and controlled NRSIs respectively. As for the median time of patients from symptoms onset (or hospitalization) to transfusion within 10 days, the similar results of quality were shown (low and very low quality for RCTs and controlled NRSIs respectively). In addition, the quality of evidence on the impact of CP transfusion on clinical improvement is of very low quality. The results were shown in table 4.

Currently, treatment strategies for COVID-19 patients are lacking [74, 75] . There are few approved specific antivirals targeting the virus, while some drugs are still under investigation. To this end, there are urgent needs to develop COVID-19-specific treatment to alleviate the symptoms and reduce the mortality.

CP therapy, a classic adaptive immunotherapy, has been applied to the prevention and treatment of many infectious diseases for more than one century. During the 2009 H1N1 infection outbreak, a study in Hong Kong showed that CP therapy with antibody titer ≥ 1:160 could significantly reduce respiratory viral load and mortality [9] . Mair JJ et al analyzed 32 studies, the results showed that CP could significantly reduce the mortality of SARS, and the effect of early use is more obvious [76] . KO et al found that CP with antibody titer ≥ 1:80 was effective in the treatment of MERS-CoV infection [7] . Luke TC et al performed a meta-analysis on the therapeutic effect of CP in patients with Spanish influenza, they identified eight studies involving 1703 patients with influenza pneumonia who received an infusion of influenzaconvalescent human blood products, which showed the range of absolute risk differences in mortality between the treatment and control groups was 8-26% (pooled risk difference, 21% [95% CI, 15-27%]), suggesting that CP would be a possible treatment for H5N1 [77] . In 2014, the use of CP collected from patients who had recovered from Ebola virus disease was recommended by WHO as an empirical treatment during outbreaks [78] . The recent COVID-19 outbreak has refocused attention on the use of CP therapy. It has recently been suggested by Food and Drug Administration that administration and study of investigational CP treatment may provide a clinical effect for COVID-19 during the public health emergency [79] . CP therapy was mentioned in the "Diagnosis and Treatment Guidelines of COVID-19(trial 6th, 7th, and 8th)" issued by NHC, especially for severe and critical cases with rapid disease progression [80] [81] [82] .

This systematic review identified and summarized 4 RCTs, 11 controlled NRSIs, 7 non-controlled NRSIs and 24 case reports(series) to evaluate the effect and safety of CP treatment. First, because of the inadequacy of randomized controlled trials, we also conducted metaanalysis of the data from controlled NRSIs. Meta-analysis results of RCTs showed that, there were no statistically significant differences between CP transfusion and control group in terms of reducing mortality and improving clinical symptoms. However, the results of controlled NRSIs showed that CP therapy may reduce mortality in COVID-19 patients. There are not sufficiently RCTs for CP treatment for COVID-19 patients until now. Therefore, the available evidence from controlled NRSIs may also serve as an option for COVID-19 treatment. The evidence was commonly of low or very low quality. Second, limited safety data suggested that CP may be a well-tolerated therapy with a low incidence of AEs. But, due to lack of safety data for the control group, it is really not easy to determine whether CP transfusion has an impact on AEs. Third, for children, pregnant, elderly, tumor and immunocompromised patients, CP may be a well-tolerated therapy, if the disease cannot be controlled and continues to progress.

However, the optimal timing, titers and dosage of CP therapy is unknown. We found that there were significant differences in CP titers, duration of administration, and doses in the included studies, which were likely to affect the efficacy and safety of CP therapy. The optimal time, dose, and titer for CP therapy still require large, high-quality studies to provide data.

For normal adults, plasma volume ranges from 39 to 44 ml/kg [83] . CP infusion may have little influence on blood concentration in the recipient, but large amounts of plasma infusion(Zhang et al reported a maximum of 2400 ml of CP administered to a 73 years old male patient [46] ) may affect the blood concentration and the therapeutic effect of the drugs. Pharmacists should develop individualized drug adjustment programs based on patient weight, plasma volume, infusion plasma dose, and plasma protein binding rate.

In addition, we should be concerned about the potential risks of drugs in donated plasma. Melanson et al reported, in the absence of drug declaration, 11% of blood donors had drug residues [84] . Medication taken by the donor in plasma for transfusion may cause an anaphylactic transfusion reaction in the recipient. In any case, the transfer of drugs from donors to recipients should be avoided, as these drugs may be allergic or potential harm to the recipients [85] . Both the relevant documents and the blood donation guidance manual have strict rules on the conditions of blood donation, including which drugs donors should not take before donating blood. However, COVID-19 patients have received antivirals, antibacterial drugs, glucocorticoids and treatment for virus-related complications due to medical need. It is conceivable that these drugs remained in the plasma donated by the convalescent COVID-19 patients. However, due to the urgency of the epidemic and the critical condition of the patients, most clinicians do not pay much attention to the risk that CP may contain drugs. To avoid these risks, pharmacists should conduct pharmaceutical care in CP patients, although the residual amount and effect of the drug are still uncertain.

A lack of high-quality studies and a paucity in the volume of relevant literature limited our analyses. The confidence of the results from metaanalysis is limited by insufficient data of the RCTs. Due to the evidence from controlled studies was insufficient, we included case reports(series), and had a low to medium quality. Some articles that are not accessible to full texts and those in languages other than English were excluded from the analysis. This might have led to overlook some critical findings or observations.

Although the results of limited RCTs showed that CP cannot significantly reduce mortality, some non-RCTs and case report(series) have found that CP may help patients improve clinical symptoms, clear the virus, and reduce mortality, especially for patients with COVID-19 within ten days of illness. Therefore, we speculate that CP may be a possible treatment option, but this effect may be affected by the time of administration, dose, titer, population, and other aspects. However, high-quality studies are needed for establishing stronger quality of evidence along with the optimal initiation time, titers, and doses for the effective usage of CP. During CP therapy, pharmacists should also be actively involved in the treatment process and provide close pharmaceutical care to the recipients. 

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 There are too few randomized controlled studies to evaluate the information size and results, so we downgraded two point for imprecision. 2 Controlled non-randomized studies. 3 We downgraded one points because the risk of bias within this study is critical. 4 There were too few studies to evaluate the information size and results, so we downgraded one point for imprecision. 5 Risk of bias within this study is some concerns, so we downgraded one point for risk of bias.

There is no potential conflict of interest for authors to disclose.

Supplementary data to this article can be found online at https://doi. org/10.1016/j.intimp.2020.107262.

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Infusion of convalescent plasma is associated with clinical improvement in critically ill patients with COVID-19: a pilot study

Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Antibody Titers in Convalescent Plasma and Recipients in New Mexico: An Open Treatment Study in Patients With Coronavirus Disease

Clinical predictors of donor antibody titre and correlation with recipient antibody response in a COVID-19 convalescent plasma clinical trial

Treatment of Coronavirus Disease 2019 (COVID-19) Patients with Convalescent Plasma

Treatment with convalescent plasma for COVID-19 patients in Wuhan, China

Treatment of 5 critically ill patients with Covid-19 with convalescent plasma

Treatment With Convalescent Plasma for Critically Ill Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Use of Convalescent Plasma Therapy in Two COVID-19 Patients with Acute Respiratory Distress Syndrome in Korea

Successful treatment of a centenarian with coronavirus disease 2019 (COVID-19) using convalescent plasma

The use of convalescent plasma therapy and remdesivir in the successful management of a critically ill obstetric patient with novel coronavirus 2019 infection: A case report

Convalescent (immune) plasma treatment in a myelodysplastic COVID-19 patient with disseminated tuberculosis

A severe refractory COVID-19 patient responding to convalescent plasma; A case series

A synergistic role of convalescent plasma and mesenchymal stem cells in the treatment of severely ill COVID-19 patients: a clinical case report

Radiological and clinical improvement in a patient with COVID-19 pneumonia postconvalescent plasma transfusion: A case report

Convalescent plasma therapy in a pregnant COVID-19 patient with a dramatic clinical and imaging response: A case report

Convalescent Plasma Therapy in Coronavirus Disease 2019: a Case Report and Suggestions to Overcome Obstacles

First case of convalescent plasma transfusion in a child with COVID-19-associated severe aplastic anemia

Non-optimal effectiveness of convalescent plasma transfusion and hydroxychloroquine in treating COVID-19: a case report

Prolonged viral shedding in a lymphoma patient with COVID-19 infection receiving convalescent plasma

Successful recovery from COVID-19 in three kidney transplant recipients who received convalescent plasma therapy

The efficacy assessment of convalescent plasma therapy for COVID-19 patients:a multi-center case series

Convalescent plasma therapy in critically ill coronavirus disease 2019 patients with persistently positive nucleic acid test, case series report

Convalescent plasma to aid in recovery of COVID-19 pneumonia in a child with acute lymphoblastic leukemia

Convalescent plasma therapy: Helpful treatment of COVID-19 in a kidney transplant recipient presenting with serve clinical manifestation and complex complications

Successful recovery of COVID-19-associated recurrent diarrhea and gastrointestinal hemorrhage using convalescent plasma

Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome, Pediatr Blood Cancer

Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients

Viral load and sequence analysis reveal the symptom severity, diversity, and transmission clusters of rhinovirus infections

Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia

Early experience with convalescent plasma as immunotherapy for COVID-19 in China: Knowns and unknowns

Potential interventions for novel coronavirus in China: A systematic review

Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo

Convalescent plasma as a potential therapy for COVID-19

Convalescent plasma transfusion for the treatment of COVID-19: Systematic review

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Treatment options for COVID-19: The reality and challenges

The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis

Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?

Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease for transfusion, as an empirical treatment during outbreaks

Content current as of: 04/13/2020

National Health Commission of the People's Republic of China. Diagnosis and Treatment of COVID-19

National Health Commission of the People's Republic of China. Diagnosis and Treatment of COVID-19

National Health Commission of the People's Republic of China. Diagnosis and Treatment of COVID-19

Drug Use and Transfusion Safety of Blood Donors, Chinese Pharmacovigilance

Does blood donor history accurately reflect the use of prescription medications? A comparison of donor history and serum toxicologic analysis

Presence of medication taken by blood donors in plasma for transfusion