Convalescent Plasma Transfusion in Severe or critically ill COVID 19 patients: A Rapid Systematic Review

Narayana Goruntla¹*, Mohammad Jaffar Sadiq², Vigneshwaran Easwaran³

¹Department of Pharmacy Practice, Raghavendra Institute of Pharmaceutical Education and Research (RIPER) – Autonomous, KR Palli Cross, Chiyyedu Post, Anantapur 515721, Andhra Pradesh, India.

²Assistant Professor, Department of Clinical Pharmacology, Batterjee Medical College,

Jeddah 21442, Kingdom of Saudi Arabia.

³Assistant Professor, Clinical Pharmacy Department, College of Pharmacy,

King Khalid University, Abha, Saudi Arabia.

*Corresponding Author E-mail: narayanagoruntla@gmail.com

ABSTRACT:

Currently, there is no availability of any proven specific treatment or prevention strategy to fight against COVID-19. Convalescent plasma (CP) therapy is expected to increase survival rates in COVID-19 as in the case of emerging viral infection (SARS-CoV and MERS-CoV). To collect all the studies relevant to CP therapy in critically ill or severe COVID-19 patients and summarize the findings. The systematic review was conducted according to the PRISMA consensus statement. A systematic search was performed in PubMed, Scopus, Web of Science, and Cochrane databases on April 25, 2020. A total of six studies (28 patients) relevant to CP therapy in severe or critical COVID-19 are considered for inclusion. Two authors extracted the data about study characteristics, demographics, symptoms, co-morbidities, clinical classification of COVID-19, drug therapies, oxygen therapy, laboratory results, chest CT, neutralizing antibody titer, SARS-CoV-2 RNA load, aal outcome. The review findings revealed that CP therapy increases lymphocyte count, reduced s serum inflammatory markers (CRP, IL-6, Procalcitonin) and liver enzyme levels (AST or ALT). There was a rise in serum neutralizing antibody titers in 10 of 14 patients after CP transfusion. In 4 of 14 patients, the titer levels remain unchanged after CP transfusion. All 28 cases (100%) achieved negative to the SARS-CoV-2 RNA after CP transfusion. The convalescent plasma transfusion can improve neutralizing antibody titers and reduces the viral load in severe/critical COVID-19 patients. The review recommends a well-controlled trial design is required to give a definite statement on the safety and efficacy of convalescent plasma therapy in severe/critical COVID-19.

KEYWORDS: COVID-19, Coronavirus, Treatment, Convalescent plasma, Critical, Severe.

INTRODUCTION: 

On March 11, 2020, the World Health Organization declared the outbreak of severe acute respiratory syndrome 2 (SARS-CoV-2) as a pandemic¹. Pneumonia caused by the SARS-CoV-2 is named as coronavirus disease 2019 (COVID 19). As of this time point (April 15, 2020) of writing, the SARS-CoV-2 affected 1,914,916 inhabitants and contributed to 123,010 deaths worldwide². Currently, there is no availability of any proven specific treatment or prevention strategy to fight against COVID-19.

The management of critically ill COVID-19 patients is focused on basic life support with oxygenation and fluid management³.A combination of low-dose corticosteroids and antiviral agents is encouraged in critically ill patients, but the evidence of the safety and efficacy of these agents is not well established by controlled trials⁴. Still, some antiviral agents like Remdesivir and Lopinavir/Ritonavir are under investigation to be used in severe COVID-19 patients⁵.

Convalescent plasma (CP) therapy is adaptive immunotherapy developed in the early 1900s and well-preferred clinically in the past two decades to treat various deadly viral infections like polio, measles, and mumps⁶. The CP therapy had shown promising results in the treatment of severe acute reparatory syndrome (SARS), and middle east respiratory syndrome (MERS) caused by the same family coronaviruses (SARS-CoV and MERS-CoV)⁷. Since, the novel coronavirus shares similar viral and clinical characteristics as that of SARS and MERS, CP therapy is an add-on option available to manage critically ill COVID-19 patients⁸. Up to date, the efficacy and safety of CP therapy in the management of critically ill COVID-19 patients were not clear. This systematic review aims to collect all the studies relevant to CP therapy in critically ill or severe COVID-19 patients and summarize the findings for the practice of healthcare professionals. and conduct a clinical trial.

MATERIALS AND METHODS:

A systematic review was performed according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) consensus statement⁹.

Study selection criteria:

All studies relevant to CP transfusion therapy in patients suffering from severe or critical COVID-19 are considered for inclusion. Irrespective of design, studies that were met the criteria and published in the English language are considered for inclusion. Review papers and studies not outlining any clear information about symptoms, co-morbidities, laboratory findings, treatment, supportive therapy, and clinical outcomes are excluded from the review.

Search strategy:

A systematic search was performed in different scientific databases including PubMed, Scopus, Web of Science, and Cochrane to retrieve research articles published up to April 25, 2020. The text words: “COVID-19”, “SARS-CoV-2”, “2019-nCoV”, “n-CoV”, “coronavirus”, “convalescent plasma”, and “plasma” are used in the search process. Searching was made by combining text words and medical subject headings (MeSH) by using Boolean words OR, AND, NOT in Title/Abstract. The search was also extended by applying a snowball method to the references of retrieved papers. In this method, each retrieved paper will be further searched their references to select the paper suitable for this review. All studies published on from the start of COVID 19 were considered for inclusion. The collected studies were screened for plasma transfusion in severe or critically ill COVID-19 patients and included in the review as per study criteria.

Data extraction and analysis:

Two authors extracted the data by using pre-designed, piloted, and customized data extraction form. The data extraction form consists of study characteristics, demographics, clinical features, co-morbidities, clinical classification of COVID-19, drug therapies, oxygen therapy, laboratory results, chest CT, neutralizing antibody titre, SARS-CoV-2 RNA load, and final clinical outcome. The corresponding author solved any disagreement in the data extraction. Descriptive statistics like mean, standard deviation, frequency, and proportion were used to represent the data. The systematic review protocol was not registered due to the limited availability of evidence and urgency of the need.

RESULT:

Study selection:

A total of 6608 articles were identified through searching databases and other resources. In these articles, 40 were duplicated, 580 were published prior to COVID-19 incident, and 5320 does not matched the search terms in abstract and title, hence were excluded from the review. A total of 668 full-text articles were selected for study eligibility screening, out of which 648 articles were not related to CPtransfusion, 9 comprises of wrong study design (2-Review, 1-Commentary, 4- Editorial, 1-News, 1-Letter to editor), and 5 were published in other languages was subjected for exclusion. Finally, 6 articles were included in the study. The complete study selection criterion was presented in the PRISMA flow chart figure 1.

Figure 1. Schematic representation of studies included in the systematic review using PRISMA checklist

Study characteristics and patient demographics:

The background details of the included studies and demographics of participants were summarized in Table 1. In total of 6 studies, case reports (3), case series (2), and descriptive (2), study designs are present in the current systematic review. A total of 28 patients (Male=15; Female=13) were offered convalescent plasma transfusion in the selected six studies. The mean age of the participants in this systematic review is 56.2± 13.4 years. In total 6 studies; 5 were conducted in China and one in Korea as shown in Table 1.

Clinical characteristics and drug therapy in COVID-19:

Distribution of the symptoms, co-morbidities, clinical classification, antiviral, antibiotic, antifungal, corticosteroid, and oxygen therapy recommended in COVID-19 patients was represented in Table 2. The most common symptoms presented at disease onset were fever (17; 73.9%), cough (15; 65.2%), and shortness of breath (13; 56.5%). Hypertension (5; 17.8%) is the most common co-morbidity observed in this review and the majority (15; 53.6%) of the participants are free from the existence of the co-morbid illness. More than half of the patients belong to critical COVID-19 (15; 53.6%). Antiviral agents like Arbidol (19; 67.8%), INF-α (10; 35.7%) and Lopinavir/Ritonavir (10; 35.7%) are widely recommended in severe and critical COVID-19 patients. Antibiotics and antifungal treatment were given when patients have co-infection. The majority of the patients are under oxygen (23; 82.1%) and corticosteroid therapy (15; 53.6%).

Effect of CP transfusion on oxygen therapy:

Before CP transfusion, three patients received extracorporeal membrane oxygenation (ECMO), seven patients received high flow nasal cannula (HFNC) oxygenation, four patients received conventional low flow nasal cannula oxygenation, and seven patients received mechanical ventilation. After CP transfusion, there was a reduction in the number of patients who need to be treated with ECMO, HFNC, LFNC, and MV, as shown in Table 3.

Effect of CP transfusion on laboratory findings:

The most common abnormal laboratory findings observed before CP transfusion include elevated C-reactive protein in 18 patients; raised AST (or) ALT in 7 patients; elevated Procalcitonin in 6 patients; increased IL-6 in 7 reduced lymphocyte count in 12 patients.  After CP transfusion, most of the patients attained normal laboratory values, as shown in Table 3.

Table 1: Characteristics of selected studies and demographics of participants

Authors	Study design	Study location	Study date	Sample size	Age (Y)Range (Mean±SD)	Gender
Duan et al, ^10	Case series	Wuhan, China	April 6, 2020	10	36-76 (54 ± 11.8)	M=6, F=4
Shen et al, ^11	Case series	Shenzhen, China	March 27, 2020	5	30-70 (54 ± 15.2)	M=3, F=2
Zhang et al, ^12	Case reports	China	March 28, 2020	4	31-73 (57 ± 18.9)	M=2, F=2
Ye et al, ^13	Descriptive	Wuhan, China	April 15, 2020	6	28-75 (58 ± 14.9)	M=3, F=3
Ahn et al, ^14	Case reports	Korea	April 23, 2020	2	71, 67a	M=1, F=1
Shi et al, ^15	Case report	China	April 2020	1	50a	M=0, F=1

a=Age indicated in number of years; M=Male; F=Female; SD=Standard deviation; CPT=Convalescent plasma therapy; Y=Years

Table 2: Clinical characteristics and drug therapy of the patients undergone CP transfusion (n=28)

Variable	Duan et al, ^10	Shen et al, ^11	Zhang et al, ^12	Ye et al, ^13	Ahn et al, ^14	Shi et al, ^15	Total (%)
Symptoms
Fever	7	NA	3	4	2	1	17 (73.9)
Cough	8		2	3	1	1	15 (65.2)
Sputum production	5		2	0	0	0	7 (30.4)
Shortness of breath	8		1	4	0	0	13 (56.5)
Chest pain	2		0	0	0	0	2 (8.7)
Sore throat	1		0	0	0	0	1 (4.3)
Nausea and vomiting	2		1	0	0	0	3 (13.0)
Diarrhea	2		0	0	0	0	2 (8.7)
Arthralgia	1		0	0	0	0	1 (4.3)
Myalgia	1		0	2	1	1	5 (21.7)
Phryngalgia	0		1	0	0	0	1 (4.3)
Poor appetite	0		1	0	0	1	2 (8.7)
Fatigue	0		0	2	0	1	3 (13.0)
Co-morbidities
HT	3	0	1	0	1	0	5 (17.8)
Cardio and cerebro	1	0	0	0	0	0	1 (3.6)
HT with MV insufficiency	0	1	0	0	0	0	1 (3.6)
COPD	0	0	1	1	0	0	2 (7.1)
HT with CRF	0	0	1	0	0	0	1 (3.6)
Pregnancy	0	0	1	0	0	0	1 (3.6)
Sjogren syndrome	0	0	0	1	0	0	1 (3.6)
Thyroid nodule	0	0	0	0	0	1	1 (3.6)
None	6	4	0	4	1	0	15 (53.6)
Clinical classification of COVID-19
Severe	10	0	0	0	2	1	13 (46.4)
Critical	0	5	4	6	0	0	15 (53.6)
Other drug therapies
Antiviral Arbidol Ribavirin Remdesivir IFN-α Oseltamivir Peramivir Lopinavir/Ritonavir Favipiravir Darunavir	9 3 1 2 1 1 0 0 0	1 0 0 4 0 0 4 2 1	3 2 0 3 1 0 4 0 0	6 0 0 0 0 0 0 0 0	0 0 0 0 0 0 2 0 0	0 0 0 1 0 1 0 0 0	19 (67.8) 5 (17.8) 1 (3.5) 10 (35.7) 2 (7.1) 2 (7.1) 10 (35.7) 2 (7.1) 1 (3.5)
Antibiotic a Cefoperazone Moxifloxacin Cefoperazone& Tazo Levofloxacin Imipenem-Sitastatin Linezolid Ceftriaxone Imipenem Vancomycin	3 2 2 1 1 1 0 0 0	NA	0 0 0 0 0 0 0 1 1	0 0 0 2 0 0 0 0 0	2 0 0 0 0 0 0 0 0	0 0 0 0 0 0 1 0 0	5 (21.7) 2 (8.7) 2 (8.7) 3 (13.0) 1 (4.3) 1 (4.3) 1 (4.3) 1 (4.3) 1 (4.3)
Antifungal Fluconazole Caspofungin Voriconazole	1 1 0	0 0 0	0 1 1	0 0 0	0 0 0	0 0 0	1 (3.6) 2 (7.1) 1 (3.6)
Corticosteroid	6	5	1	0	2	1	15 (53.6)
Others Hydroxy chloroquine GSF Low dose dopamine Thymalfasin	0 0 0 0	0 0 0 0	0 0 0 0	0 0 0 0	2 0 0 0	0 1 1 1	2 (7.1) 1 (3.6) 1 (3.6) 1 (3.6)
Oxygen	8	5	3	4	2	1	23 (82.1)

^a Proportion of symptoms and antibiotics prescribed was calculated by removing Shen et al. study; NA=Not available; CP=Convalescent plasma; HT=Hypertension; COPD=Chronic obstructive pulmonary disease; CRF=Chronic renal failure; INF=Interferon

Table 3: Effect of CP transfusion therapy on oxygen therapy and laboratory findings

Parameter	Before							After
	Duan et al, ^10	Shen et al, ^11	Zhang et al, ^12	Ye et al, ^13	Ahn et al, ^14	Shi et al, ^15	Total	Duan et al, ^10	Shen et al, ^11	Zhang et al, ^12	Ye et al, ^13	Ahn et al, ^14	Shi et al, ^15	Total
Oxygen therapy
ECMO HFNC LFNC MV None	0 5 2 1 2	3 0 0 1 0	0 2 0 2 0	0 0 2 0 4	0 0 0 2 0	0 0 0 1 0	3 7 4 7 6	0 4 2 1 3	0 0 0 2 3	0 1 0 0 3	0 0 0 0 6	0 0 0 0 2	0 0 0 0 1	0 5 2 3 18
Laboratory findings ^a
Elevated CRP	9	5	NA	1	2	1	18	8	1	NA	0	0	0	9
Lymphopenia	9	0	NA	0	2	1	12	7	0	NA	0	0	0	7
Elevated ALT or AST	5	NA	NA	NA	1	1	7	3	NA	NA	NA	0	0	3
Elevated Procalcitonin, ng/ml (normal range, <0.1)	NA	5	NA	1	NA	0	6	NA	2	NA	0	NA	0	2
Elevated IL-6, pg/ml (normal range 0-7)	NA	5	NA	NA	2	NA	7	NA	2	NA	NA	0	NA	2

^a Percentage of laboratory findings was made by considering only the sample size of studies in which test is available; NA=Not available; AST=Aspartate aminotransferase; ALT=Alanine aminotransferase; CRP=C-reactive protein; ECMO=Extra corporeal membrane oxygenation; HFNC=High flow nasal cannula; MV=Mechanical ventilation; LFNC=Low flow nasal cannula; IL=Interleukin.

Effect of CP transfusion on neutralizing antibody titer and viral load:

Among 28 patients, 14 patients were screened for the serum neutralizing antibody titers before and after CP transfusion. There was a rise in serum neutralizing antibody titers in 10 of 14 patients after CP transfusion. In 4 of 14 patients, the titer levels remain unchanged after CP transfusion. All 28 cases (100%) achieved negative to the SARS-CoV-2 RNA after CP transfusion.

Effect of CP transfusion on chest CT and the final outcome:

There was a great (27; 96.4%) improvement in the abnormal chest CT findings after CP transfusion. Among 28 patients, 14 (50.0%) discharged, and 14 (50.0%) improved in their clinical condition, as shown in Table 4.

Table 4: Chest CT and Clinical status of the patients with COVID-19 after CPT

	Duan et al, ^10	Shen et al, ^11	Zhang et al, ^12	Ye et al, ^13	Ahn et al, ^14	Shi et al, ^15	Total (%)
Improved Chest CT	10	5	4	5	2	1	27 (96.4)
Clinical status Discharge Improved	3 7	3 2	3 1	4 2	1 1	0 1	14 (50.0) 14 (50.0)

CPT=Convalescent plasma transfusion; CT=Computerized tomography

Adverse effects:

One of the patientswho experienced facial red spots upon transfusion of CP in a study conducted by Duan et al. can be considered an exception; other than this single notable reaction, there were no serious adverse effects observed upon CP transfusion.

DISCUSSION:

The current systematic review reviewed 28 patients (15 critical and 13 severe COVID-19) treated with convalescent plasma. Evidence has shown that convalescent plasma transfusion is effective in the fight against MERS-CoV, H1N1, H5N1 avian flu, and SARS-CoV^12–14,7. A systematic review and meta-analysis of the clinical effects of CP transfusion show a significant reduction in mortality¹⁷. In this context, CP transfusion is a promising option in treating COVID-19. To the best of our knowledge, this is the first review done on the effectiveness of convalescent plasma transfusion in severe/critical COVID-19 patients.

Previous evidence shows that viral loads are strongly associated with disease severity and progression²⁰. A human influenza A (H5N1) mediated death is associated with a high viral load and hypercytokinemia²¹. In this review, antiviral therapy has been recommended in all studies, but there was no complete clearance of the virus from the host. Hence, it could be advised that the CP transfusion was added to standard management and supporting therapy of COVID-19 crisis management. The virus-specific neutralizing antibodies present in convalescent plasma help in virus clearance and prevent the entry of the virus into a cell^17,18.This current review revealed that 15 critical/13 severe COVID-19 patients became negative for the SARS-CoV-2 virus after convalescent plasma therapy^22–28.

Recent studies on COVID-19 demonstrated that Lymphocytopenia, elevated liver enzymes (AST or ALT), and high inflammatory markers (CRP, Procalcitonin, and IL-6) are prominent laboratory changes observed in COVID-19 patients⁵. The review findings revealed that convalescent plasma transfusion increases lymphocyte count, and reduces serum inflammatory markers and liver enzyme levels. The findings suggest that hyperactivity of the immune system was suppressed by the antibodies present in the convalescent plasma.

In the current review, antiviral agents like Arbidol (19; 67.8%) and Lopinavir/Ritonavir (10; 35.7%) are widely recommended to treat severe and critical COVID-19 patients. Arbidol is a well-known drug used in influenza that binds with haemagglutinin (HA). A small portion of the SARS-CoV-2 spike glycoprotein trimerization domain (S2) (aa947 – aa1027), which is similar to H3N2 HA, is essential for host cell adhesion through ACE2 and CD26 receptors. Identicalto H3N2 HA binding mechanism, Arbidol could bind with SARS-CoV-2 spike glycoprotein and inhibits the host cell adhesion²⁹. Lopinavir/Ritonavir is a licensed treatment for Human Immuno Deficiency Virus (HIV). The replication of SARS-CoV-2 depends on the cleavage of polyproteins mediated by a protease enzyme called 3-chymotrypsin-like protease (3CLpro). In-vitro studies revealed that Lopinavir/Ritonavir inhibits 3CLpro, which is highly conserved in SARS-CoV-2^4,30. The findings of a clinical study of Lopinavir/Ritonavir versus standard of care (SOC) in severe COVID-19 revealed a lower, but not statistically significant, mortality rate (Lopinavir/Ritonavir=19.2%; SOC=25.0%), and shorter ICU stay (Lopinavir/Ritonavir=6 days; SOC=11 days)³¹. The findings in in-vitro and in-vivo encourage use of Lopinavir/Ritonavir in severe COVID-19.

The principal feature of severe/critical COVID-19 illness is the development of acute respiratory distress syndrome (ARDS). The WHO interim guidelines recommend extracorporeal membrane oxygenation (ECMO) to support patients with ARDS. This review revealed that the need for ECMO, high flow nasal cannula oxygenation, low flow nasal cannula oxygenation, and mechanical ventilation in severe/critical COVID-19 was reduced after providing convalescent plasma transfusion.

There was a rise in serum neutralizing antibody titers in 10 of 14 patients after CP transfusion in the current review. The serum neutralizing antibody titer levels are raised in; five cases up to 1:640, one point up to 1:480, one case up to 1:320, one case up to 1:240, and two cases up to 1:160. The antibody titers in plasma used in COVID-19 treatment is high compared to the MERS patient (1:80)³². This may be a reason for the drastic improvement of the neutralizing antibody titers in severe/critical COVID-19 patients receiving CP.

Among 28 patients, 14 (50.0%) were discharged, and 14 (50.0%) patients were improved in their clinical condition. These findings support the previous study on SARS by viral Etiology,showing a high discharge rate in the convalescent plasma group compared to the corticosteroid group¹⁷.

In the current systematic review, no severe adverse effects were found in any study. One of the patients experienced a facial red spot in Duan et al. study. The significant risk of CP transfusion is the transmission of pathogens and the development of transfusion-related reactions. In a previous study, one of the Ebola virus diseases, a female developed transfusion-related acute lung injury on CP therapy²³. One more important and rare risk of CP transfusion is antibody-dependent infection enhancement at sub-neutralizing concentrations due to suppression of the innate antiviral system²⁴. In this current review, no such type of infection enhancement reaction was observed; this is probably due to high levels of neutralizing antibodies, timely transfusion, and adequate amount of plasma volume transfusion in all studies.

Strengths and limitations:

This is the first systematic review on the effectiveness of convalescent plasma therapy in severe/critical COVID-19 patients. These findings are helpful for healthcare professionals to provide better care to severe/acute COVID-19 patients. The current review included 28 COVID-19 patients from 6 studies; this is not a sufficient number to draw conclusions and generalize the data. In the recent systematic review, there was no comparative controlled trial to support the outcomes due to convalescent plasma therapy and not recommended Antiviral or INF-α therapy. Most of the patients received corticosteroid therapy; this may interfere with and delay viral clearance. This systematic review does not explain the long-term effects of plasma transfusion in COVID 19. The development of CP on the case-fatality rate is unknown.

CONCLUSION:

The current preliminary rapid systematic review concludes that the convalescent plasma transfusion can improve neutralizing antibody titers and reduces the viral load in severe/critical COVID-19 patients. There were no serious adverse reactions observed in this review. Based on our findings in this review, CP therapy can be an easily accessible, promising, and safe option in severe/critical COVID-19 patients. The review recommends, that a well-controlled trial design is required to give a definite statement on the safety and efficacy of convalescent plasma therapy in severe/critical COVID-19. The controlled trials can provide the optimal dose, treatment time points, and definite clinical benefits of CP therapy in COVID-19.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank Research and Development Cell, Raghavendra Institute of Pharmaceutical Education and Research, for constant encouragement to complete this systematic review

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Received on 21.12.2021            Modified on 14.06.2022

Accepted on 07.10.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(4):1992-1998.

DOI: 10.52711/0974-360X.2023.00327