Abstract
Aim : Till date, no proven treatment exists for coronavirus disease (COVID-19), though different types of treatment modalities are being practiced around the world. Small-scale convalescent plasma (CP) therapies from COVID-19 recovered donors have shown favorable results with fewer adverse consequences. In this systematic review, we aimed to determine the safety and efficacy of CP as a therapy for COVID-19.
Methods: The English language databases of PubMed, Google Scholar, and ScienceDirect were searched upto 22 May 2020. Eligibility for inclusion, risk of bias assessment, and data extraction from the included studies was determined and a narrative synthesis was conducted.
Results : A total of 12 studies were selected for review. The overall risks of bias was high. The results revealed that the initiation of CP therapy during the early stages of viremia was significant in a safety and efficacy viewpoint. The patients were also receiving concomitant drugs and other supportive therapies in 10 studies. Viral loads were documented to decrease and become negative in 8 studies within 3-26 days post-transfusion. The improvement in clinical symptoms following CP therapy was demonstrated in 9 studies. Most of the patients experienced very few adverse effects. There were a total of 622 mortalities out of 5079 patients in total studies.
Conclusions : The rational practice of CP therapy based on a risk-benefit judgment can prove to be an efficacious therapeutic option until the approval of any therapeutic and/or prophylactic agent(s), though substantial randomized controlled trials (RCTs) are necessary to validate the effectiveness of such therapy.
INTRODUCTION
COVID-19 is a respiratory tract infection caused by a new strain of coronavirus called severe acute respiratory syndrome conoravirus -2 (SARS-CoV-2) that spread so rapidly from its first outbreak in late December 2019 in Wuhan, Hubei province of China. There are altogether 5,267,419 confirmed cases with the death toll climbing at 341,155 worldwide as of 25 May 2020.1 This infectious disease is associated with mild to severe symptoms such as fever, cough, fatigue, shortness of breath to acute respiratory disease syndrome (ARDS), sepsis, multi-organ failure including acute kidney injury and cardiac injury in a complicated status resulting in death2. Old age, immune-compromised cases, and comorbidities are the risk factors that lead to death in COVID-19.2,3 A recent structural analysis indicated the probable origin of the virus as a bat, from where it has transmitted to humans after mutation in the spike glycoprotein and nucleocapsid protein.4 Then human to human transmission started mainly through contact with an infected person as it gets airborne and by touching the face by hand after contact with an object containing the virus.5 The world health organization (WHO) has already declared it as a pandemic on 11 March 2020 due to the over 118,000 reported cases from 110 countries around the world by that time with the sustained risk of further global spread.6
Still, there is no proven treatment to cure the condition due to the lack of substantial evidence. The time constraint and pandemic outbreak are the major challenges to deal with COVID-19. Supportive care has been practiced as stated in the WHO interim guidance for COVID-19 management with a major focus on oxygenation, ventilation, symptomatic treatment, fluid management, and prevention of complications based on the clinical status of patients.2 Different therapeutic agents are being used in clinical settings around the world, some of which are like a combination of azithromycin and hydroxychloroquine, antivirals like remdesivir, oseltamivir, ganciclovir, combination of lopinavir and ritonavir, and steroids.7 Recently conducted RCT has shown a lower rate of seroconversion and more adverse effects with hydroxychloroquine among mild to moderate COVID-19 cases.8 Other observational studies also showed no clinical efficacy with hydroxychloroquine.9 As a ray of hope, the emergency use of remdesivir has been recently approved by the US-Food and Drug Administration (US-FDA) to be used in certain conditions10, though its use has not led to significant benefit in RCT conducted by China.11
CP therapy is one of the approaches adopted following the guidance provided by the US-FDA to use CP as an investigational product during such a global health crisis.12,13 The lack of effective intervention has made it necessary to explore and review CP therapy as a potential therapeutic modality for COVID-19. It is a classical adaptive immunotherapy where antibodies from the plasma samples of patients recovered from a virus are transfused with adequate neutralizing antibody titers to the patient affected by the same virus as a therapy or a prophylactic measure to patients exposed to the same virus.14,15
Figure 1: Convalescent plasma therapy process for COVID-19
METHODS
This review article was based on the PRISMA protocol.16
Search strategy
PubMed, Google Scholar, and Science Direct were searched for “COVID-19”, “Convalescent plasma therapy”, “COVID-19 plasma therapy”, “Plasma therapy coronavirus”, and “SARS-CoV-2 plasma therapy” for articles published till 25 May 2020. The search strategies used can be found insupplementary data 2.
Inclusion criteria
The original research articles including case reports, case series, observational studies, retrospective studies, randomized or controlled studies about CP therapy for the treatment of COVID-19 were reviewed and included.
Exclusion criteria
The exclusion criteria considered were articles about other viral pandemics without any discussion of COVID-19 and its management with CP therapy. Review articles, viewpoints, editorials, letters, perspectives, comments, and protocols were excluded along with non-English literature and articles with no full text.
Extraction of data
Data were extracted by two reviewers separately and a table was filled according to the data. Studies were selected by two reviewers (SK and PB) owing to the criteria and any differences between articles selections were resolved based on the review of a third person (DBS).
Assessment of bias
The overall bias for our study was determined to be high. All our studies were non-randomized. The sample size was small in most of the studies except Joyner’s study (n = 5000), but it was a non-randomized trial. We found the selection bias to be high among all our studies. No blinding of treating physicians and patients was done in most of the cases. In a few studies, the lack of proper follow up of the patient’s outcome was mentioned like Joyner’s study. In most studies, other prognostic factors like chronic medical conditions were not taken into account. The detailed bias assessment is done in thefigure 2.
Statistical analysis
It was not possible for a meta-analysis because of the inadequacy of research articles.
  1. RESULTS
  2. Study selection
A total of 1128 potentially eligible articles were retrieved from the initial database searches. After the exclusion of 132 duplicates, the abstracts of 996 articles were reviewed. 939 articles were excluded because of the unavailability of full texts, other languages, and being predominantly not related to plasma therapy and COVID 19. Full texts of 57 articles were extracted and among them, we selected 12 studies for review as depicted in figure 3 .
Figure 3: Prisma flow diagram of the study process
Out of the 12 studies included; 6 studies were case-series, 3 case reports, and the rest of the 3 studies were a single-arm prospective intervention, retrospective observational study, and clinical trial. The extracted studies are mentioned in table 1 , including their important particulars. Eight studies were conducted in China, three in the United States (US), and the rest in South Korea.
Study population
A total of 5079 patients were involved in 12 studies with 3197 males, 1856 females, and 23 other genders. The age range of the people was 19 – 97 across the 12 studies. Two pregnant patients were present in studies.17,18 Comorbidities like chronic obstructive pulmonary disease (n = 2), hypertension (n = 17), and diabetes mellitus(DM) (n = 16) were present in the 7 studies.14,17-23
Dosage and neutralizing antibody titer
The dosage of CP therapy was varied from 200 – 2500 ml across 12 studies. The most frequently used dosage was 200 ml across 7 studies. Only 2 studies conducted by Shen et al and Duan et al mentioned the neutralizing antibody titer following CP therapy, which was found to be 1:80-1:480 and 1:640, respectively.14,19
Initiation of CP therapy
CP therapy was initiated 1-37 days after admission to the hospital or 4 – 31 days after onset of symptoms. Initiation of CP therapy during the early stages of viremia has generally been shown to be more beneficial in various studies.18,23 The quickest initiation of CP therapy on the first day of admission was done in the study of Anderson et al.18
Intensive care unit (ICU) admission and mechanical ventilation
A total of 3391 patients were admitted to ICU in 12 studies. 49 patients were mechanically ventilated in 10 studies. In nine studies, nine patients received low oxygen flow therapy, while 17 patients received high flow oxygen therapy. According to Joyner et al, 72% (n=3600) patients had respiratory failure and most likely required ventilator support or other forms of oxygen therapy, but the modality has not been mentioned.24 ARDS was diagnosed in 1750 cases across 10 studies except for Pei et al and Joyner et al.
Concomitant therapy
Antiviral, interferon, and steroids were widely used across all studies. Remdesvir was used in 2 studies done in the US by Andersen et al and Salazar et al.18,23 Antibacterials like azithromycin, levofloxacin, and vancomycin were used along with antifungals. Hydroxychloroquine was used in 4 studies. Azithromycin, hydroxychloroquine, and remdesevir were used concomitantly in 2 studies done by Salazar et al and Andersen et al in the US.18,23 The Chinese herbal medication was practiced in a study by Tan et al in China.25
Clinical benefit and discharge following CP therapy
The improvement in clinical symptoms following CP therapy has been mentioned in 9 studies. Studies conducted by Joyner et al and Pei et al did not properly mention such improvement.24,26 About 75 patients in 9 studies required different forms of respiratory support at baseline. In Tan’s study, the patient was clinically stable before CP therapy and remained stable until the end.25
Shen et al reported a normal temperature of patients within 3 days (n = 4).19 An increase in PaO2/FiO2 was obtained within 12 days (Range: 172 – 276 before and 284 - 366 after) despite patients having severe ARDS before CP therapy. Neutralizing antibody titers increased (Range: 40 - 60 before and 80 - 320 on day 7) with the resolution of ARDS (n = 4) at 12 days and weaning of mechanical ventilation (n = 3) in 2 weeks. Three patients were discharged 32-35 days post CP therapy.
Zhang et al described extubation of 2 patients in 31 and 39 days of hospital stay, although all 4 patients had severe ARDS at baseline.20 Three patients were discharged from 7 – 27 days post CP therapy. One patient got shifted to the ICU. Chest computed tomography (CT) showed a complete resolution in 1 case.
Ahn et al reported an increase in PaO2/ FiO2 to 230 and 300 on days 9 and 18 in 2 patients who had severe ARDS at baseline.21 Weaning from ventilation and tracheostomy was done in 1 patient. Another patient was extubated and discharged at 18 days post CP therapy.
Duan et al mentioned improvement in clinical symptoms in 1-3 days following CP therapy and decreased respiratory support in 4 of the 10 patients.14 The resolution of CT abnormalities was seen in 7 days. Normal lab findings and improvement in pulmonary functions reported after CP therapy. Then, 3 cases were discharged and 7 were prepared for discharge.
Ye et al reported improvement in clinical symptoms and resolution of CT scans in 4 patients requiring oxygen support following CP therapy.17 Four patients were discharged 4 - 10 days post-transfusion.
Zeng et al described the discharge of 2 patients, one from treatment and another from the control group.22 Nothing was mentioned about the clinical benefit following CP therapy with a primary focus on the clearance of viral load. All 21 patients were in ICU from both control and treatment groups at baseline.
Pei et al described 2 successful cases of CP therapy who were discharged on 7 and 14 days post-transfusion. The patient who had anaphylaxis to such therapy was discharged later than successful cases on 23 days post failed transfusion.26
Salazar et al described changes in clinical status on day 7 and day 14 using a 6 point WHO ordinal scale.23 All 25 patients were in critical condition and admitted to ICU at baseline. At day 7 post-transfusion, 9 patients got improvement, while 13 remained static and 3 deteriorated. At day 14 post-transfusion, 19 patients got clinically better, while 3 were unchanged, 3 deteriorated, and 1 died. At days 7 and 14, the discharged cases were 7 and 11, respectively. This was a prospective study that demonstrated clinical benefit following CP therapy.
Anderson et al described a patient who required high flow oxygen on the day of CP therapy and was intubated a day post CP transfusion.18 She was extubated after 9 days, oxygen support was withdrawn after 10 days, and discharged after 13 days post-transfusion. The patient was continued on remdesivir which affects the certainty of evidence regarding the benefit being solely due to CP therapy.
Yang et al described a patient who required non-invasive positive pressure ventilation at baseline. Upon 4 doses of CP therapy, the clinical and radiological improvement was demonstrated after 3 days of the fourth plasma transfusion.27
Mortality
Out of 5079 patients across 12 studies, the mortality reached 622. No mortalities were there in 9 studies (n=33). Among the rest 3 studies; 1 mortality in Salazar’s study, 19 in Zeng’s study where 5 in treatment and 14 in the control group, and 602 mortality in 7 days after CP therapy in Joyner’s study were demonstrated.22-24
Viral load after CP therapy
Viral loads were documented to decrease and become negative in 8 studies.14,17,19-22,25 The time frame for negative viral load post CP therapy varied from 3-26 days. Zeng et al performed a retrospective observational study in which viral clearance was 100 % in the treatment group (n = 6) and only 21.4% in control group, which supports the evidence of quicker viral clearance with CP therapy.22 Similarly, a study conducted by Tan et al demonstrated a negative viral load a day after transfusion.25