|Ahead of print publication
Convalescent plasma therapy in severe coronavirus disease-2019: A narrative review
Rasmi Ranjan Sahoo, Kasturi Hazarika, Prashant Bafna, Manesh Manoj, Anupam Wakhlu
Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow . 226 018, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Passive immunotherapy using whole blood or plasma from recovered patients is a potential therapeutic strategy for infections with no known drug therapy or prophylactic vaccines. Much before, the concept of transfusing neutralizing antibodies through convalescent blood or plasma was established; this modality demonstrated its effectiveness in containing the havoc caused by diphtheria and tetanus during the early 20th century. Convalescent blood products were effective in reducing the mortality risk when administered early in the disease course during the deadliest pandemic of Spanish flu in 1918. Even in the antibiotic era, the use of passive immunization strategy continued to expand with promising results against measles, Ebola, Argentine hemorrhagic fever, and Zika viruses. It was also effective in reducing the mortality and viral load in severe acute respiratory syndrome, H5N1, H1N1, and Middle East Respiratory Syndrome. Convalescent plasma administration carries the risk of anaphylactic reactions, transfusion-related acute lung injury, and transfusion-associated circulatory overload, but these are extremely rare. The impact of the recent coronavirus disease 2019 is enormous with significant morbidity and mortality. Until, a specific antiviral therapy or an effective vaccine is made available, the consideration for use of convalescent blood products, especially plasma, is warranted. Conceptual and observational wisdom often blossoms among therapeutic penury.
Keywords: Convalescent plasma, coronavirus disease-2019, critically ill, passive immunity, severe acute respiratory syndrome coronavirus 2
| Introduction|| |
Coronavirus disease-2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has ravaged humankind in a matter of few months, since its possible origin in Wuhan city, China, in December 2019. This has led the World Health Organization (WHO) to declare COVID-19 as a pandemic on March 11, 2020. The brunt of SARS-CoV-2 seems relentless with approximately 1.9 million people in 213 countries or territories being affected and mortality of 0.12 million as of April 15, 2020. The lack of a specific antiviral therapy or an effective vaccine makes the situation even more gloomy, with a greater number of deaths being imminent. Although the studies on effectiveness of antivirals remdesivir and favipiravir in severe COVID-19 are encouraging, their efficacy against SARS-CoV-2 is yet to be established., With the deteriorating scenario, it may be prudent to look back the way the world handled the previous epidemics and pandemics. Passive immunization can be a promising option in the treatment of viral infections, which are novel and carry serious morbidity and mortality. The empiric use of convalescent plasma (CP) in SARS-CoV, H1N1, and H5N1 influenza was effective in improving the survival rates and reducing viral load.,, Treatment with CP was also effective in Middle East Respiratory Syndrome (MERS) patients. Thus, possibly, the administration of CP in severe COVID-19 could be of considerable importance to reduce infectivity, mortality, and help in the containment of the pandemic.
This review aims to study the current status of CP transfusion in COVID-19 and its future applications.
| Search Strategy|| |
A PUBMED search was conducted using the search terms “Convalescent Plasma and COVID-19” on April 15, 2020, and 21 articles were retrieved. Articles published in the English language were included. After screening the titles and abstracts of these articles, 11 articles, including review articles, case reports, and case series were finally considered. In addition, cross-referencing of the selected articles was done to include the relevant literature.
| Convalescent Plasma Use: Historical Perspective|| |
The concept of CP administration as a therapeutic option was introduced by von Behring and Shibasaburo Kitasato way back in 1890s. In 1898, von Behring along with Kitasato demonstrated that serum from an animal with tetanus could confer protection to another animal with the disease, and the same would be applicable for diphtheria also. This discovery bestowed the world a new victorious weapon to fight against other viral and bacterial infections and led von Behring to receive the Noble prize in Physiology or Medicine in 1901. The use of passive immunotherapy continued to expand in the preantibiotic era against many viral and bacterial infections to control severe disease.
The Spanish flu pandemic
CP therapy showed promising results during the Spanish flu pandemic in 1918. A meta-analysis of eight studies on convalescent blood products for Spanish influenza pneumonia involving 1703 patients reported 21% reduced mortality in the treatment arm compared to the control arm. The studies also showed early transfusion (<4 days of pneumonia complications) to be more effective than late therapy. In the subsequent decades, CP therapy demonstrated favorable outcomes in the treatment of measles, yellow fever, Argentine hemorrhagic fever, influenza, and a number of other viral illnesses.
Severe acute respiratory syndrome coronavirus and H1N1 pandemics
The efficacy of CP therapy in the treatment of SARS caused by SARS-CoV was evaluated in 80 patients in Hong Kong in 2003. Outcomes were divided as good for those who could be discharged by day 22 following the onset of symptoms or poor for those who died or remained hospitalized beyond day 22. Significantly higher number of patients receiving CP therapy were discharged at day 22 compared to those who did not (58.3% vs. 15.6%; P < 0.001). Plasma therapy also showed promising results during severe influenza A (H1N1) pandemic in 2009. In addition to the reduction in mortality rates, the respiratory tract viral load and cytokine levels (interleukin 6, interleukin 10, and tumor necrosis factor α) were significantly decreased in patients who received CP therapy.
CP therapy was evaluated during Ebola virus outbreak in 2013–2016 in Western Africa. Since the disease had a case fatality rate of 40%-60%, plasma therapy was prioritized by the WHO to assess its effectiveness in reducing the mortality. The risk of death was slightly less in the treatment arm compared to the control arm, although it did not achieve statistical significance. However, the study had several limitations, namely the Ebola virus neutralizing antibodies were not assessed in the donor plasma, the control group was not followed till 30 days, which could have affected the mortality rate in addition to the historical control group used in this study.
Middle East Respiratory Syndrome epidemic
The use of CP was suggested to be a potential therapy for the MERS coronavirus (MERS-CoV) infection. CP administration in three critically ill patients with pneumonia requiring ventilatory support possibly led to their survival during the Korean MERS epidemic in 2015. The suitability of collecting large scale CP for the treatment of MERS-CoV infection was also analyzed in one study and it was found to be feasible. The study highlighted that screening patients who had recovered from more severe disease and at earlier points post recovery would be optimal strategies to identify donors with high neutralizing antibody titers.
Efficacy of convalescent plasma in severe acute respiratory infections
A metaanalysis of 32 studies looking at the efficacy of CP and hyperimmune immunoglobulin for the treatment of SARIs of viral etiology reported a definite reduction in mortality, particularly with early CP administration. The exploratory post-hoc meta-analysis showed the pooled odds of mortality to be 0.25 in the treatment group (95% confidence interval:.14–0.45).
| Use of Convalescent Plasma in Coronavirus Disease-2019|| |
The therapeutic use of CP in COVID-19 pandemic has also been suggested. A number of published and unpublished case series have shown the efficacy of CP use in severe COVID-19 [Table 1].,, The administration of CP led to the improvement in clinical symptoms, reduction in viral load, and withdrawal of ventilatory support. This has triggered clinicians and researchers to carry out controlled clinical trials of CP administration in COVID-19 patients, currently underway in the United States, Europe, China, and India. [Table 2] lists the clinical trials of CP administration in COVID-19 patients registered with Clinical Trial Registry, India and ClinicalTrial.gov, National Institute of Health, USA., The trials of CP in COVID-19 patients which are currently not recruiting but are registered in ClinicalTrial. government are not included (total 24).
|Table 1: Summary of convalescent plasma use in the recent Coronavirus disease 2019 pandemic|
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|Table 2: Clinical trials on covalescent plasma therapy in Coronavirus Disease 2019patients registered in Clinical Trials Registry, India and National Institute of Health, USA|
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| Current Recommendations for Convalescent Plasma Therapy in Coronavirus Disease-2019|| |
The use of CP for the treatment of serious or immediately life-threatening COVID-19 infections has been approved by the US Food and Drug Administration (FDA) in March 2020, provided the treating physician gets approval from the FDA by either submitting a form online or a verbal approval over the telephone. Severe disease include dyspnea, respiratory rate ≥30/min, SPO2 ≤93%, PaO2/FiO2 <300, or lung infiltrates >50% within 24–48 h, whereas life-threatening disease is defined as respiratory failure, septic shock, or multiple organ failure.
In India, the Indian Council of Medical Research has invited centers to participate in a phase II, open label, randomized controlled study and recommend CP administration as a treatment option in critically-ill COVID-19 patients as part of the clinical trial. Kerala has become the first state to get approval to initiate CP therapy in COVID-19 patients by the end of April 2020.
| United States Food and Drug Administration Recommendations for Convalescent Plasma Administration in Coronavirus Disease-2019|| |
FDA has issued guidelines for the health-care providers and investigators for the use of CP in COVID-19 as an investigational new-drug application (IND) under the IND regulatory pathway, an expanded access IND and a single-patient emergency IND application (eIND). Investigators wishing to conduct the clinical trials of CP are required to get approval as per the traditional IND requirements. Expanded access IND is for those serious or immediately-life threatening COVID-19 patients who are not eligible for or who are unable to participate in clinical trials, whereas single-patient eIND is for individual patients in urgent need.
The patient selection and donor eligibility criteria for CP therapy in COVID-19 patients as per FDA recommendations are described in [Table 3].
|Table 3: Food and Drug Administration recommendations xsfor patient selection and donor eligibility criteria for convalescent plasma therapy in Coronavirus Disease 2019|
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| Proposed Mechanisms of Action of Convalescent Plasma|| |
The effectiveness of CP therapy is mediated through the presence of polyclonal antibodies, which either directly neutralize the infectious agent or by antibody-dependent mechanisms, namely antibody-dependent cellular cytotoxicity and phagocytosis, and complement activation. Besides, nonneutralizing antibodies, which do not interfere with viral replication, also play a role in promoting early recovery.
| Adverse Effects of Convalescent Plasma|| |
CP administration can lead to allergic/anaphylactic reactions, including serum sickness and local Arthus reaction, transfusion related acute lung injury (TRALI), transfusion-associated circulatory overload and less commonly, transmission of infections, red blood cell-alloimmunization and hemolytic transfusion reactions. However, reports of serious adverse event with CP use are extremely rare, with two cases of TRALI after CP therapy for Ebola virus disease and MERS., The meta-analysis of studies on SARIs due to viral etiology reported CP administration to be a safe therapeutic modality. Antibody-dependent infection enhancement is one proposed mechanism for increased virus replication with CP therapy and has been reported with HIV, dengue, and feline coronaviruses. It has also been shown with SARS-CoVin vitro model of HL-CZ human promonocyte cell line with diluted antisera against SARS-CoV, especially with antibodies against envelope spike proteins. This could be a potential hindrance in the development of an effective SARS-CoV vaccine. The results of a phase 1 study to evaluate the safety of CP therapy in SARS-CoV-2 patients, which is scheduled to be completed by April 30, 2021, would definitely shed light on the above dilemma (Clinical Trials registry no. NCT04333355).
| Timing of Administration of Convalescent Plasma|| |
Since viremia occurs in the 1st week of most viral illnesses, it has been suggested to administer CP as early as possible to prevent the dissemination of infection. Once the primary immune response sets in 10–14 days of the onset of illness, the neutralizing antibodies help in the clearance of viruses. This concept is also supported in the meta-analysis by Luke et al. who demonstrated early CP administration within 4 days was associated with improved survival during the Spanish flu pandemic.
| Limitations of Convalescent Plasma Administration|| |
Although the use of CP in various infectious diseases is more than a century old, there are no well-designed clinical trials to establish its effectiveness. Available data from case series or case reports tends to be low-quality evidence, as they lack control groups and were possibly subjected to bias. The optimal dosage, timing of administration, and selection of patient group are to be validated in randomized controlled trials, if feasible. Feasibility of large-scale collection of CP is a challenging issue. As per the current understanding of COVID-19 disease, elderly individuals and those with preexisting comorbidities are at a high risk of severe disease. However, these criteria alone are too broad as blanket criteria warranting the early administration of CP. Donor selection as per the national guidelines is another practical issue to be addressed. Assessment of neutralizing antibodies before transfusion and apheresis technique availability are other difficulties. One study of CP on patients who had recovered from Ebola showed not all patients had anti-Ebola neutralizing antibody. Adequate screening of CP to mitigate possible transfer of other endemic blood borne infections is of considerable importance.
| Future Perspectives|| |
As discussed above, the challenges of CP administration are to be addressed before this form of therapy becomes feasible, widely available, and applicable and is considered as a definitive therapeutic recommendation by the national and international governing bodies. Local attitudes and beliefs will also need to be addressed. Alternative strategies to provide passive immunization should be sought during the time of epidemic or pandemic. Intravenous immunoglobulin can be a therapeutic option in severe COVID-19 patients and has been shown to be effective in a retrospective analysis of 58 COVID-19 pneumonia in reducing hospital and/or intensive care unit stay and mortality. However, its availability, cost, and largescale requirement would significantly limit its use during the pandemic. Should CP become a time trusted and recommended therapeutic option, proven to work in the current COVID-19 pandemic, the subsequent increase in the requirement for CP could be supplemented by the large-scale manufacture and use of concentrated COVID-19 hyperimmune globulin (H-Ig), which is an established therapy for various bacterial and viral diseases. The effectiveness of H-Ig in H1N1 pandemic has already been demonstrated to reduce lower respiratory tract viral load and mortality among patients who were transfused. The feasibility of H-Ig preparation was also established. The development of a monoclonal antibody could be another therapeutic option, needing significant research.
| Conclusion|| |
The relentless onslaught of the COVID-19 pandemic warrants an urgent curative treatment, either an antiviral agent or a vaccine. Until such therapy is available, CP administration in severe disease is undoubtedly the time-tested strategy at present. Further, it is a unique opportunity to conduct the clinical trials to validate the effectiveness of CP against SARS-CoV-2 infection.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]