key: cord-0718190-l1vayql6 authors: Pawar, Ashish Yashwantrao; Hiray, Apoorva Prashant; Sonawane, Deepak Devidas; Bhambar, Rajendra Sudhakar; Derle, Deelip Vishram; Ahire, Yogesh Suresh title: Convalescent plasma: A possible treatment protocol for COVID- 19 patients suffering from diabetes or underlying liver diseases date: 2020-05-12 journal: Diabetes Metab Syndr DOI: 10.1016/j.dsx.2020.05.023 sha: 3d795c662b4fe8a4c38dacc1a3f84546409fcfdb doc_id: 718190 cord_uid: l1vayql6 BACKGROUND & AIM: As on date, no specific treatment is available for devastating COVID-19 (SARS-CoV-2) infection. This pandemic viral infection has affected over 200 countries within a very short time and created a calamitous situationacross the globe. As per WHO guidelines, the treatment is mainly symptomatic andsupportive. This clinical protocol has not proven sufficient to save the lives of COVID-19 patients suffering from diabetes or having underlying liver diseases; hence there isutmost need to tackle this situation by other means such as Convalescent Plasma (CP)therapy. METHODS: A comprehensive literature survey was carriedout using Elsevier, PubMed, Taylor & Francis, Springer, Nature and Google searchengines. RESULTS: The patients suffering from diabetes or liverdysfunction or any other underlying diseases are at greatest risk of SARS-CoV-2infection. From the study, it is proved that plasma collected from the recovered patientsof viral infection has considerable potential to treat the viral disease without theoccurrence of adverse effects. CONCLUSION: The CP therapy can bea possible life saving alternative to treat critical COVID-19 patients having diabetes orunderlying liver dysfunction. Hence, randomised clinical trials are recommended at theearliest to save the lives of infected individuals of COVID-19. A novel Coronavirus disease 2019 is the infection of the respiratory tract caused by Severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) which has created a disastrous situation in most of the countries. The first case of COVID-19 was reported in China's Wuhan State (capital of Hubei province) in December 2019 [1] . It is a highly infectious disease and almost reached every country across the globe (Over 200 counties) within a very short span. By April 20, 2020 over 24 lakh people were infected with COVID-19 and caused over 1.7 lakh deaths worldwide [2] . The mortality rate based on the cases which had an outcome is on higher side, i.e. 20% [2] . Most of COVID-19 patients were asymptomatic (or with very mild symptoms) and recovered themselves, which were very difficult to be detected; otherwise the total number of COVID-19 cases reported so far would be on the higher side. As on date, no effective therapy is available to treat devastating SARS-CoV-2, the treatment is mainly experimental or empirical. According to the figures of the International Diabetes Federation, more than 463 million peoples were suffering from diabetes globally [3] . Very limited data is available regarding COVID-19 patients with diabetes, but it is reported that the diabetic patients are at the utmost risk of SARS-CoV-2 infection. The recent report published by Chinese Centre for Disease Control and Prevention of 72,314 cases of COVID-19 shown that, the mortality rate is on the higher side if the virus infected patient is suffering from diabetes. (7.3% in patients with diabetes while only 2.3% in other patients) [4, 5] . Similarly, those suffering from advanced chronic liver diseases are also at greatest risk of infection owing to autoimmune liver diseases and cirrhosis-associated immune dysfunction [6] . It has been confirmed that, the liver cells get infected with SARS-CoV-2 infection as the receptor of the virus is ACE2, which has been revealed to be expressed on cholangiocytes [7, 8] . The study confirmed that, 43 out of 99 patients infected with SARS-CoV-2 had some sort of liver function abnormality. The drugs like Chloroquine, Hydroxychloroquine and Remdesivir [9] were reported to be effective in some studies, but not efficacious in critically ill and aged patients of COVID-19. The patients with diabetes or any other severe underlying condition may develop serious respiratory diseases if infected with the COVID-19 infection. To combat such a devastating situation, this article highlights research in the fields of neutralizing antibodies (nAbs) present in convalescent plasma for the treatment of SARS-CoV-2. A comprehensive literature survey was carried out using Elsevier, PubMed, Taylor & Francis, Springer, Nature and Google search engines to prepare a descriptive review on this topic. The Professors from University of Oxford, UK and SP Pune University, India as well as the Physicians of COVID 19 hospitals of India were consulted to discuss the use of the CP therapy and its potential to combat COVID-19 infection. The search terms, "SARS-CoV-2", "COVID-19" and "Neutralizing Antibodies" along with "Convalescent plasma", "Diabetes" and "Liver diseases" were thoroughly investigated using search engines. The SARS-CoV-2 is an enveloped, single-stranded and positive (+) sense RNA virus. It belongs to the beta-CoV genera of Coronaviridae family. Structural proteins like membrane (M), nucleocapsid (N), spike protein (S) and envelope (E) protein play a vital role in the entry of virus and its replication in the host cell [10] . The recovered patients of COVID-19 have high neutralizing antibody titre, which can be an important donor source of Convalescent Plasma. The neutralizing antibodies can be efficacious in virus clearance and can act as a key immune product to treat viral diseases [11] . If nAbs specific to particular virus are administered in infected individual, it may reduce viral replication and disease severity. It may be possible means to limit the COVID-19 pandemic infection. The S protein of SARS-CoV-2 is one of the major targets for developing neutralizing antibodies to inhibit the binding and fusion of SARS-CoV-2. Schematic mechanism of neutralizing antibodies is highlighted in Figure 1 . Neutralizing antibodies binds with Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein as shown in the aforesaid figure. The protruding portion (blue colour) highlights the antibody epitope [12] . It has been reported that the ACE2 is the cell entry receptor for SARS-CoV-2 as like SARS-CoV because ACE2 shows binding to the receptor binding domain of both SARS-CoV and SARS-CoV-2 [13] . In the present scenario the research in the globe is focused on identifying neutralizing antibodies which can target the spike protein responsible for viral entry into the host cell, producing protective results in affected individuals. It has been reported that; the antibodies isolated from the recovered individuals of viral diseases were administered to an infected individual at an early stage, may magnificently reduce the viral load and disease mortality associated with SARS viral infections [11] . Suppression of the viraemia was also reported because of antibodies present in convalescent plasma. Hung and his associates highlighted the effective use of convalescent plasma in H1N1 viral infection. The dramatic reduction in viral load was observed within 5 to 7 days of symptom onset [14] . Besides, significant reduction in mortality was also observed in patients treated with convalescent plasma. The research conducted by Hung IF et al. revealed successful treatment over 20 patients suffered with pandemic influenza A (H1N1)2009 viral infection [15] . The serum cytokine response, viral load of the respiratory tract and the mortality rate were greatly reduced with the treatment of convalescent plasma. In a study in Hong Kong, 80 patients who were suffering from severe acute respiratory syndrome (SARS) infection were administered with convalescent plasma [16] . Some patients received convalescent plasma after day 14 of infection, while some received immediately after the infection. It was observed that, patients treated earlier successfully recovered from the clinical symptoms of infection than those who received plasma after day 14. It signifies the efficacy of CP therapy, which depends on how early you start the treatment of affected individuals after confirmed identification of infection. A clinical study conducted on three patients of SARS infection in Taiwan also highlights the effective use of convalescent plasma [17] . All these three patients were critical and did not respond to available therapy. They were administered with convalescent plasma and the therapy was found to be successful within a span of 24 hours of administration of CP. The viral load decreased from day 2, the hyperthermia dropped dramatically and all patients survived. The major limitation of the study was a very small sample size. Effectiveness of CP therapy along with brincidofovir was also reported against the devastating Ebola virus disease in the year 2015 in Africa [18] . The viral load decreased immediately after starting investigational therapy with CP in most of the infected persons. Zhou B. highlighted promising use of passive immunotherapy for the treatment of influenza A (H5N1) infection in China [19] . The critical patients were not responding to Oseltamivir alone, but recovered by combinational approach using Oseltamivir with CP therapy. Immediately after transfusion (within 8 hrs) of CP therapy, the viral load was found to be reduced by a factor of 12 (from 1.68×105 to 1.42×104 copies per millilitre). Arabi Y. has also demonstrated the use of CP at early stages of MERS-CoV [20] which has considerable potential for clinical improvements in affected individuals. Chenguang S. efficaciously carried out treatment of five critical patients of SARS -CoV-2 (COVID-19) with convalescent plasma [21] . The significant improvements in clinical status of four infected individuals out of five were reported within ten days of transfer of convalescent plasma. The body temperature normalised within three days of initiation of treatment. It was observed that, the viral loads were also decreased and it seems to be negative after 12 days of transfer of CP. Chen L. has clearly stated the use of convalescent plasma for COVID-19 as a promising approach [22] . It has emphasised on the successful use of CP against the SARS -CoV, Ebola, MERS and H1N1 viral species. One of the promising clinical studies carried out against the devastating SARS-CoV-2 (COVID-19) successfully demonstrated the operational use of CP therapy [23] . The therapy was adopted to treat 10 severe adult cases from China who was intolerant to available therapy. The single dose of 200 ml of CP showed the remarkable results in affected serious patients. The dose was well tolerated by all individuals with minimal side effects. The clinical symptoms were improved within 3 days of CP therapy and the viraemia was also disappeared on day 7. The increase in oxy-haemoglobin saturation on day 7 along with lymphocyte counts was also observed. The recent useful study carried out in China over 175 patients recovered from COVID-19 viral infection clearly highlights the generation of SARS-CoV-2-specific neutralising antibodies (spike binding) from day 10 to 15 after infection [24] . From day 10 the peak levels of neutralising antibodies were detected in all patients and these antibodies were remained stable thereafter. The clinical trials of Convalescent plasma therapy conducted /initiated against COVID-19 pandemic across the globe are summarised in Table 1. The said table highlights the doses, participants and findings of different studies of CP therapy. In India, Drug Controller General of India (DCGI) has given permission to the Indian In India, many of the recovered patients of COVID -19 are ready to donate their plasma to save the lives of other infected individuals. The plasma collected from one recovered patient can be sufficient to treat two to three COVID -19 patients. In the present outbreak of COVID-19, whole blood consisting of plasma collected from SARS-CoV-2 patients, which may be administered to infected persons and can be investigated as one of the possible means of treatment. The schematic representation of passive antibody therapy for COVID -19 patients, highlighting the major steps is shown in 13. The adverse effects (if any) after the administration of CP should be closely monitored. No serious adverse effects were reported in the CP therapy previously carried out in SARS, MERS, H1N1 and Ebola infection outbreak [15, 16, 20] . The therapy was well tolerated in most of the patients while some reported non-lethal adverse effects. The adverse effects like increase in body temperature, nausea, itching, chills and skin rashes were reported in some studies [32] . These events were resolved spontaneously by symptomatic treatment or by reducing the rate of transfusion. The transfusion related adverse effects like circulatory overload, anaphylactic reactions and transfusion related acute lung injuries (TRALI) were also reported in few patients [33] . The incidence of TRALI is very rare (affecting one in every 5,000 patients) and observed in severe patients only. The risk of Hepatitis B virus, Hepatitis C virus and HIV disease transmission through the donated plasma should be thoroughly investigated. Very limited information is available on the safety of CP therapy in pregnant patients of viral diseases; hence sufficient results are warranted prior to use of CP therapy in pregnancy. From the evidences highlighted in the aforesaid study, convalescent plasma from the recovered patients of COVID-19 can be effectively used as a treatment protocol for SARS-CoV-2 viral infected patients having diabetes or underlying liver diseases. The CP therapy has greatest potential to treat the devastating COVID -19 viral infections. Most of the earlier studies were carried out with fewer numbers of patients having diabetes or liver diseases; hence further in-vivo studies on a large scale will be required to generate statistically significant data in terms of its efficacy and to investigate possible adverse effects associated with it. The optimal dose, time of administration and clinical aspects of CP therapy should be investigated. There is utmost need to assess available in vitro-in vivo data and to carry out randomised clinical trials on COVID -19 patients having diabetes or any other comorbidity to save the valuable lives of infected individuals across the globe. Table 1 : Summary of clinical trials of Convalescent plasma therapy conducted /initiated against SARS-CoV-2 (COVID-19) viral strain across the globe A pneumonia outbreak associated with a new coronavirus of probable bat origin International Diabetes Federation. 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