**Abstract**

Novel Coronavirus (nCoV-2019) is a highly infectious viral outbreak that has so far infected more than 110 million people worldwide. Fast viral transmission and high infection rates have severely affected the entire population, especially the old aged and comorbid individuals leaving significantly less time to find some effective treatment strategy. In these challenging times, convalescent plasma (CP) therapy came as a ray of hope to save humankind. It is a form of passive immunization that has been used to treat various infectious diseases since 1890, including the 1918 Spanish flu, 2002/03 SARS-CoV, 2009 H1N1, 2012 MERS-CoV, and 2014 Ebola outbreak. The transfusion includes administration of CP containing a high value of neutralizing antibodies against the virus in hospitalized patients. This chapter summarizes the potential outcome of CP therapy in the treatment of nCoV-2019 patients.

**Keywords:** nCoV-2019, CP therapy, viral infection, neutralizing antibody

#### **1. Introduction**

Convalescent plasma (CP) is defined as a blood plasma that is withdrawn from an individual who had encountered some infectious disease and had recovered with a required amount of antibodies against the disease [1]. It is a way of passive immunization [2]. The concept has been widely used in medical sciences, especially in the case of infectious disease outbreaks. It is an old therapy used since late 1800 [3]. In Germany (1890), researchers treated diphtheria patients with sera from immunized animals. Afterward, the patients were treated with the sera from the recovered ones [4, 5]. The wide use of CP therapy was established during the Spanish influenza outbreak between 1918 to 1920 [6]. Humanity faces a great survival challenge when a new infectious disease emerges and becomes a pandemic. We do not have much to do in such cases, and we mostly rely on our scientific or medical fraternity. Therefore, during such a pandemic/epidemic, there is an urgent need to have a quick, available therapeutic option [3]. A study estimates that on an average basis, there have been 5.3 newly emerged viruses between 1940 to 2004, which includes 60–70% of viruses having an animal origin and have potential to the infect humans [7]. In such circumstances where there are very few options available for

the treatment, and when a patient condition is worsening, CP therapy has always been an excellent choice for clinicians. Humans can get exposed to these viruses by different means of exposure, and generally, these are considered "unavoidable or by chance." In viruses, the major therapeutic challenges arise because of the high degree of genetic changes, which may be due to mutation or genomic instability [8].

In December 2019, a new virus emerged in the Huanan Seafood market and resulted in a dreadful outbreak in China, and the virus rapidly spread to more than 200 countries globally [9]. Further sequence-based analysis of respiratory tract samples identified a novel strain, which was distinct from the other known coronavirus strains, subsequently named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and the disease caused by SARS-CoV-2 infection was designated as novel coronavirus-2019 (nCoV-2019) by the World Health Organization (WHO) [10]. The emergence of novel coronavirus came up as a big challenge for the concerned authorities of the various country [11]. Clinicians had no clue regarding its treatment approaches that made the situation even worse [12]. Soon, on March 11, 2020, WHO declared it a pandemic. In its initial days, the unavailability of any potential drug/therapy resulted in an exponential increase in infections.

For more than a century, this therapy has been widely explored against various outbreaks. During the 2002/3 SARS-CoV outbreak, 2012 Middle East Respiratory Syndrome (MERS-CoV) outbreak, and H1N1 pandemic (2009), CP therapy was successfully explored [13–16]. Similarly, for the 2013/14 Ebola virus infection treatment, CP therapy was recommended as an empirical treatment approach [17]. Based on previous experiences and similarities in terms of virological and clinical characteristics among the SARS-CoV, MERS-CoV, and nCoV-2019 [18], CP therapy was explored for its efficacy in the battle against newly emerged (nCoV-2019) pandemic. In February 2020, for the first time, a group of researchers from China reported and published the usefulness of CP in nCoV-2019 severe patients in Journals like JAMA [17] and PNAS [16]. CP therapy can be used as a prophylaxis for various infectious diseases, primarily when an outbreak occurs.

Many studies showed a significant correlation between CP therapy and improved clinical symptoms. In a preliminary study involving 5 critically ill nCoV-2019 patients, 400 mL CP administration (high neutralizing antibody (NAb) titer >40) resulted in improved clinical characteristics [17]. A similar study with 10 critically ill patients who received 200 mL of CP (one dose; NAb>1:640) significantly improved clinical symptoms within 3 days and viremia resolution within 7 days [16]. Altuntas et al. carried out a CP-based study on 888 patients, reported that CP administration reduced the ICU stay (p = 0.001) and MV support (p = 0.02) [19]. However, there is some uncertainty with large-scale CP transfusion. A PLACID trial published on 464 patients found that CP therapy did not reduce the progression to severe illness or 28-day mortality (19% treatment Vs. 18% control group) [20]. A clinical trial on 228 patients reported no significant benefits in symptoms and overall mortality between the intervention (10.93%) and the placebo group (11.43%) [21]. Similarly, a review article that studied 20 articles reflected that the efficacy of CP therapy in nCoV-2019 patients is uncertain [22]. Therefore, the US FDA recommended the use of CP as an investigational product [23]. Here, in this chapter, we have explored CP therapy potentials on nCoV-2019 based on available literature.

#### **2. Methods**

Relevant review search was done using keywords "nCoV-2019 or COVID-19, Convalescent Plasma or Plasma therapy". The search engine included electronic databases like PubMed, Google Scholar, and ClinicalTrials.gov.

## **3. History of convalescent plasma**

This therapy is not new for nCoV-2019, as physicians used this therapy more than a century ago [24]. Convalescent plasma has been used historically for a long time to develop passive immunity in patients suffering from various bacterial and viral diseases such as measles [25], mumps [26], and poliomyelitis [27] by transferring plasma carrying NAb from previously recovered patients. Although antibiotics have replaced CP usage in bacterial diseases, it remains a useful tool for novel viral infections for which the vaccine is not available.

A literature study reported that serotherapy was used during the Spanish flu (influenza A) pandemic in 1918–1920 for the first time, but this therapy was also used before the Spanish flu pandemic [3]. Serotherapy was tried as a therapeutic treatment in a poliomyelitis outbreak in New York in 1916 [28]. In 1916 (Tunis), some researchers again performed this therapy for the measles [6]. Hess AF in 1915 applied serotherapy to treat mumps and successfully prevented the testicular complications in the affected patients [29]. However, the credit goes to the Italian Francesco Cenci, who for the first time used convalescent serum as a therapeutic means to save the children that were exposed to measles [30]. Cenci performed this experiment by withdrawing 600 mL blood from a patient who recovered from measles after 21 days. After that, he administered this therapy to four children aged 4–8 years [30]. The results were overwhelming as the children did not contract measles following the treatment. Since the mortality rate in measles was high, ranging from 6–7%, this prophylactic therapy lasted for a long time [31]. There was again a measles outbreak in December 1906 in Italy where this therapy was administrated in forty sick children, and all the patients recovered successfully. One children had severe symptoms, but after therapy, the child showed milder symptoms. Luigi Concetti performed a similar therapy in 1900 on two children affected with diphtheria in Rome, Italy [6, 32]. After that, CP therapy was used for treating many diseases like MERS, Ebola, SARS etc. (**Table 1**) [33].

During H1N1 influenza epidemics in 2009, CP therapy was given to the patients who were in critical conditions and were presented to the hospitals with severe respiratory problems. The patients showed reduced viral load in the respiratory system and there was also decreased cytokine response and mortality rate [14]. CP therapy was also used in the Ebola epidemic in 2013 in West Africa regions [34]. SARS-CoV in 2002/2003 and MERS-CoV in 2012, the two outbreaks with


#### **Table 1.**

*Use of CP therapy during various diseases outbreak.*

high mortality occurred in early 21st century [35]. In South Korea, MERS became endemic, and there was an urgent need for CP therapy as the mortality rate was very high, and there was no effective treatment available [35]. Eighty patients of SARS-CoV in Hong Kong were given early administration of convalescent plasma, and they demonstrated an increased prognosis and got early discharge from the hospital [15]. A study in Taiwan showed that the administration of CP in 3 patients reduced the viral load [36].
