Perspective: Better preparedness needed while harping on initial success with Convalescent Plasma Therapy in Covid-19 patients

On 24th April, 2020, the Delhi Government announced initial success with this Convalescent Plasma therapy in some critically ill Covid-19 patients. Delhi Chief Minister appealed the recovered Covid-19 patients to come forward and donate plasma to benefit other patients. On 13th April 2020, the Central Drugs Standard Control Organisation (CDSCO) has permitted the Indian Council of Medical Research (ICMR) to conduct clinical trial of convalescent plasma for the treatment of Covid-19, under accelerated approval process in light of the prevailing situation of Covid-19.1 This open label, randomised, controlled Phase-II study to evaluate the safety and efficacy of convalescent plasma in patients with moderate Covid-19 infection is on and ICMR has permitted five Indian states – Kerala, Delhi, Gujarat, Punjab and Rajasthan. Maharashtra and Tamilnadu states may also get permissions soon.

Covid-19 caused by Coronavirus SARS-CoV-2 is a pandemic with no specific therapeutic treatment or vaccine and has a substantial mortality ranging upward of 4% in general and over 20% in those above 60. In the absence of definitive treatment, several non-specific therapeutic agents licensed for usage in other medical conditions are being tried with varied degree and different combinations such as Hydoxy- chloroquin (HCQS), Azithromycin, Oseltamavir, Remdesvir and Lopinavir/ritonavir. Randomised, double-blind trials are underway in some worst-affected countries. Shen et al reported findings in JAMA from a preliminary study of 5 severely ill patients with coronavirus disease 2019 (Covid-19) who were treated in the Shenzhen, China, using plasma from recovered individuals.2 All patients had severe respiratory failure and were receiving mechanical ventilation. In another small series of four patients, including one pregnant woman, all four recovered eventually.

What is Convalescent Plasma therapy?

Convalescence is the gradual recovery of health and strength after illness or injury, refers to the later stage of an infectious disease, when the patient recovers and returns to previous health, but may continue to be a source of infection to others. Convalescent plasma involves the use of antibodies from the blood (plasma) of patients who have recovered from Covid-19 to treat infected patients who could be moderately or critically ill, to change the course of disease.

Passive immunisation (PI) for the prevention and treatment of human infectious diseases and its related concept of artificially acquired passive immunity can be traced back to the 20th century, when specific antibodies were sought from serum of stimulated animals (especially rabbits and horses). Human blood was also identified as a source of antibodies.3 PI is a technique to achieve immediate short-term immunisation against infectious agents by administering pathogen-specific antibodies.

Use of convalescent plasma is not new. It was used in Spanish flu (1918), in SARS (2003), MERS (2009), H1N1, avian influenza A or H5N1, several hemorrhagic fevers such as Ebola, and other viral infections. In 2005, Cheng et al reported outcomes of patients who received convalescent plasma in Hong Kong during the 2003 SARS outbreak.4 The CDSCO noted that convalescent plasma was historically used in viral diseases, such as poliomyelitis, measles, mumps and influenza, before vaccines were developed.

Deploying passive antibody therapies against rapidly increasing Covid-19 cases provides an unique opportunity to perform clinical studies of the efficacy of this treatment against a viral agent. If the results of rigorously conducted investigations, such as a large-scale randomized clinical trial, demonstrate efficacy, use of this therapy also could help change the course of this pandemic. 5 Shen et al used apheresis products produced in the hospital. 2 Even though the cases in the report by Shen et al are compelling and well-studied, it has important limitations that are characteristic of other 'anecdotal' case series. The administration of convalescent plasma, was not evaluated in a randomized clinical trial, and the outcomes in the treatment group were not compared with outcomes in a control group of patients who did not receive the intervention. Therefore, it is not possible to determine the true clinical effect of this intervention or whether patients might have recovered without this therapy. Despite these limitations, the study does provide some evidence to support the possibility of evaluating this well-known therapy in more rigorous investigations involving patients with Covid-19 severe illness.

What preparedness is required:

Harping on initial success of convalescent plasma, better preparedness is required. Plasma from recovering or discharged Covid-19 patients should be routinely collected with their comprehensive consent, indicating that their plasma may be used for treatment and/or for making vaccine or therapies or for academic, industry and government research purposes. In jubilation of being declared Corona-free and discharged from isolation, most patients will readily agree to provide consent. Once that stage is missed, the willingness of those who are requested to return may be compromised.

At this stage blood banks in the Covid-19 affected cities can start collecting plasma from recovering Covid-19 patients, at the time when the Covid-19 patient start showing negative PCR. Healthcare providers, counselors and hospital authorities should encourage Covid-19 patients to donate blood on discharge. Blood contains plasma, platelets, White and Red Blood Cells. If required cells can be reinjected in the donor or can be utilized for packed-cell transfusion. There are plasma fractionation units, such as the one at KEM Hospital Mumbai that can be used to draw plasma, store frozen plasma and to issue the same on demand to hospitals. The risk of transfusion-transmissible infections can be greatly minimised with pre-transfusion screening for HIV, Hepatitis B, hepatitis C and Syphilis.

The need for each state or hospitals approaching authorities should be replaced by just an executive order. No specific permission of authorities is taken when transfusing blood or plasma in several health conditions. Remove regulatory barriers that often ends-up being red-tape. Prioritise treating patients, expedite use of such therapies, create a database and maintain inventory to be made widely available.

For better efficacy of this therapy, recovering Covid-19 patients with IgG antibody titre of more than 1:1000 are preferred. Hence, the treatment centre or the designated Covid-19 facility should have facilities for performing Covid-19 Antibody tests by ELISA and record the IgG antibodies titre. There is no authentic information available on whether such techniques are available and where. A mere Rapid Antibody test for Covid-19 is mired with a huge controversy.

References:

1. https://www.clinicaltrialsarena.com/news/india-convalescent-plasma/

2. Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA... Published online March 27, 2020 doi:10.1001/jama.2020.4783

3. Rajam G, Sampson J, Carlone GM, Ades EW. An augmented passive immune therapy to treat fulminant bacterial infections. Recent Pat Antiinfect Drug Discov. 2010;5:157–67

4. Cheng Y et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44-46. doi:10.1007/s10096-004-1271-9

5. Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest. 2020;138003. doi:10.1172/JCI138003

Dr. Ishwar Gilada is consultant in HIV and Infectious Diseases in Mumbai, is President AIDS Society of India and Governing Council Member, International AIDS Society. Email: gilada@usa.net

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