In search of an effective treatment for COVID 19, an old method of fighting infectious disease resurfaced which is ‘transfusions with convalescent plasma’. ‘Plasma’ is a component of blood and ‘Convalescence’ is the period in which the body recovers from a serious illness, injury or surgery. The patients’ blood, during convalescence, is highly rich in antibodies, thus helping him to recover from illness. The liquid part of blood that is collected from patients who have recovered from an infection is called Convalescent Plasma and the treatment is called ‘Convalescent Plasma Therapy’. Historically, it has been used in many viral infections such as poliomyelitis, measles, mumps and influenza.
Convalescent Plasma or passive antibody therapy was introduced in 1898 when physiologist Emil Von Behring working with bacteriologist Shibasaburo Kitasto showed that injections of serum from an animal with tetanus could confer immunity to the disease in other animals and also that the same was true for diphtheria. Since then doctors have used passive antibody therapy to treat or prevent both bacterial and viral infections including forms of pneumonia, meningitis and measles. Earlier, convalescent plasma has been used with variable benefit in cases of H1 N1 influenza, SARS, Ebola. After the outbreak of COVID 19, researches and health care professionals started looking into the possibility of using Convalescent Plasma Therapy to treat people with COVID 19, the respiratory disease caused by SARS-CoV-2 virus. In the United States, Dr Arturo Casadevail, chair of Molecular Microbiology & Immunology Department at John Hopkins Bloomberg School of Public Health Dr Liise-anne Pirofski, professor of Infectious Diseases in the Department of Medicine at the Albert Einstein College of Medicine argued the potential merits of passive antibody therapy in COVID 19. “I know that in epidemics when you don’t have a lot of things, the blood of those who have recovered can have antibodies that can have antibodies that can be used [as treatment],” Dr Casadevail explained. Considering the lack of efficacious treatments for COVID 19 and the epidemic situation with high mortality rate, United States FDA (Food and Drugs Association) has approved convalescent plasma single patient emergency IND (Investigational New Drugs). This multi-centric, open label, randomized control trial has been planned to assess the efficacy and safety of convalescent plasma collected from recovered COVID-19 patients.
On May 4, 2020, top medical experts said that Convalescent plasma therapy is no “magic bullet” to deal with coronavirus, and only large-scale controlled trials can ascertain its efficacy as part of the treatment strategy. Several states are now considering the use of the therapy to treat critically-ill COVID-19 patients. The therapy involves taking antibodies from the blood of a person who has recovered from COVID-19 and transfusing those antibodies into an active COVID 19 patient to help kickstart the immune system to fight the infection. The health ministry recently warned against its use, saying that plasma therapy was at an experimental stage and has the potential to cause life-threatening complications. However, some state governments, including Rajasthan, Punjab, Maharashtra and Delhi, have shown keenness for plasma therapy treatment, and the Centre has permitted few states to perform it on a limited number of COVID-19 patients.
On May 6, 2020 the ICMR (Indian Council of Medical Research) had initiated a multi-centre clinical trial, titled ‘A Phase II, Open-Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease (PLACID Trial). “We have received an overwhelming response. The expression of interest was received from 111 institutions. On May 4, the ICMR has approved 21 institutions in the PLACID trial which was registered with CTRI (Clinical Trial Registry of India). The study has also received approval from the COVID-19 National Ethics Committee (CONEC). With the Ethics Committee approval in hand on May 8, 2020, the ICMR (Indian Council of Medical Research) cleared the hurdle to conduct a multi-centric phase 2 trial using Convalescent Plasma on COVID 19 with moderate illness. Its three feasibility studies in about 20 severely ill patients found the therapy to be safe and able to resolve illness or improve the clinical symptoms. As per ICMR guidelines, patients with moderate COVID-19 illness would be randomly assigned to receive either convalescent plasma (226 participants) or only standard of care (control group). The primary outcome of the trial in 21 hospitals would include prevention of illness from progressing to a severe form, and avoidance of deaths from all causes at 28 days after plasma infusion and secondary outcome would will include resolution of symptoms, reduction in hospital stay and respiratory support. Plasma is to be collected from donors 28 days after they make a complete recovery from illness or are symptom-free and have more than the required level of antibodies against the COVID 19. Molecular and other routine tests were the other requirements before plasma use. The medical facilities which have been given the approval to be a part of the trial include Postgraduate Institute of Medical Education and Research in Chandigarh, Madras Medical College in Chennai, Smart NHL Municipal Medical College in Ahmedabad, BJ Medical College and Civil Hospital in Ahmedabad, Sawai Man Singh Medical College in Jaipur, Government Medical College, Nagpur, Gandhi Medical College, Telangana and Gandhi Medical College, Bhopal.Besides, 90 more hospitals have applied to be a part of the trial and are under consideration depending upon the completion of necessary documents, officials said. Convalescent plasma therapy is at an experimental procedure for COVID-19 patients. As per the guidelines, hospitals and institutions planning to provide this modality of treatment should do so in a clinical trial with protocols that are cleared by the Institutional Ethics Committee, the ICMR had said earlier while seeking participation in the trial. At this moment, the ICMR does not recommend this as a treatment option outside of clinical trials. The ICMR is doing clinical trial on convalescent plasma treatment across several hospitals in the country.
Plasma therapy is considered in patients with moderate disease who are not improving (oxygen requirement is progressively increasing) despite use of steroids in them. Plasma therapy has been well tolerated in most patients with significant increase in neutralizing antibodies and disappearance of virus in the blood (viremia) in 7 days. The Clinical symptoms rapidly improved in 3 days.
There are several inclusion criteria which need to be met for initiating plasma therapy:
• (i) Age: >18 years [more than 18 years]
• (ii) Patients with RT-PCR confirmed COVID-19 illness.
• (iii) Has any of the two [(i) or (ii)]
• (iv) Pressure of Oxygen in Patient’s arterial blood (PaO2)/ Fraction of
Oxygen in the Airbeing used for Oxygenation (FiO2): 200-300
• (v) Respiratory Rate > 24/min and SaO2 < 93% on room air
• (vi) Availability of matched donor plasma at the point of enrolment
There are several exclusion criteria as well in which Plasma Therapy cannot be used:
• (i) Pregnant or Breastfeeding women
• (ii) Known hypersensitivity to blood products
• (iii) Has been a recipient of pooled immunoglobulin in last 30 days
• (iv) Critically ill patients:
• P/F ratio <200 (moderate – severe ARDS)
• Shock (Requiring Vasopressor to maintain a Mean Arterial Pressure (MAP) >=65mmHg or MAP below 65)
• (v) Participating in any other clinical trial
• (vi) Clinical status precluding infusion of blood products
Eligibility of Donor
- 18 years of age
- Males or nulliparous female wt>55Kg
- Prior diagnosis documented by RT-PCR with symptomatic disease with at least fever and cough and
- Complete resolution of symptoms at least 28 days prior to donation or
- Complete resolution of symptoms at least 14 days prior to donation and two negative RT PCR for COVID-19 – nasopharyngeal swab, 24 hours apart.
- In addition, donor eligibility criteria for whole blood donation
Essentials for transfusion
- standard transfusion of FFP should be followed with special care to monitor these patients during and post-24 hours of transfusion.
- Use blood transfusion sets.
- An ABO compatible plasma bag of approx. 200mL will be issued maintaining all the blood bank records after thawing at 37 degree Celsius.
There are several adverse effects commonly associated with transfusion of plasma include
*TRALI (Transfusion Related Acute Lung Injury],
*TACO (Transfusion Associated Circulatory Overload),
*Allergic/Anaphylactic Reactions
*TTI(Transfusion Related Transmission of Infections).
*FNHTR(febrile non-haemolytic transfusion reactions),
*HTR (HaemolyticTransfusion Reactions)and
* RBC allo-immunization (happens rarely)
Till date, there is no robust scientific proof to support that plasma therapy can be used as a treatment for COVID-19. The U.S. FDA and India have thus approved the use of plasma from recovered COVID-19 patients only for trial purposes. The ICMR’s insistence on an evidence-based approach to plasma therapy is in contrast to its earlier approval of the anti-malarial HCQ (hydroxychloroquine) without carrying out any trial and also when the risks were unknown. The apex health research body is yet to conclude its study and till such time plasma therapy is to be used only for research or trial purpose. Top medical experts feel it should not be looked upon as something that could make a “huge difference” in the treatment of COVID-19 and only randomised controlled trials can prove its efficacy as an important treatment strategy. If plasma therapy is not used in a proper manner under proper guidelines, then it can also cause life-threatening complications.”AIIMS director Dr Randeep Guleria had also stressed on the need to have good and well-conducted research trials before the mode of therapy can be recommended for routine use in COVID 19 patients. ICMR does not recommend this as a treatment option outside of clinical trials. The Ministry of Health and Family Welfare, Government of India in Version 3 of Clinical Management Protocol: COVID 19 dated 3.06.2020 has incorporated ‘Convalescent plasma’ as an investigational therapy. Convalescent plasma (Off Label) may be considered in patients with moderate disease who are not improving (oxygen requirement is progressively increasing) despite use of steroids. Special prerequisites while considering Convalescent plasma include:
- ABO compatibility and cross matching of the donor plasma,
- Neutralizing titre of donor plasma should be above the specific threshold (if the latter is not available, plasma IgG titre (against S-protein RBD) above 1:640 should be used),
- Recipient should be closely monitored for several hours post transfusion for any transfusion related adverse events,
- Use should be avoided in patients with IgA deficiency or immunoglobulin allergy
Dose: Dose is variable ranging from 4 to 13 ml/kg (usually 200 ml single dose given slowly over not less than 2 hours.
Conclusively, Convalescent Plasma Therapy no longer remains a clinical trial but is considered to be a treatment for COVID 19 patients with moderate disease.
The Author is an Advocate-On-Record, the Supreme Court of India.