Convalescent Plasma Therapy in Covid-19: A Question of Timing

Dr. G. Dominic Rodriguez

Department of General Medicine, Kauvery Hospital, Trichy, Tamilnadu, India

*Correspondence: [email protected]

Convalescent plasma therapy (CPT) has a 100-year-old history. In 1890, Behring and Kitasato, published their discovery that graduated doses of sterile broth cultures of diphtheria or of tetanus bacilli, when injected, caused the animals to produce, in their blood, substances which could neutralize the toxins which these bacilli produced (antitoxins). Behring exposed horses to diphtheria and later extracted the sera from these horses and injected it into patients with diphtheria and found that it prevented fatal complications. In 1898, Behring and F. Wernicke found that, immunity to diphtheria could be produced by the injection into animals of diphtheria toxin neutralized by diphtheria antitoxin [1]. The first Nobel Prize in Physiology and Medicine was awarded in 1901 to Emil von Behring for his life-saving work.

Von Behring’s antitoxin was not a vaccine, but the earliest example of a treatment method called “serum therapy” which conferred passive immunity that protected an affected patient from dying of diphtheria or tetanus.

Convalescent plasma is blood plasma extracted human patient who has “convalesced” or recovered from infection with a particular disease.

  • Studies from the Spanish influenza era reported that transfusion of influenza-convalescent human blood products reduced mortality in patients with influenza complicated by pneumonia. Eight relevant studies involving 1703 patients were found. Patients with Spanish influenza pneumonia who received influenza-convalescent human blood products may have experienced a clinically important reduction in the risk for death [2].
  • Serotherapy from convalescent patients has long been used even before the Spanish influenza pandemic. In 1901, an Italian public health doctor, Francesco Cenci, is credited to be the first to use convalescent serum as a therapeutic tool, to protect children exposed to measles infection [3]. In 1915 Hess used the same therapeutic option to treat mumps and prevent its testicular complications [4], while in 1916, this was tried as a medical treatment of acute paralysis in the New York outbreak of poliomyelitis [5]. Nicolle and Conseil, applied serotherapy to contain a small measles epidemic in Tunis in 1916 [6].

What is Convalescent plasma?

  • Similar to fresh frozen plasma
  • Lacks infectious particles
  • Has sufficient titer of relevant antibody
  • ABO and Rh compatible
  • Can be frozen for future use

What is COVID- 19 Convalescent Plasma (CCP)?

The use of CCP from patients who have recovered from Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection is an example of passive immunity. Antibodies from recovered patients are transfused to a new host with the goal of mediating protection via suspected viral neutralization. This can potentially decrease viral entry into the cells, enhance viral clearance through antibody mediated phagocytosis or antibody mediated cellular toxicity. Therefore, it may be most efficacious when used in the early viremic phase of illness

Who is an ideal CCP donor?

  • COVID-19 positive patient who has recovered from illness and is antigen (RT–PCR) negative
  • At least two weeks have elapsed after recovery
  • May/may not be vaccinated against COVID-19
  • Has sufficient anti-COVID antibody levels
  • If apheresis is possible, same donor can donate twice, two days apart, in one week.

Who can receive CCP?

  • Only COVID-19 positive individuals
  • May/may not be vaccinated against COVID-19
  • First week of illness (the viremic phase)
  • Moderate illness (respiratory rate > 24 < 30 breaths/minute, oxygen saturation < 94% on room air
  • Administered at a dose of 200 ml over 2 h – can be repeated 24 h later.

What are the safety concerns with CCP?

Transfusion reactions

Minimized by ABO compatibility and HLA screening. With adequate precautions, risk of reactions that are transfusion related, thromboembolic and cardiac events were less than 1% each in a group of 20,000 patients who had received CPT [7].

Antibody mediated enhancement

This occurred with the Dengue vaccine, however has not been reported so far with CCP [7].

Attenuation of antibody response

Theoretically it is possible, but since patients with moderate COVID-19 are mostly selected for CCP, this risk appears to be less.

After CCP, is vaccination needed?

Anti-COVID-19 vaccination can be done, three months after plasma therapy.

What are the logistical barriers to collecting and processing CCP?

In COVID-19 infections, most patients need at least two units of plasma. The demand for CCP as therapy would far exceed donor supply if relying on whole blood preparation. A plasmapheresis machine, when available, can be used to draw blood, then separate and return blood cells and platelets to the donor. The collected plasma is frozen and stored. The plasma should be available at the right time.

The CCP collection centres will only be effective if the public are aware of and have access to the facilities. Information has to be disseminated to the public in ways that the lay person can understand.

How do we measure the efficacy of CCP?

To monitor efficacy, two issues will have to be addressed

  • How long do those antibodies remain at high enough levels to continue providing therapeutic effect?
  • Are multiple transfusions necessary during the patients’ disease course and recovery?

Only randomized controlled trials can answer these questions

  • PLACID trial [8]: This was a multicentric, randomized controlled trial conducted in 39 tertiary care hospitals across India. Four hundred and sixty-four adults with moderate COVID-19 infection were enrolled, out of which 235 received CCP and best standard of care (intervention arm) and 229 were randomized to receive best standard of care only (control arm). This study found no difference in 28-day mortality or progression to severe disease among patients with moderate COVID-19 treated with convalescent plasma along with best standard of care compared with best standard of care alone. Additionally, outcomes did not differ between participants receiving convalescent plasma with detectable neutralizing antibody titers compared with participants receiving best standard of care alone; or between those receiving convalescent plasma with neutralizing antibody titers of 1:80 or higher and those receiving best standard of care alone. Limitations of this study were, that the median day of enrolment from symptom onset was eight days and 83% of the trial participants had detectable neutralizing antibodies at the time of enrolment itself.
  • Another open-label, multicenter, randomized clinical trial [9], performed in seven medical centers in Wuhan, China, studied the effect of CCP added to standard treatment, compared with standard treatment alone, on clinical outcomes in patients with severe or life-threatening COVID-19. The authors inferred that among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation, was however, limited by early termination of the trial.
  • At a geriatric unit in Argentina, a randomized, double-blind, placebo-controlled trial [10], of convalescent plasma with high IgG titers against SARS-CoV-2, was conducted in older adult patients within 72 hours after the onset of mild COVID-19 symptoms. The authors observed that the administration of high-titer CCP to infected older adults within 72 h after the onset of mild symptoms reduced the progression of COVID-19 to severe illness. There was a 48% relative risk reduction in the group that received high titer CCP. The trial was stopped early at 76% of its projected sample size because cases of COVID-19 in the trial region decreased considerably and steady enrollment of trial patients became impossible.

What is our current problem?

Within a year, we have seen several variants of COVID-19, with different antigenic characteristics and protean disease manifestations, an inadequate protection by the vaccines and also failure of neutralization by anti-sera. Multiple variants are likely to make CCP ineffective if derived from patients who have recovered from older strains.

Our experience with CCP

To study the effect of CCP in COVID-19, a retrospective analysis was done on two groups of patients, with mild and moderate COVID-19, admitted during the second wave of the pandemic, during March and April 2021. One group (Group A – 11 patients), received CCP along with best standard of care, in the first seven days of the illness and the second group, (Group B – 10 patients), received CCP beyond seven days of onset of illness. Plasma was obtained only from patients, who had recovered from the infection acquired during the course of the second wave.

Although the clinical improvement (ordinal scale), was comparable in both groups, we found that the patients in Group A, had a shorter hospital stay (8.8 ± 3.79 days), when compared to subjects in Group B (10.45 ± 3.61 days) (p = 0.006).

Is there still a role for CCP in COVID- 19?

In the early phase of illness (first week), when patients progress from mild to moderate disease and are most likely to develop complications, CCP and anti- viral agents can delay such an occurrence

  • Use of steroid can be delayed up to the beginning of second week of illness, even when the patient is hypoxic.
  • We need to understand that newer variants (of the virus) are likely to emerge in the coming months.
  • Convalescent plasma obtained from recently recovered COVID-19 subjects, is most likely to provide, the best protection with neutralizing antibodies against the newer variants.
  • In our experience, administration of CCP with high antibody titers, to at risk patients, early (within seven days of onset of illness) appears to be both a reasonable and safe modality, to prevent disease progression.
  • The need for even delayed use of CPT has risen due to rampant use of steroids in very early Covid. A subset of patients present in the second week with severe disease and probable ongoing viral replication and this subgroup may also benefit even if CPT is given in the second week of illness.

To conclude, use of convalescent plasma in COVID-19, needs to be limited to those with early disease, in patients at risk for developing a severe illness, and in patients showing early signs of worsening of disease. Care should be taken to obtain high titer CCP from recently recovered individuals from COVID-19. Non-pharmaceutical interventions (such as face masks, social distancing, personal hygiene) and widespread vaccination, will still remain the key to managing and preventing future outbreaks.

References

  • Nobel Lectures, Physiology or Medicine 1901-1921, Elsevier Publishing Company, Amsterdam, 1967.
  • Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med. 2006;145(8):599–609.
  • Pontecorvo M. Ciba Geigy Edizioni; Origgio: 1991. Storia delle vaccinazioni: dalle origini ai giorni nostri; p. 104.
  • Hess A.F. A protective therapy for mumps. Am J Dis Child. 1915;310:99–103.
  • Anonymous Monograph on the epidemic of poliomyelitis (infantile paralysis) in New York City in 1916. New York City Department of Health, New York, 1917 (cited by Wyatt HV. Before the vaccines: medical treatments of acute paralysis in the 1916 New York epidemic of poliomyelitis. Open Microbiol J. 2014;8:144–7.
  • Nicolle C, Conseil E. Pouvoir preventif du serum d’un malade convalescent de rougeole. Bull Soc Méd Hôp Paris. 1918;42:336–8.
  • https://www.medrxiv.org/content/10.1101/2020.05.12.20099879v1.full.pdf
  • Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939.
  • Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020;324(5):460–470. doi:10.1001/jama.2020.10044
  • Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021;384(7):610.

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