COVID-19 Convalescent Plasma: To Use or Not To Use

What is it?

The dictionary meaning of the word convalescence is recovery. A patient who recovers from a given disease and develops high titres of antibodies can become a donor of such antibodies after his/her recovery. The extra vascular component of these antibodies is difficult to collect, but the intravascular part can easily be harvested by collection of the plasma. When this plasma is harvested from a recovered person of COVID-19, we term that as COVID-19 convalescent plasma (CCP).

Mechanism of Action

The virus-neutralizing anti-SARS-CoV-2 antibodies in CCP serve as a source of passive immunity for recipients who were unable to launch a timely and adequate antibody response to the virus. We do not know yet why the human immunity has been behaving in an absurdly varying manner in COVID-19. Some produce a good antibody titre, while some develop a poor and unstable response, as seen in a big chunk of potential CCP donors who get deferred due to low antibody titres. Adding to the woes, some patients develop cytokine storm-induced systemic hyper-inflammatory response. It is not the virus that has been killing us in this pandemic, but the inflammatory response by our immunity that is leading to multi organ failures, especially lungs. This passive Immunity is meant for such recipients, albeit before the multi organ failures develop.

Apart from this, CCP has been mentioned to have other indirect immunomodulatory effects like anti-inflammatory cytokines, antibody-dependent complement activation, and cytotoxicity defensins leading to better viral clearance and reduction of hyper-inflammation. The non-specific IgG that gets transferred in the plasma neutralize cytokines like IL-1β and TNFα.

F(ab´)2 mechanism: IVIg has been long used in auto-immune diseases and auto-inflammatory conditions like aplastic anaemia, ITP, and graft vs. host disease (GvHD) after marrow transplantation, etc. The anti-idiotypic antibodies of IVIg block autoreactive recipient antibodies. The same has been contemplated for CCP, whereby the exaggerated inflammatory cascade due to the pathogenic antibodies and the cellular damage by the uncontrolled complement pathway activation get tamed down.

Is this a new kid in the playground?

No. Convalescent plasma (CP) has been used successfully in the 1918 Spanish flu pandemic, in Severe Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) in 2003, and Middle East Respiratory Syndrome (MERS) in 2012. Literature suggests that there are two keys to success in CP: choosing donors with high antibody titres, and choosing proper patients. There is no role of giving low titres CP to moribund with already developed multi organ failures!

In these pandemics, there have been observations that only a small fraction of patients generate high titres of neutralizing antibodies. It is good to learn from history that, studies without proper antibody titres lead to failure. This has been verified in the current pandemic, too.

Why CCP?

SARS-CoV-2 has got no proven therapy even after more than 10 months of the virus discovery. The recent Solidarity Trial by WHO has shown that most of the antivirals and other drugs have failed to reduce morbidity and mortality. But, the IgG antibodies against the Spike protein (S-RBD) in CCP donors can be measured by laboratory tests, and this has got direct and specific antiviral effect against this virus!

There have been some trials like the PLACID trials that show the inefficacy of CCP, but there have been multiple good trials that vote for CCP. As the effect of CCP is not clear yet, the US FDA calls it as an investigational therapy under evaluation. All users should collect data about its use to collate later. Nevertheless, the compassionate use of CCP is continuing, but the data should be gathered concurrently.

The hyperimmune serum has been historically used for post-exposure prophylaxis against infectious diseases with no specific cure after they develop, like tetanus, diphtheria, and rabies. CCP exploits the same phenomena. Development of hyperimmune serum for COVID-19 is difficult and not practical during the evolving pandemic, where the knowledge about the pathogen and its therapy is getting refreshed too rapidly. CCP will continue to play its role till then.

Who is the ideal candidate for CCP transfusion?

Most studies point out to early transfusions as one of the keys to success. As the usage of antibiotics in Sepsis Bundles, the CCP should be used to hit the virus early and hit it hard during the moderate disease with dyspnoea and persistently falling oxygen levels. The CCP, if planned to be used anytime in the therapy of the patient, should be added on at this time point itself to the standard care medications that the patient is receiving. As per the American Association of Blood Banks (AABB), the ideal period of transfusion will be within 3 days of admission. The next best period is within a week. There may not be much benefit post 10 days of the infection. Though the US FDA has indicated severe illness as a criterion for CCP usage, many trials show little benefit in such patients. The usage in moderately sick patients with increasing use of other standard therapy, without waiting for the condition to deteriorate and leading to organ failures has been appreciated. The CCP’s most important mechanism of action is through direct neutralisation of virus. The virus actively replicates in the initial part of the disease. Later damage is caused by the exaggerated immune response, which is less responsive to most of the therapies in current use. After the cytokine storm has damaged the lung, there is no role of CCP. The burnt-out furniture cannot be restored, whether the fire-extinguisher sprays water or milk!

Again, there exists a potential of misuse of CCP, wherein, it may be offered non-judiciously to any affording patient with COVID-19, even without significant symptoms. The CCP is a precious resource with limited donors for it. Also, it is a product of human origin and has all the infective and non-infective potential adverse effects.

Is CCP transfusion safe?

As per a trial at Mayo Clinic, <1% of the 5000 patients had serious adverse events (SAE), proving its relative safety, even when considering that it was given to sick patients in ICU. Of the 36 SAEs, only two were finally stated as definitely related to CCP.

Potential adverse effects of CCP include transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), and severe allergic transfusion reactions. The circulatory overload in TACO causes left atrial hypertension leading to pulmonary oedema. Chances of TACO is less, as only 200-500 ml CCP is not an unsafe volume. The input-output balance of the patient needs to be simply balanced to prevent it. TRALI features include bilateral pulmonary oedema in absence of circulatory overload. It results from the anti-HLA and anti-HNA antibodies in the donor’s plasma. It is avoided by choosing males and nulliparous females as donors. Allergies happen in the same probability as of any other regular blood transfusion, and need to be handled accordingly.

A theoretical worry on the CCP usage is antibody-dependent enhancement (ADE), where the non-neutralizing antibodies bind the virus and lead to its widespread intracellular inclusion and the accompanying damage. Or, it can lead to an antigen-antibody immune complex formation and cause a pro-inflammatory immune response. The absence of any toxicity being reported in the thousands of CCP transfusions that have happened till date quenches this concern as non-significant clinically.

COVID-19 is a hypercoagulable state. Many fear that the use of plasma may aggravate this. This fear is uncalled for. Human plasma is a mix of both naturally occurring pro- and anti-coagulants suspended in a balanced manner. There have been no SAE reporting thrombo-embolism post CP transfusions.

Is it safe to donate CCP?

Yes. When donated by a whole blood donation, it is just like a regular blood donation. The plasma is centrifuged away from the red blood cells after the blood donation is over. The red blood cells can be used for any regular patient. When donated by plasmapheresis, all of the cellular elements of blood are returned to the body from the same needle, and only plasma, which is 90% water in composition, is retained outside. The volume loss is easily recovered by oral fluids supplementation. As there is minimal red cells loss, the haemoglobin does not drop, and the donation can be safely repeated after 14 days again. The kits for the apheresis come with integrated needles and bags so that there is zero possibility of any sort of contamination or mix-up between two donors. Like the blood donation blood bags, they come with sterility matching the same as of surgical grade instruments. The computer controls the various in-built safety sensors, valves, and pumps to remove any human error.

The antibodies in the recovered person may remain high for a few months, or may be undetectable immediately after recovery. For those where it remains high, it remains so whether someone donates repeatedly or does not donate at all. The amount of plasma collected in one procedure is <10% of the total blood volume of the donor. S/he retains 90% of the intravascular antibodies, apart from the extravascular pools of the same, and there is also the constant production of such antibodies by the activated mast cells. The antibody levels were noted to remain high despite >4 plasmapheresis procedures and donating > two litres of CCP cumulatively in some active donors. The antibodies will gradually come down in due time, whether one donates or not, just like the pulse rate that normalizes after a temporary spurt in physical activity. So, it’s not bad for this altruistic approach to saving some lives. Not all will be as lucky to see the dawn again, many will never return from ICU.

If the CCP reduces the ventilator requirement by even a couple of days, or reduces the bed-occupancy by some days, it will be appreciable, considering that the global health infrastructure has already started crumbling due to an acute shortage of resources. Cumulatively, the savings will be huge, and many more will get a chance to at least get admitted in the freed-up beds of the hospitals.

How to mobilise CCP donors?

It is important to educate the recovered patients during the follow-up visits, as there is no alternative to human donors currently. They may be given printed education material, apart from counselling, to increase their knowledge and modify their attitude towards blood or plasma donation. Use of media like television and radio by the public authorities, and including prominent figures and leaders of society in such campaigns, can aid in removing myths and fear from the public minds. These drives will pull in many first-time donors into the repeat voluntary blood donor pool.

To conclude, the pros of CCP is the availability of a large pool of donors in the community, safe ways of harvesting the plasma, easy availability of the infrastructure to manufacture CCP locally, relative safety even in transfusing those with serious illness, and proven benefits in past pandemics as also in many trials in the current pandemic.

The cons include motivating donors, testing of the recommended antibodies in the donor while knowing that many will get deferred, the non-zero risks of transfusion-transmitted infections, and the uncertainty in the global medical fraternity about the benefits of CCP.

The pandemic is expanding, while the armaments are shrinking day by day. Availability of an effective vaccine to the general masses does not seem to be near. A large population has been fatally affected already. Convalescent plasma can be a hope for the ones who are inching towards the ICU, or have just landed into it.