|Year : 2022 | Volume
| Issue : 1 | Page : 6-11
Convalescent plasma for coronavirus disease 2019: A boon or bane
L V Simhachalam Kutikuppala1, Nijora Deka2, Mohd Umar Farooq3, Aisha Abeer Abdul Gaffar3, Anna Mary Jose4
1 Intern, Konaseema Institute of Medical Sciences and Research Foundation, Amalapuram, Andhra Pradesh, India
2 Department of General Medicine, Al Ameen Medical College, Vijayapur, Karnataka, India
3 Department of Intern, Al Ameen Medical College, Vijayapur, Karnataka, India
4 Intern, Jawaharlal Nehru Medical College, Sawangi, Maharashtra, India
|Date of Submission||04-Oct-2021|
|Date of Acceptance||05-Nov-2021|
|Date of Web Publication||22-Apr-2022|
Mohd Umar Farooq
Al Ameen Medical College, Bijapur, Vijayapura, Karnataka
Source of Support: None, Conflict of Interest: None
Coronavirus disease 2019 (COVID-19) pandemic emergence has re-evaluated the functionality of the notable convalescent plasma transfusion (CPT). It is a source of neutralising antibodies, which when transfused into severe acute respiratory syndrome coronavirus 2 infected patients are believed to employ an antiviral effect, suppressing the replication of virus before the patients regain their own effective humoral immune responses. The major accepted mode of action of the CPT therapy is viremia clearance, that happens mostly between 10 and 14 days after infection. Hence, CPT has been administered to the recipients typically after the emergence of early symptoms for anticipating maximize the efficacy of the therapy. CPT has been used in treating viral diseases including measles, mumps, poliomyelitis, and influenza in the pre-vaccine era. More recently, it has been used as a treatment approach for influenza, Ebola virus disease, and severe acute respiratory syndrome coronavirus epidemics, with varying success. The available evidence till date suggests that convalescent plasma which is collected from the COVID 19 survivors contains “receptor binding domain specific antibodies” possessing potent antiviral activity. Multicentred and well-designed clinical trial studies in establishing the efficacy of CPT among COVID-19 patients are being conducted globally. PubMed, EMBASE, and Medline databases were screened till November 01, 2020. This is an attempt to review studies of convalescent plasma on clinical outcomes in patients with COVID-19. From the outcomes of some of the completed studies, it is suggested that CPT therapy among COVID-19 patients seems to be safe and clinically efficacious to some extent.
Keywords: Clinical trial, convalescent plasma transfusion, coronavirus disease 2019, pandemic, severe acute respiratory syndrome coronavirus 2
|How to cite this article:|
Kutikuppala L V, Deka N, Farooq MU, Gaffar AA, Jose AM. Convalescent plasma for coronavirus disease 2019: A boon or bane. J Sci Soc 2022;49:6-11
| Introduction|| |
Convalescent plasma therapy is a passive immunisation process. It is the transfusion of plasma containing antibodies from immune survivors of infectious diseases to the affected individuals. During the infectious period, virus-infected cells stimulate B lymphocytes to produce antibodies, these antibodies neutralize the virus activity and remain in the plasma of patients even after the recovery hence, Convalescent plasma refers to the plasma obtained from such an individual who has recovered from an infection.
History for the use of convalescent products dates back to the 1880s, convalescent blood products (CBP) was used to prevent and treat many bacterial and viral infections in humans and animal models. In 1890, the first trial was done to treat diphtheria. It was initially done using blood serum produced from immunised animals previously infected with diphtheria, but soon whole blood or serum from recovered donors with a specific humoral immunity were identified as a possible source of specific antibodies of human origin. CBP was eventually used for the prophylaxis or treatment of bacterial infectious diseases such as scarlet fever in the 1920s and pertussis until about 1970.,
In 1918–1920, studies conducted during the Spanish influenza pandemic suggested that the use of CBP was effective and for the first time Convalescent plasma was identified as a potential therapy for a number of viral infections. In the following decades, it showed efficacy for the management of measles, Argentine haemorrhagic fever, influenza, chickenpox, infections by cytomegalovirus, parvovirus B19 and recently, Middle East respiratory syndrome coronavirus, H1N1 and H5N1 avian flu, Ebola, and severe acute respiratory infections viruses.
The effectiveness and safety of convalescent plasma therapy have not been fully proven yet however studies suggest it to be a valid option in the treatment prophylaxis of several infectious diseases with other drugs/preventive methods and the only therapy when specific treatment is not available. Convalescent plasma transfusion (CPT) may be helpful to people who are affected with coronavirus disease 2019 (COVID 19) and are not showing improvement when on other modalities of treatments. It is also helpful to treat people with weak immunity, people who belong to high-risk groups (such as diabetic patients and people with heart diseases). Convalescent plasma is also being considered as a prophylaxis to those exposed to COVID-positive patients such as health care workers, family members at high risk.
PubMed, EMBASE, and Medline databases were screened till November 01, 2020. This is an attempt to review studies of convalescent plasma on clinical outcomes in patients with COVID-19.
| Who Can Act as a Donor?|| |
Patients with a laboratory-confirmed COVID-19 diagnosis, who have fully recovered and been discharged from the hospital for at least 14 days with no persisting COVID-19 symptoms are selected as donors. Convalescent plasma donor screening and selection is done based on the guidelines of the Food and Drug Administration (FDA). Males or nulliparous females, or females who have been tested negative for human lymphocyte antigen (HLA) antibodies qualify as donors.
Convalescent plasma collection is performed based on routine plasma collection procedures via plasmapheresis. The plasma products are prepared as fresh-frozen plasma. To ensure the therapeutic potency of the convalescent plasma, only the plasma units with an S-RBD–specific IgG titre of at least 1:160 are used.
| Procedure of Convalescent Plasma Transfusion?|| |
The transfusion dose of COVID-19 convalescent plasma is yet to be proven approximately 4–13 mL/kg of recipient body weight is taken. The ABO Type of the convalescent plasma transfused should be compatible with the patient's ABO type. Following which, to ensure compatibility the convalescent plasma is crossmatched with the patient's red blood cells. CPT is administered at approximately 10 mL for the first 15 min, then increased to approximately 100 mL/h with close monitoring. Adjustments in the infusion rates are done based on the patient's risk for volume overload and tolerance, by the decision of treating physicians. Patients are considered for convalescent plasma therapy if they are seriously ill with COVID-19 in the hospital. Convalescent plasma therapy is investigational therapy which is under study yet hence, during and after the transfusion of plasma patients is closely monitored. Patients' responses and reactions are recorded.
| Results to be Expected|| |
After receiving CPT, patients may show improvement especially fever, cough, shortness of breath, and chest pain, disappear or largely tend to improve within 3 days of CPT.
Viral load and antibody titre levels after convalescent plasma transfusion
It has been widely noted that CPT significantly reduces the viral load and increases the level of neutralizing antibodies. Viral loads may decrease and become negative between day 1 and 30 days after the CPT. IgG titres of the treated patients have increased, but a study conducted in China where ten patients were transfused with CP, eight patients showed a rise in titres and the other two patients' titres were the same as before. Patients also tend to show gradual absorption of pulmonary lesions after CPT.
All studies reported unanimously positive findings of zero mortality after patients received CPT in varying doses. However, it is being studied to determine whether the high percentage of survival is due to the treatment of patients with multiple other agents (including antiviral medications) or CPT treatment or a combinatorial/synergistic effect of both.
| Risks Attributed to Convalescent Plasma Transfusion|| |
Blood products have been used to treat many other conditions, and plasma transfusions are safe and well tolerated by most patients. The risk of transmitting COVID-19 infection from donor convalescent plasma (CP) therapy has not been tested yet but it is believed that the risk is very low because the plasma from the donor is only taken after 2 weeks of discharge from the hospital and after two negative throat swabs and many studies prove the viral load to be diminished and a sharp rise in antibodies by 4 weeks in plasma of donor. Side effects of CP are similar to those of regular plasma transfusions such as fever, chills, anaphylactic reactions, serious complications like transfusion-related lung injury, circulatory overload and hemolysis can occur but are rare. Blood is screened for blood type compatibility as well as infections like hepatitis B and C, human immunodeficiency virus (HIV), and many other less common infections. Because donated blood must meet certain requirements outlined by the FDA.
| Convalescent Plasma Therapy-A Take on Coronavirus Disease 2019|| |
Coagulation disorders in coronavirus disease 2019 patients. Can convalescent plasma therapy be a solution?
The COVID-19 pandemic has taken over millions of lives and is currently a big threat to global health. With no specific antiviral agents available for its treatment, CP therapy seems to be a promising yet to be proven method to rescue critically ill patients suffering from COVID-19.
| What is the Current Evidence of Convalescent Plasma Therapy on the Participants?|| |
Where the studies were done, and what is the evidence generated?
The CP obtained from recovered COVID-19 patients with established humoral immunity against the virus, contains a large quantity of neutralizing antibodies which majorly neutralizes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and helps eradicate the pathogen from blood circulation and pulmonary tissues. Studies suggest, patients achieve serum SARS-CoV-2 RNA negativity after CP transfusion and there is an increase of oxygen saturation along with the improvement of liver function and CRP. Suggestive of the fact is that the inflammation and overreaction of the immune system were alleviated by antibodies contained in the CP.
The use of CP therapy in COVID-19 has shown that the lymphocyte counts in the peripheral blood decrease remarkably post the treatment however the levels of cytokines in the plasma from patients requiring intensive care unit (ICU) support, including interleukin (IL)-6, IL-10, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor, are significantly higher than in those not requiring ICU admissions. Moreover, the clinical symptoms significantly improved along with increase of oxyhaemoglobin saturation with no adverse effects. A lot of parameters improved as compared to pretransfusion, including the decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L) and increased lymphocyte counts (0.65 × 109/L vs. 0.76 × 109/L).
Five critically ill patients, in a case series with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) had high viral load despite the antiviral treatment and required mechanical ventilation, following the plasma transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased (ranged from 2 to 10 prior to plasma transfusion, and decreased to a range of 1–4) at 12 days following transfusion the Pao2/Fio2 increased (improved) for 4 of 5 patients within 7 days (priorly 172-276-206-290 post the transfusion), Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2–specific enzyme-linked immunoassay (ELISA) and neutralizing antibody titres increased following the transfusion (range, 40–60 before and 80–320 on day 7). ARDS was resolved in the four patients, among which three patients were weaned from mechanical ventilation within 2 weeks of treatment. However, these patients received antiviral drugs continuously until the SARS-CoV-2 viral loads became negative. The computed tomography scans of the lungs of these patients all demonstrated severe pneumonia prior to plasma transfusion and demonstrated gradual improvement post the transfusion.
Therapeutic Plasma therapy has also been invariably linked to the prognosis of cytokine storm syndrome in COVID 19 patients recently. Cytokine storm is a general term applied to maladaptive cytokine release in response to infection and other stimuli. The pathogenesis includes loss of regulatory control of pro-inflammatory cytokine production, both at local and systemic levels leading to endothelium dysfunction, capillary leak syndrome, hypercoagulable state, fulminant lung damage, respiratory failure and ARDS also causing multi-organ dysfunction with different target organs in severe forms. Hence, early recognizing and controlling the dysregulated immune reaction is very essential in the management of COVID 19. In severe COVID-19 infection, TPE removes toxins and deleterious inflammatory cytokines such as IL-1, IL-6, granulocyte-colony stimulating factor, tumour necrosis factor and other inflammatory parameters (Seguin et al., 2016). CP helps to improve hypercoagulable state, reduce cytokine response including improvement in the SOFA score, increase in the ALC and reduction in all inflammatory parameters such as CRP, D-dimer, ferritin and IL-6.
CPT is also being associated to be a post exposure prophylaxis for susceptible individuals and the only effective short-term strategy for conferring the immunity based on the knowledge that antibodies present in immune (i.e., “convalescent”) plasma which can mediate the therapeutic effect by a variety of mechanisms:
- Antibody can bind to a given pathogen (e.g., virus), thereby neutralizing its infectivity directly,
- Antibody-mediated pathways such as complement activation, antibody-dependent cellular cytotoxicity and/or phagocytosis also contribute to its therapeutic effect. Nonneutralizing antibodies that bind to the pathogen but do not interfere with its ability to replicate in vitro systems also contribute to prophylaxis.
However, a group which cannot donate plasma are the previously pregnant women, who carry an increased risk of a rare but potentially fatal transfusion reaction called transfusion-related acute lung injury, or TRALI. TRALI occurs when HLA antibodies in the donor's plasma interact with white blood cells lining the lungs of the recipient and will further damage the already injured lung by COVID-19. The HLAs are part of the immune system which helps the human body to recognize itself from the nonself. Our body develops antibodies whenever it detects a nonself-entity. In the plasma of women who have been pregnant, HLA antibodies are very common and the chance of a woman having them increases with each pregnancy. This is because foetuses have HLA from both parents, and the mother can be exposed to the HLA of the other parent during pregnancy. Her body then develops HLA antibodies against the portion of the foetus's HLA that comes from the other parent. LA antibodies are normal in pregnancy and do not harm the foetus, but they can cause TRALI if they're transfused to a patient. Pregnant women need to be additionally screened for HLA antibodies.
Till date (as of December 2020) there are around 353 registered clinical trials going on which are being done to figure out different aspects of CP therapy as a major intervention to treat COVID-19. These studies are listed on the website of: Clinicaltrial.gov [Figure 1] and [Table 1].
|Figure 1: Showing clinical trials registered globally regarding Convalescent plasma therapy pertaining to COVID 19. (as of December 2020)|
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|Table 1: Country-wise registered trials pertaining to convalescent plasma therapy in COVID 19 (as of December 2020)|
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The antibodies present in the CP provide passive immunity to the recipients by supplementing the IgG and IgM antibodies with various other benefits as well. IgM antibodies are formed from seroconversion (the production of antibody) within a week after the onset of symptoms of COVID-19 and within 2 weeks for IgG antibodies.
However, the plasma selected for donation has to have a minimum titre of antibodies which is also defined as the neutralizing titre of the plasma.
In a study conducted in Wuhan, the neutralizing activity of plasma was determined by a plaque reduction neutralization test using SARS-CoV-2 virus in the high biosafety level-4 laboratory. Neutralization titre was defined as the highest serum dilution with 50% reduction in the number of plaques, as compared with the number of plaques in wells in the absence of novel coronavirus antibodies as blank control. SARS-CoV-2 IgG antibody titre was tested by ELISA. The neutralizing titre in various studies have been varying but most of them lying in a range nearing the FDA guidelines. The FDA recommends neutralizing antibody titers of at least 1:160. If an alternative matched unit is unavailable, a titre of 1:80 can be considered as acceptable. Whereas, selecting subjects after 4 weeks of COVID-19 infection for plasma donation can ensure achieving high S-RBD specific IgG titres.
To optimize the yield of CP, apheresis is recommended. Apheresis refers to an automated technology in which whole blood is continuously centrifuged into its components (i.e., red blood cells, plasma, platelets); this allows for selective collection of the desired blood fraction with return of the other components to the donor. During apheresis, additional to neutralizing antibodies other proteins such as anti-inflammatory cytokines, clotting factors, natural antibodies, defensins, pentraxins and other undefined proteins are obtained from donors. In this way, transfusion of CP to infected patients provide further benefits such as immunomodulation via amelioration of severe inflammatory response.
| Limitations for Convalescent Plasma Use|| |
Some early trials did not demonstrate significance (e.g., China, Netherlands, Spain) but had to be stopped early due to inability to meet enrolment goals. Most trials have included only moderate to severely ill hospitalized patients, despite evidence that supports early Convalescent Plasma (CCP) use relative to symptom onset. One large trial in India phase II multicentre randomized controlled trial (PLACID Trial) did not find a significant difference in outcome in moderately ill patients with COVID-192. However, a high proportion of recipients had low or absent antibodies. Post trial results, The Indian Council of Medical Research issued an advisory on CP therapy, saying that indiscriminate use of CPT is not advisable.
A randomized, double-blinded, placebo-controlled Argentinian multicentred trial enrolled hospitalized patients with COVID-19 pneumonia a median of 8 days from symptom onset and failed to show clinical or mortality benefit for CCP, despite the use of high titre units. Another trial in Argentina preliminarily reported favourable outcomes in elderly subjects following use of CCP within 3 days of symptom onset.
| Applicability of Convalescent Plasma in Low-income Countries|| |
What was the previous evidence that is present around this and what else governments should keep in mind before giving approvals to CP therapy?
Feasibility in developing countries?
It is worth noting that low-income countries seem to be absent in the list of most affected nations, possibly as a result of their limited capacity for testing and case reporting. It is obvious that a pandemic hits a developing nation a lot more disastrous than it would a developed nation or high-income country. The biggest setback any developing nation has at present is the lack of personnel, reagents, and equipment to manage a pandemic of such a scale. While high-income nations wait for a vaccine comfortably with economically affecting measures such as instituting a lockdown, or social distancing, low-income countries who cannot afford such luxurious measures continue to succumb to the deadly virus.
Acknowledging the situations and perspectives of undeveloped and developing countries where a greater number of people could not afford the ventilators, pandemic must be slowed down so that health infrastructure can handle it efficiently. Localized herd immunity may help in decelerating the spread at sensitive locations in the absence of tested vaccines and validated treatment. There, the CP transfer could be the most critical weapon in the fight with COVID-19 in severe cases, alongside COVID 19 survivors playing a key role. A few out of the many challenges faced would be that without adequate infrastructure to support critically ill patients, it is difficult to establish CPT in such areas since most studies although conducted in developed nations, use CPT in association with other drugs and well-equipped ICUs both of which are far from accessible in the remote areas of these nations.
Beyond the systemic challenges of resource-poor settings, acquiring CCP mandates a functioning blood collection system. Most low-income countries lack sufficient blood supply to contend with the need for transfusion. Although plasmapheresis is the preferred mode of CP collection, it is limited in low-income countries due to the high cost of equipment and need for technical expertise.
The earlier outbreaks have made evident that when the health systems are devastated, mortality from the vaccine-preventable and even treatable conditions can also escalate dramatically. The increased number of deaths caused by HIV/AIDS, Malaria, Measles, and tuberculosis attributable to health system downfalls far exceeded deaths from Ebola, during the 2014 to 2015 Ebola outbreak.
Another option would be to have it transported from high-income countries, but this is posed with plenty of challenges such as CP continues to be an investigational blood product, complexity of transporting it across international borders, equitable distribution among these low-income countries and the cost of collection and shipping of CP can be discouraging for low-income countries.
Collection of apheresis plasma in low-resource settings requires proper planning to overcome issues of electrical power supply, for frozen storage capacity, climate control, maintenance of equipment and internet connectivity.
Keeping in mind, the apheresis collection study for Ebola virus that was established in Liberia on short notice reminds us of how the low-income countries continue to fight the battle against COVID19 as they did with various other dangerous infectious diseases in the past and set an example for the world of all that can be achieved in dispiriting times such as these.
| Conclusion|| |
From the evidence generated from various clinical trials globally, CP therapy had shortened the time for clinical recovery resulting in expeditious improvement in the respiratory parameters, although no significant reduction in mortality was observed. Hence, there is a requirement for larger trials in drawing conclusive evidence on the use of CP in COVID-19.
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Conflicts of interest
There are no conflicts of interest.
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