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The COVID-19 pandemic is still raging in India, with more than 4.37 million cases and almost 90,000 new cases a day today. There are few effective therapeutic options, which means that healthcare providers face ongoing challenges in managing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A new study based in India and published in the medRxiv* Preprint Server explores the role of convalescent plasma (CP) in the treatment of moderate COVID-19 within the resource constraints faced by a developing country.
Study: Convalescent Plasma in the Treatment of Moderate COVID-19 in India: An Open Parallel Arm Phase II Multicenter Randomized Controlled Trial (PLACID Trial). Image Credit: Vadim Pipunyrov / Shutterstock
Convalescent plasma
CP is a means of inducing passive immunity, which is used to fight various lethal infections in the past, such as polio, mumps, measles, and influenza. It has also been used in the recent 2002-2004 Ebola and SARS outbreak.
COVID-19 has renewed research on its clinical utility in the pandemic. The physiological basis for the use of CP is the content of specific neutralizing antibodies (Nabs) in the plasma. However, it can also include antibody-dependent cellular cytotoxicity, complement activation, or phagocytosis. Furthermore, it may also contain anti-inflammatory cytokines and other immunomodulatory proteins, which can regulate systemic inflammation.
This is important as severe COVID-19 pneumonia is characterized by a systemic inflammatory response syndrome (SIRS), which causes acute respiratory distress syndrome (ARDS) and increases the mortality rate.
Previous research does not demonstrate the benefits of PC
A recent systematic review showed that CP did not reduce the mortality rate in severe respiratory viral infections. Despite some evidence that convalescent CP contains specific receptor-binding domain (RBD) antibodies that have potent neutralizing activity, much remains to be done to establish the appropriate timing, dose, and patient characteristics for optimal use. from the PC.
Many observational studies have appeared supporting the role of CP in mortality, hospital stay, and viral load in COVID-19 patients. However, randomized controlled trials are available, but both were stopped before the endpoint. One was stopped due to lack of a sufficient number of patients, the other because preliminary findings made it necessary to change the trial design.
Coupled with this lack of experimental evidence on the usefulness of PC in COVID-19 is the fact that it is being used in many countries with regulatory approval. In reality, therefore, this treatment is being incorporated into the therapeutic regimen for patients with a broad spectrum of COVID-19 severity.
The PLACID trial
The current PLACID trial focused on evaluating the efficacy of CP in hospitalized patients with moderate COVID-19 across India. The outcomes assessed were whether it could prevent the progression of the condition to serious disease and its short-term adverse effects.
All patients in the multicenter study were over 18 years of age, had confirmed reverse transcriptase polymerase chain reaction (RT PCR), and met criteria for moderate COVID-19 based on their ability to maintain arterial blood oxygenation . They were taking various medications, including antivirals, antibiotics, immunomodulators, and oxygen through various routes, as well as mechanical ventilation, according to treatment center protocols.
The 224 patients in the treatment group received two doses of CP at 200 ml each, 24 hours apart, preferably from different donors to increase the chances of receiving Nab-containing plasma, in addition to the best standard of care from the participating center (BSC ). The patients were admitted to the ICU according to the protocols followed in each center. The control arm had 225 patients who received only BSC.
All patients except two were followed up to 28 days. There were similar baseline characteristics in both arms of the trial. Most of the donors were male, the majority had recovered from mild COVID-19, and their average age was 34. The Nab titer was greater than 1:20 for more than two-thirds of the donors, the average titer being 1:40. Plasma was collected at a median of 41 days from diagnosis.
The combined outcome was the ability to prevent progression to serious illness or death from any cause during the 28 days of the study period.
PLACID shows no difference with CP
The researchers could not find any difference in the intervention arm. Mortality was comparable in both groups, as was the proportion of patients who progressed to severe disease. The combined result was achieved in approximately 18% of the patients in either arm.
Patients in the intervention group were more likely to report easier breathing and less fatigue, but not less fever or cough. There was a reduction in median FiO2 on days 3 and 5 from the day of enrollment, 5 vs. 3.7 and 9 vs. 7, in the intervention and control arms. Thus, the oxygenation status improved after the intervention. Thereafter, the FiO2 reduction remained similar in both arms.
The rate at which the CRP became negative on day 7 was higher in the CP arm compared to the control arm.
However, there was no difference in disease progression or clinical severity according to the WHO ordinal scale at any time, or in the mean levels of inflammatory markers during the first 7 days. Of the 38 patients who were on mechanical ventilation, only 2 were alive at 28 days from the start of the trial.
The NAb title is not related to the difference in the result
Analysis showed that at least one PC unit with detectable NAb was administered to 160 participants. Even with this subgroup, there was no difference in the composite outcome compared to those who received NAb at a titer of 1:80, or with no detectable NAb at all, or with the control arm.
Participants’ NAb titer was also measured, but there was no difference in either arm from the composite outcome, whether or not they had detectable NAb.
This remained true even when those who received CP with detectable NAb were compared to those who received BSC alone, or when those who received CP with NAb titers equal to or greater than 1:80, or controls. CP use was associated with a lower need for FiO2 on day 3 and day 5, but not after that. More patients became PCR negative in the CP arm.
In a Chinese RCT, which included 103 patients with severe or critical COVID-19, there was no clinical impact from the use of PC. However, when the subgroup of 45 patients with a severity comparable to that of the patients in the current trial, there was a clinical improvement in the CP group.
The researchers also compare their results with those of the ConCOVID trial, in which nearly 80% had detectable antibodies at the start of the trial, and other studies showing that about a third of patients showed very low or no detectable antibodies.
The NAb titers were higher with age and severe disease, and indeed, PC donors had lower NAb titers than PC donors because the latter were typically younger and had recovered from mild disease.
The researchers comment: “There may be no benefit from PC collected from young recovered mild COVID -19 donors to moderately to severely ill elderly patients who have a strong antibody response. “
An interesting sidelight on the feasibility of CP therapy is seen in that convalescents who had had moderate to severe illness were typically not ready to donate plasma. This could seriously affect the availability of PC as this therapy is expanded.
Therefore, the PLACID trial found no difference with respect to mortality or prevention of disease severity progression at 28 days after PC administration, when used in a group of COVID-19 patients. moderately severe who also received BSC.
These findings echo those of a recent Cochrane review of 20 studies that concluded that “There is uncertainty regarding the effectiveness of CP in improving mortality or clinical improvement in patients with COVID-19.. “
Adverse effects of PC
The trial participants experienced minor adverse effects, such as infusion site pain or chills, dizziness, and bradycardia, in one patient each. Three patients in each arm had fever and tachycardia. Two patients in each arm had shortness of breath and blockage of the IV catheter. Mortality in three patients was considered possibly related to PC infusion.
Transcendence
Therefore, the study showed evidence that CP could result in the reversion of a positive PCR to a negative one, but could not present evidence of better clinical outcomes with this therapy. CP also did not show any immunomodulatory effects, as evidenced by the absence of any difference in the titers of the inflammatory markers. This may explain the lack of difference in the primary outcome.
The safety profile of CP was confirmed, with the three deaths possibly related being those that occurred within 6 hours of CP, but could also have been due to the exacerbation of COVID-19.
The PLACID trial included both public and private hospitals, covering a wide range of healthcare facilities and socioeconomic and demographic factors, as well as coexisting conditions. This also allows a better feel for the real world conditions in which the PC is likely to be administered in resource-limited regions and the expected results.
Of course, this also limits the findings as it was not blinded and therefore subjective improvement may have been due to verification bias. Different test kits were used for inflammation biomarkers. The number of patients varied between centers as the pandemic was in different phases in different regions of India.
The unapproved use of PC for the treatment of COVID-19 in India has received mixed praise. Although it is a safe therapy, it is resource intensive and therefore limits the number of institutions that can ensure quality of use. Second, the possibility of a rampant sale of CP on the Indian black market is very much present. And third, its clinical value has yet to be proven. More research is needed to validate its use in COVID-19, including its efficacy in patients lacking NAb and the usefulness of PC with elevated NAb titers.
*Important news
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or be treated as established information.
