Convalescent Plasma Does Not Improve Indian COVID-19 Outcomes

The COVID-19 pandemic is still raging in India, with more than 4.37 million cases now, and about 90,000 new cases per day. There are few effective treatment options. That is, health care providers are facing ongoing challenges in the management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based in India, medRxiv*The preprint server is Convalescent plasma (CP) Moderate COVID-19 treatment within the resource limits facing developing countries.

Study: Convalescent Plasma in Moderate COVID-19 Management in India: An Open-Label, Parallel Group, Phase II, Multicenter, Randomized Controlled Trial (PLACID Trial). Image credit: Vadim Pipunyrov / Shutterstock

Convalescent plasma

CP is a means of inducing passive immunity used to combat some deadly infectious diseases of the past such as polio, mumps, measles, and flu. It has also been used in the recent Ebola and the 2002-2004 SARS outbreak.

COVID-19 has renewed its study of its clinical utility in pandemics. The physiological basis of the use of CP is specific Neutralizing antibody (Nab) in plasma. However, it may also include antibody-dependent cellular cytotoxicity, complement activation, or phagocytosis. In addition, it may also contain anti-inflammatory cytokines and other immunomodulatory proteins that may regulate systemic inflammation.

This is important because severe COVID-19 pneumonia is characterized by a systemic inflammatory response syndrome (SIRS) that causes acute respiratory distress syndrome (ARDS) and increases mortality.

Previous studies cannot show the benefits of CP

A recent systematic review showed that CP did not reduce mortality in severe respiratory virus infections. Despite some evidence that convalescent CP contains specific anti-receptor binding domain (RBD) antibodies with strong neutralizing activity, the right timing for optimal use of CP Much remains to be done to establish dose, dosage, and patient characteristics.

Numerous observational studies emerge supporting the role of CP on mortality, hospitalization, and viral load in COVID-19 patients. However, although randomized controlled trials are available, both were discontinued before the endpoint. One was discontinued because there were not a sufficient number of patients, and the other was discontinued due to a need to change study design due to preliminary findings.

In addition to the lack of evidence for the usefulness of CP in COVID-19, there is the fact that CP is used in many countries with regulatory approval. Therefore, in practice, this treatment is being integrated into the treatment regimen for patients with a wide range of COVID-19 severities.

PLACID trial

Current PLACID test with focus on evaluation Effectiveness of CP for hospitalized patients with moderate COVID-19 throughout India. The results evaluated were whether the progression of the condition to severe disease could be prevented and its short-term side effects.

All patients in the multicenter study were older than 18 years and had confirmed reverse transcriptase-polymerase chain reaction (RT PCR) and met the criteria for moderate COVID-19 based on their ability to maintain arterial oxygenation. It was They used different drugs, including antivirals, antibiotics, immunomodulators, and oxygen by different routes, and ventilators, depending on the protocol of the treatment center.

224 patients in the treatment group received two 200 mL CPs, preferably from different donors at 24-hour intervals to increase the probability of receiving plasma containing Nab in addition to the best standard of care (BSC) of the participating centers. It was. The patient was admitted to the ICU according to the protocol used at each center. The control group had 225 patients who received BSC only.

All patients except 2 were followed for up to 28 days. There were similar baseline characteristics across both groups of trials. Most donors were male, most recovered from mild COVID-19, with an average age of 34 years. Nab titers were over 1:20 in more than two-thirds of donors with a median titer of 1:40. Plasma was collected with a median of 41 days from diagnosis.

The combined result was the ability to prevent progression to severe illness or death from any cause during the 28-day study.

PLACID shows no difference from CP

The researchers found no difference in the intervention groups. Mortality was similar in both groups, as was the proportion of patients with advanced disease. A composite outcome was achieved in approximately 18% of patients in both groups.

Patients in the intervention group were more likely to report reduced breathing and fatigue, but no reduction in fever or cough. In the intervention and control groups, median FiO2 decreased by 5 vs 3.7 and 9 vs 7 on days 3 and 5 from the date of enrollment. Therefore, oxygenation status improved after the intervention. After that, the reduction of FiO2 remained almost the same in both groups.

The rate of negative PCR by day 7 was higher in the CP group compared to the control group.

However, there was no difference in disease progression, or clinical severity on the WHO’s normal scale, or mean levels of inflammatory markers during the first 7 days. Of the 38 patients on the ventilator, only 2 survived 28 days from the start of the study.

NAb titers not linked to different results

The analysis showed that at least 1 unit of CP containing a detectable NAb was administered to 160 participants. Using this subgroup, there is no difference in composite outcomes compared to patients who received a NAb at a titer of 1:80 or no detectable NAb or control arms. was.

Participants’ NAb titers were also measured, and there was no difference between the two groups in terms of combined results, whether or not there were detectable NAbs.

This is compared to patients who received CP with detectable NAb compared to patients who received only BSC, or to patients who received CP with a NAb antibody titer of 1:80 or higher, or controls. Was also true. The use of CP was associated with a reduced need for FiO2 on days 3 and 5, but not thereafter. More patients in the CP group were PCR negative.

In China’s RCTs, including 103 patients with severe or severe COVID-19, there were no clinical effects of CP use. However, a clinical improvement was seen in the CP group in a subgroup of 45 patients with a severity comparable to that of patients in the current trial.

The researchers also compare the results with those of the ConCOVID trial. In the ConCOVID trial, almost 80% of the detectable antibodies were found at the start of the trial.

NAb titers were higher with age and severe disease, with CP donors actually having lower NAb titers than CP donors. The latter was generally young and had recovered from mild disease.

The researchers comment, “CP collected from young, mild COVID-19 recovered donors may not benefit elderly patients with moderate to severe illness who have robust antibody responses.. “

There is an interesting sidelight on the feasibility of CP therapy. Convalescent patients with moderate to severe disease were usually unprepared to provide plasma. This can seriously impact the availability of CP as this treatment expands.

Therefore, in the PLACID trial, when used in a group of moderately severe COVID-19 patients who also underwent BSC, there was no difference in preventing mortality or progression of severity 28 days after CP administration. ..

These findings reflect that of a recent Cochrane review of 20 studies that concluded:There is uncertainty about the effectiveness of CP in improving mortality or clinical improvement in COVID-19 patients.. “

The adverse effects of CP

One participant in each study experienced minor side effects such as pain at the injection site, chills, dizziness, and bradycardia. Three patients in each arm showed fever and tachycardia. Two patients on each arm had problems with breathing and occlusion of the IV catheter. Mortality in 3 patients was determined to be possibly related to CP infusion.

Implication

Thus, this study provided evidence that CP may convert positive PCR back to negative PCR, but this treatment does not prove to be a better clinical outcome. CP also failed to show an immunomodulatory effect, as shown by the lack of differences in inflammatory marker titers. This may explain that there is no difference in the main results.

The CP safety profile has been confirmed. The three potentially relevant deaths occurred within 6 hours of the CP, but could also be due to the exacerbation of COVID-19.

The PLACID trial included both public and private hospitals and was able to cover a wide range of healthcare facilities, socioeconomic and demographic factors, and co-morbidities. This allows CPs to better feel the real-world situations and expected outcomes where such resources are likely to be managed in an extended area.

Of course, this wasn’t blind, which limits the findings. Therefore, the subjective improvement could have been due to confirmation bias. Various test kits were used as biomarkers of inflammation. The number of patients varied from center to center as pandemics were at different stages in different parts of India.

Off label use of CP for the treatment of COVID-19 in India has received various accolades. While this is a safe remedy, it requires intensive resource use, which limits the number of facilities that can guarantee quality of use. Secondly, there is a very high possibility of selling in the black market where CP spreads in India. And third, its clinical value has not yet been proven. Further studies are needed to validate its use with COVID-19, including its efficacy in patients lacking NAbs and the utility of CP with high NAb titers.

*Important Notices

medRxiv It publishes preliminary, non-peer reviewed scientific reports and should not be considered conclusive and should not guide clinical practice/health-related behavior or be treated as established information.