The COVID-19 pandemic is still raging in India, with over 4.5 million cases, 75.000 deaths and more than 90,000 new cases a day. At present there are few effective therapeutic options, which means that healthcare providers are faced with ongoing challenges in managing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A new study based in India and published on the medRxiv* preprint server explores the role of convalescent plasma (CP) in the treatment of moderate COVID-19 within the limitations on resources faced in a developing country.

Convalescent Plasma

CP is a means of inducing passive immunity, used to fight several lethal infections in the past such as polio, mumps, measles, and influenza. It has also been used in the recent Ebola and the 2002–2004 SARS outbreak.

COVID-19 has renewed investigations into 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 may also embrace antibody-dependent cellular cytotoxicity, complement activation, or phagocytosis. Moreover, it may also contain anti-inflammatory cytokines and other immunomodulatory proteins, which may regulate systemic inflammation.

This is important since 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.

Prior Research Fails to Show Benefit of CP

A recent systematic review showed that CP did not reduce the mortality rate in severe respiratory viral infections. Despite some evidence that convalescent CP does contain specific anti-receptor binding domain (RBD) antibodies that have potent neutralizing activity, much remains to be done to establish the right timing, dosage, and patient characteristics for the optimal use of CP.

Many observational studies have appeared which support the role of CP on mortality, hospital stay, and the viral load in COVID-19 patients. However, randomized controlled trials are available, but both were stopped before the endpoint. One was stopped because of the lack of a sufficient number of patients, the other because preliminary findings made it necessary to change the trial design.

Alongside this lack of experimental evidence on the usefulness of CP 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 regime for patients over a wide 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 severe disease, and its short-term adverse effects.

All patients in the multi-center study were above 18 years, had a confirmed reverse transcriptase-polymerase chain reaction (RT PCR), and met the criteria for moderate COVID-19 based on their ability to maintain arterial blood oxygenation. They were on various drugs, including antivirals, antibiotics, immunomodulators, and on oxygen by various routes, as well as mechanical ventilation, depending on the treatment center’s protocols.

The 224 patients in the treatment arm received two doses of CP at 200 mL each, 24 hours apart, preferably from different donors to increase the odds of receiving Nab-containing plasma, in addition to the participating center’s best standard of care (BSC). Patients were admitted to the ICU according to the protocols followed at each center. The control arm had 225 patients who received only BSC.

All patients but two were followed up to 28 days. There were similar baseline characteristics across both arms of the trial. Most donors were male, most had recovered from mild COVID-19, and their mean age was 34 years. The Nab titer was over 1:20 for more than two-thirds of the donors, the median titer being 1:40. The plasma was collected at a median of 41 days from diagnosis.

The composite outcome was the ability to prevent progression to severe disease or death from any cause during the 28 days of the study period.

PLACID Shows No Difference with CP

The researchers failed to find any difference in the intervention arm. The mortality was comparable across both groups, as well as the proportion of patients who progressed to severe disease. The composite outcome was achieved in about 18% of patients in either arm.

Patients in the intervention arm were more likely to report easier breathing and reduced fatigue, but not reduced fever or cough. There was a reduction in the median FiO2 on days 3 and 5 from the day of enrolment, by 5 vs. 3.7, and by 9 vs. 7, in the intervention and control arms. Thus, the oxygenation status improved after the intervention. Thereafter, the reduction in FiO2 remained similar across both arms.

The rate at which PCR became negative by day 7 was higher in the CP arm compared to the control arm.

However, there was no difference in the progression of the disease, or clinical severity by the WHO ordinal scale at any time point, or in the mean levels of inflammatory markers over 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.

NAb Titer Not Linked to Difference in Outcome

The analysis showed that at least one unit of CP with detectable NAbs was given to 160 participants. Even with this subgroup, there was no difference in the composite outcome compared to those who received NAbs at a titer of 1:80, or with no detectable NAbs at all, or to the control arm.

The NAb titer of the participants was also measured, but there was no difference in either arm concerning the composite outcome, whether they had detectable NAbs or not.

This remained true even when those who received CP with detectable NAb were compared with those who received BSC alone, or when those who got CP with NAb titers at or above 1:80, or the controls. The use of CP was linked to 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, including 103 patients with severe or critical COVID-19, there was no clinical impact from the use of CP. However, when the subgroup of 45 patients with 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 to that of the ConCOVID trial, in which almost 80% had detectable antibodies at the start of the trial, and other studies showing that a third or so of patients showed very low or no detectable antibodies.

NAb titers were higher with age and severe disease, and in fact, CP donors had lower NAb titers than the CP donors because the latter were typically younger and had recovered from mild disease.

The researchers comment, “There may not be any benefit of CP collected from young mild COVID -19 recovered donors to moderate to severely sick elderly patients who have a robust antibody response.”

An interesting sidelight on the feasibility of CP therapy is seen in that convalescents who had had moderate to severe disease were not typically ready to donate plasma. This could seriously affect the availability of CP as and when this therapy is scaled up.

The PLACID trial, therefore, found no difference with respect to either mortality or prevention of progression of disease severity at 28 days following the administration of CP, when used in a group of moderately severe COVID-19 patients who also received BSC.

These findings echo that 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 COVID-19 patients.”

Adverse Effects of CP

The participants in the trial experienced minor adverse effects such as pain at the infusion site or chills, dizziness, and bradycardia, in one patient each. Three patients in each arm had a fever and tachycardia. Two patients in each arm had difficulty with breathing and intravenous catheter blockage. Mortality in three patients was judged to be possibly related to the CP infusion.

Implications

The study thus showed evidence that CP could result in the reversion of a positive PCR to a negative one but failed to turn up proof of better clinical outcomes with this therapy. CP also failed to show any immunomodulatory effect, as shown by the absence of any difference in the inflammatory marker titers. This may explain the lack of difference in the primary outcome.

The safety profile of CP was confirmed, with the three possibly related deaths being those which occurred within 6 hours of CP but could also have been due to exacerbation of COVID-19.

The PLACID trial included both public and private hospitals, which allowed a wide range of healthcare facilities and socioeconomic and demographic factors to be covered, as well as coexisting diseases. This also allows a better feel of real-world conditions in which CP is likely to be administered in such resource-stretched regions and the expected outcomes.

Limits of the PLACID trial

The PLACID trial has many limits, since it was not blinded, and thus subjective improvement may have been due to bias in ascertainment. Different test kits were used for the biomarkers of inflammation. The number of patients varied across centers since the pandemic was in different phases in different regions in India. The most important limit is the NAb titers at or above 1:80, which is probably too low in respect with other clinical trials worldwide.

Thus the conclusions can’t be considered conclusive.

Further research is needed to validate its use in COVID-19, including its efficacy in patients who lack NAb and the usefulness of CP with high NAb titers.