Disclaimer: This post represents my personal opinion. This does not represent the opinion or policy position of my employer or any organization or agency or group that I am affiliated with.

A friend, who received a pre-print version of the Dutch ConCOVID trial, forwarded it to me yesterday, and after giving it a quick read, I felt a sinking feeling that convalescent plasma therapy may not be working in the way we have envisioned it to be. Right now it seems like the pre-print is not online on Biorxive, so I am uploading it here for reference.

UPDATE: The paper is online here: LINK.

The CONCOVID trial enrolled patients who were RT-PCR proven to have SARS-CoV-2 infection from 14 hospitals across the country. Donors were also selected from a pool of eligible individuals who had a demonstrable, RT-PCR proven episode of COVID-19 and had been asymptomatic for at least 14 days.

Interestingly, in this trial, they looked at the antibody titers of both donors and recipients (patients). Both were tested for anti-SARS-CoV-2 antibodies using an anti-SARS-CoV-2 Plaque Reduction Neutralization Test (PRNT). Donor plasma with PRNT50 titer of >1:80 was only considered usable for infusion. Patients received ABO compatible plasma with the highest PRNT50 titer available to the trial sites at the time point of the intervention.

Patients received 1 unit of 300 ml convalescent plasma. Those without clinical response or persistent RT PCR positivity were eligible to receive a second unit after 5 days. Off-label drugs were used based on institutional protocols and standard of care. The pre-print lists the following drugs being used as off-label therapy: chloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, anakinra.

The primary end-point of the study was overall mortality until discharge or at 60 days after admission, whichever happened earlier. Although the pre-print covers only a few key secondary outcomes (clinical improvement measured in WHO ordinal scale, length of hospital stay, safety), their clinicaltrials.gov entry listed the following exploratory secondary end-points:

Secondary (exploratory) objectives

• Evaluate the effect of 300ml convP on hospital stay
• Evaluate the change of the 8-point WHO COVID19 disease severity scale on day 15 and 30
• Evaluate the change of the 8-point WHO COVID19 disease severity scale on day 15 in the subgroup of patients with a baseline neutralizing antibody titer (PRNT50) <80
• Evaluate the effect of 300ml convP on mortality in patients admitted to the ICU
• Evaluate the effect of 300ml plasma therapy on hospital days for patients admitted to the ICU within 24 hours after admission
• Evaluate the impact of plasma therapy on the decrease in SARS-CoV2 shedding from airways
• Evaluate the difference in effect of convP on mortality in patients with a duration of symptoms < or > the median duration of symptoms in the study population
• Evaluate the impact of CTL and NK cell immunity on the likelihood of being protected from immune serum transfer
• Safety of convP therapy
• Evaluate the impact of covP on long-term lung function

The study was halted early, after recruting 43 patients in the intervention and control arms each.

Donors were overwhelmingly males, who had been symptomatic for a median of 12 (IQR 8-18) days. Donors were younger than the patients, and had a milder disease course as well. Plasma donated by 19 donors were used in the study and all the units used had a pretty high antibody titer, with median titer of 1:640 (IQR 1:320 to 1;1280). This was possible because the protocol specified that the patients would receive ABO matched plasm with the highest antibody titer available at the point of intervention.

The patients enrolled in the trial were mostly males, aged 63 (IQR 56-74) years, symptomatic for 10 (IQR 6-15) days, and admitted for 2 (IQR 1-3) days. Out of the 86 patients enrolled, 13 had been directly admitted to the ICU and were on mechanical ventilation.

A very worrisome trend was noted in the antibody levels tested from the patient samples. Blood samples were collected from 66 patients, and 80% (53/66) tested positive for anti-SARS-CoV-2 antibodies. The PRNT50 titer was measured in 56 of these 66 patients, and in 44 of them, titers >1:20 were measured. Also, interestingly, the media antibody titers were comparable between the patient and donor groups, both being 1:160.

The CONCOVID team went one step further, to check if the trends of antibody responses observed in the patients enrolled for the trial were also seen in other, similar patient groups. An additional 37 serum samples, collected within 3 days of admission, from mainly male, elderly patients, with a symptom duration of 9 (IQR 4-13) days also yielded similar results. 70% of these samples had antibodies, with 62% of them showing “high neutralization capacity”.

Although numerically fewer patients died in the convalescent plasma arm compared to the control arm (14% vs 26%), this was not a statistically significant difference. Also, only 32 of the enrolled patients had been followed up for the full 60 day period, so the numbers could have changed had the study progressed further. As far as the secondary outcomes were concerned, there was absolutely nothing to pick in clinical improvement scores using the WHO ordinal scale, with 25 improvements in both arms. Plasma therapy was also not linked to shorter hospital stay or any serious adverse events.

The investigators felt compelled to change the study design in a fundamental way and felt that it would warrant termination of the current trial, as the design would have to be changed substantially to accommodate for the surprising finding of antibody response noted in the patient group. The basic assumption that most patients would not develop a substantial antibody response in course of their illness was found to be untrue based on the 86 patients enrolled. This would necessitate antibody testing in all patients prior to their entry into the trial. For convalescent plasma to work, patients with limited or no antibody response need to be provided with the therapy.

Around 60% of the donors had antibody titers less than 1:320, which could be linked to the fact that most of them had a substantially milder disease episode. This again provides support to the hypothesis that a more severe course of the disease is linked to a better antibody response, although without more evidence this is just yet another conjecture. The CONCOVID team also raises the uncomfortable uncertainty around the titer at which plasma therapy would produce clinically significant results in plasma recipients, given the volume of distribution. They suggest that screening patients for antibody response prior to initiating plasma therapy could be a potential way forward. Donors should be selected from patients who survived a severe episode of COVID-19, which comes with its own ethical, moral and practical challenges. Using hyperimmune immunoglobulin preparations, or specific neutralizing (?monoclonal) antibodies is yet another alternative they propose.

This brings me to the crux of the issue around plasma therapy and the controversies swirling around it in India. Many clinicians and patient groups have started considering plasma therapy as a panacea for COVID-19, a hopeful conjecture which the current study seems to refute. However, we need to have a look at the trial results emanating from the multiple plasma therapy trials ongoing in India, before taking a final call on burying this option. Given that it was used quite early in the Dutch study, yet, failed to make a statistically significant dent in the mortality, it appears to be yet another therapy which should be initiated as close to diagnosis or appearance of symptoms as possible. Many patients and their families, and even clinicians, have been advocating for plasma therapy in critically ill patients in India; this is likely to be a last-ditch effort unlikely to result in favorable clinical outcomes. Again, we need to wait for the Indian trials to yield results before jumping to any conclusions.

This virus is proving to be a very tricky customer indeed, with its own complex biology and an even more complicated immune response from its host!