Dutch trial of convalescent plasma in COVID-19 discontinued

There are many different opinions in the medical and broader scientific community as to what works and does not work concerning the management of COVID-19 patients. Now, a recent trial published on the preprint server medRxiv* in July 2020 reports that a majority of hospitalized COVID-19 patients have a high titer of neutralizing antibodies, at the time of admission, within 10 days of symptomatic disease.

Study: Convalescent Plasma for COVID-19. A randomized clinical trial. Image Credit: pirke / Shutterstock
Study: Convalescent Plasma for COVID-19. A randomized clinical trial. Image Credit: pirke / Shutterstock

Promising Therapies in COVID-19

Researchers in recent trials have described a salutary effect of the corticosteroid dexamethasone on the mortality rate in these patients, probably due to its anti-inflammatory effects. Remdesivir was also shown in a recent study to reduce the recovery time, as well as other medications and antibodies such as ribavirin, lopinavir-ritonavir combination, and interferon beta-1b.

There are significant issues with these drugs, including lack of adequate evidence as to their efficacy, their lack of availability, and their relatively higher cost. Thus, the use of convalescent plasma (CP) is being examined in many studies.

The earlier outbreaks of SARS and MERS also saw CP being used to treat affected individuals. The preclinical evidence is undoubtedly in favor of the use of this modality for the treatment of human coronavirus infections, but large adequately-powered trials have not yet been conducted.

The Study: Convalescent Plasma in COVID-19

The researchers, therefore, carried out the current study, assuming that the effectiveness of CP is due to the direct reduction of virus titer by neutralizing antibodies. This means that benefit can only occur if the patient being treated has an inadequate antibody response.

The safety of CP is another issue to be explored. The ConCOVID study was planned to discover the impact of CP on the death rate of COVID-19 patients when given early in the course of hospital stay. At this point, knowledge was scarce on the actual time when neutralizing antibodies developed, and patients were not expected to have detectable levels of these antibodies at the point of admission.

Patient and Donor Characteristics

The trial was carried out in 14 hospitals in the Netherlands, from April 8, 2020, onwards. All patients were 18 years or above, and had a positive reverse transcriptase-polymerase chain reaction (RT-PCR) test for SARS-CoV-2 in the previous 96 hours. There were 86 patients who entered the study.

The 100 donors who contributed CP had recovered from a COVID-19 infection confirmed by RT-PCR, had no symptoms for 14 days or more, and the plasma used had neutralizing antibodies specific to the virus, as confirmed by a plaque reduction neutralization test (PRNT) with a titer of 1:80 or more. Most donors were younger than the patients, and the disease course in their case was typically milder.

Each patient received the plasma with the highest PRNT titer available at the time of entering the study. Patients were randomly assigned to receive or not receive CP. If there was no clinical response and if the PCR remained positive after 5 days, a second dose was given at this point.

All patients in both groups received approved drugs like chloroquine, the antibiotic azithromycin, the antivirals lopinavir/ritonavir, the IL-6 inhibitor tocilizumab, and the IL-1R inhibitor anakinra.

The severity of the disease was scored using the WHO ordinal score at three points, day 1, 15, and day 30. Serum and nasopharyngeal swabs were tested by RT-PCR repeatedly.

Patients were mostly male, with a mean age of 63 years. Of the total, 13 were seriously ill and were directly admitted to the intensive care unit (ICU), and put on mechanical ventilation.

High Specific Antibody Titers

Of the blood samples taken at entry, 53/66 showed the presence of specific antibodies against the virus. The PRNT50 titer, measured in 56 samples, was above 1:20 in 44 of them, or almost 80%. The median PRNT titer in all measured samples was similar to that found in the donor population. The median titer in the plasma units actually used in patients was higher than that measured in the patients at enrolment.

In short, the investigators looked at another 37 samples from patients with COVID-19. All samples had been collected within 3 days of admission. The age, sex, and symptom duration of these patients were comparable to those in the ConCOVID study. Here again, about 70% of patients had antibodies to the virus, while about 62% had an Ig ratio more than 10, or a potent neutralization ability.

The researchers also wanted to see if the administration of CP speeded up the increase in neutralizing antibodies with time. They compared PRNT50 titers on day 7 with those on day 1 in 9 patients whose titers were less than 1:160 at the beginning. All of them showed a fourfold increase in titer over this period.

There was no significant improvement in the odds of death, or of severe disease, in patients treated with CP. This treatment did not reduce the time to discharge, while there were no serious adverse effects.

The follow-up in all patients, by the time these deaths were recorded, had lasted for a minimum of 15 days, while it was as long as 30 days and 60 days in 75 and 32 patients, respectively.

What is Wrong with Current Studies on CP Use?

The researchers comment, “The observations we made on antibody titers in patients and donors, convinced us that a complete redesign of the study was needed and could not be resolved with a substantial study amendment.” As a result, the study was prematurely ended, since the administration of CP in patients who already had high levels of neutralizing antibodies was not expected.

The study cautions against conducting similar studies without first testing for antibodies at the time of inclusion. Secondly, they point out that only 40% of donors had high neutralizing titers crossing 1:320, probably because of a milder course of disease. It is known that antibodies in plasma are diluted tenfold or more when given to an adult. This means that the titer should be adequate.

However, most current trials do not measure the neutralizing capacity of donor plasma, despite this being the gold standard. Some depend on a positive ELISA test, while others fail to test for the presence of antibodies at all.

The effect of CP may be independent of the titer of neutralizing antibodies, brought about by its inhibitory or modulatory effect on inflammation and the immune response.  However, this may not be the case in these patients since immunomodulation occurs only when Ig is used at doses which are tenfold that found in 300 ml of plasma.

Implications and Future Applications

The current study suggests that when a Wantai ELISA for the virus is positive with the OD ratio at 10 or above, the PRNT50 titer is 1:80 or more. This means that if the PRNT50 is not measured, the donor will at least have a respectable titer of neutralizing antibody.

Another possible way to avoid recruiting donors with low antibody levels is to take only those who had severe disease, and to use hyperimmune Ig prepared from pooled convalescent plasma, or to separate only specific antibodies with high neutralization capacity.

In short, the study concludes, “The majority of patients in the ConCOVID study already had high titers of virus-neutralizing antibodies upon enrollment in the study. This observation should trigger investigators to reconsider the design of current studies on convalescent plasma for the treatment of patients with COVID-19.”

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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