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EBM Focus

 

Convalescent plasma for COVID-19: Caveat emptor

Reference: BMJ. 2020 Oct 22

In June of this year, the EBM Focus reviewed preliminary reports about convalescent plasma for COVID-19 which more or less highlighted the need for high-quality data before this treatment could be deemed effective. In October, a Cochrane analysis made a similar statement. It has been noted that trials of convalescent plasma can be hard to aggregate because of the heterogeneity of their methods, and at least one trial in China was halted because of a lack of people sick with COVID-19. Recently, however, the Indian Council of Medical Research has published a randomized multicenter open-label trial comparing convalescent plasma with usual care in 464 adults with moderately severe COVID-19.

Patients were enrolled if they had COVID-19 and a room air saturation ≤ 93% with a respiratory rate of > 24/ minute or a PaO2/FiO2 level of 200-300 mm Hg when an ABO compatible plasma donor was available. Blinding was not possible, but the groups were randomized with unequal-size-block-randomization, a technique that can minimize allocation bias in non-blinded studies such as this one. Both the usual care and intervention groups had comparable baseline data (including blood type), and received care including antivirals, steroids, and various anti-inflammatory medications.The intervention group also received two 200-mL infusions of convalescent plasma. Plasma donors were adults who had COVID-19 with cough and fever and who were symptom-free for at least 14 days prior to donation (if two subsequent RT-PCR tests were negative) and sometimes 28 days (without the requirement for subsequent testing). Plasma titers for the COVID-19 antibodies weren’t available until halfway through the protocol, and at least half the titers were analyzed retrospectively. The plasma titers were lower than have been reported in other trials, with a median value of 1:40. The primary outcome in this study was progression to a PaO2/FiO2 ratio of < 100 mm Hg or all-cause mortality in the 28 days following allocation.

There was no difference in primary outcomes of progression to worse illness, death, or a composite of both outcomes (19% in intervention vs. 18% in control group). The risk ratio (RR) of 1.04 (95% CI 0.71-1.54) for the composite primary outcome was mirrored in secondary outcomes such as inflammatory markers or SOFA scores, and although there was statistically less shortness of breath (RR 1.16, 95% CI 1.02-1.32) and fatigue (RR 1.21, 95% CI 1.02-1.42) at 7 days in the intervention group, these somewhat subjective outcomes were not matched by a decline in length of stay, ventilator use, or other more objective outcomes.

This trial finds no benefit for convalescent plasma in the most meaningful outcomes for patients. An important limitation to the generalizability of this study is the relatively low average titer level of 1:40, since other studies showing benefit have used plasma with much higher titer cutoffs such as > 1:640 or > 1:1,000. The NIH has not yet issued standards for screening donor plasma for antibody levels. However, the multi-center nature and relatively large number of people who participated suggests the results may be more generalizable. The authors mention a black market for convalescent plasma – this study suggests that buyers should be aware that at least in low titers, convalescent plasma doesn’t seem to do much.

For more information, see the topic COVID-19 (Novel Coronavirus) in DynaMed.

DynaMed EBM Focus Editorial Team

This EBM Focus was written by Dan Randall, MD, Deputy Editor for Internal Medicine at DynaMed. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School, and Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed.

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