On the eve of Christmas in 1891, Emil von Behring, the “Father of Serum Therapy,” injected Diphtheria therapeutic serum into an eight-year-old child suffering from severe diphtheria, and created history when the child was completely cured. He went on to win the Nobel Prize in 1901 for opening “a new road in the domain of medical science” and placing “in the hands of the physician a victorious weapon against illness and deaths.” The promise of serum therapy holds more importance now in the era of emerging infectious diseases. (1, 2)
In the midst of the largest Ebola outbreak to date, van Griensven et al. conducted a trial to evaluate the therapeutic potential of convalescent plasma for Ebola virus disease in Guinea. The NEJM has published a report of this open-label treatment experience, conducted in the volatile setting of an ongoing outbreak situation, that attempts to assess the treatment efficacy and safety of convalescent plasma for acute Ebola infection. The study was conducted at Ebola treatment units in Conakry, Guinea, between February and August 2015. The control group was historically assembled from patients who had received treatment at the same facility in the previous five months.
The study primarily looked at the adjusted survival of patients, discharged as cured 3-16 days after diagnosis, between the two groups. After day 2 of diagnosis, per WHO Guidance (3), 400-500ml of convalescent plasma from 2 different donors, or 10ml/kg for small adults and children <45kg was given in two infusions. The estimated sample size of 130 patients for the intervention arm could not be assembled as the Data and Safety Monitoring Board advised early closure of the study owing to low caseloads. The primary analysis included 84 patients in the intervention and 418 in the control groups. The mortality in the intervention arm was 31%, whilst that in the control arm was 38%. The absolute risk difference (-6.9%; 95% confidence interval (CI): -17.8% to 4.1%) was not statistically significant and did not achieve the targeted 20% reduction.
Considering the non-randomized nature of the study and the fact that a historical cohort was used as controls, there is a possibility that the results are affected by unadjusted confounders. The inability to achieve the targeted sample size was also a limitation. In addition, the study was hampered by the absence of a clear understanding of the antibody titers in the convalescent plasma used or the optimal dosages and dosing frequency of convalescent plasma. NEJM Deputy Editor Dr. Lindsey R. Baden concurs, adding, “lack of real time controls is a tremendous limitation, and there was no way to ensure that this therapy included proper dosing of the antibody. But this is a critically important investigation to conduct under extreme circumstances.”
Emerging infectious diseases are a major threat to public health, mainly because these are novel diseases for which we have limited interventions available. In such a setting, devising a new intervention in time to control an outbreak situation is very difficult. Dr. Baden elaborates on this issue, stressing the importance of the study ‘’Convalescent plasma was part of the countermeasure plan in 1976 during the initial investigation which identified Ebola. Developing counter measures for emerging infectious diseases, especially those with explosive potential, is a high priority. Developing these measures in the midst of an epidemic is an extreme challenge”.
The current study goes a long way to establish the relative safety of convalescent plasma administration as a treatment modality and to assess the feasibility of obtaining and administering the convalescent plasma in the setting of an ongoing Ebola virus disease outbreak. Future studies need to look at dosing schedules, role of hyperimmune immunoglobulins, and changing patterns of antibody titers in the convalescence period to shed further light on these results.