Saturday, October 05, 2019

The Lancet: Clinical Trial On Use of Convalescent Plasma To Treat Severe Influenza


Over the the past 14 years we've looked at a number of attempts to use convalescent plasma - donated by survivors of H5N1, H1N1, H7N9, SARS and most recently MERS and  Ebola - to treat severely infected patients.
It's not a new idea; human and animal serum therapy was used extensively during the first half of the 20th century to treat a variety of infectious diseases, including anthrax, scarlet fever, measles, tularemia, diphtheria, rabies and pandemic influenza.
A relatively high percentage of adverse reactions (serum sickness) and the development of more effective antibiotics and drugs have made this option less attractive in recent decades. But with a rising number of emerging infectious diseases; like MERS, Avian Flu, and Ebola - many with few, if any therapeutic options - convalescent serum has been getting a second look.
Along the way we've seen a smattering of promising results (see 2011's CID Journal: Convalescent Plasma Therapy For Severe H1N1 and 2015's Int J Infect Dis: Convalescent Plasma Treatment Of An H7N9 Patient In China).
But large, rigorous clinical trials have been few in number, and we've seen some  failures as well (see NEJM: Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea) and  Clinical Trial E NCT02190799 for Anti-MERS-CoV Convalescent Plasma Therapy was never completed due to logistical and technical problems.

This past week The Lancet published a summary of the results of a Clinical Trial (#NCT02572817), which looked to evaluate the use of convalescent plasma for the treatment of severe influenza A infection, and found it wanting.

A brief description, from follows:
Comparing the Efficacy and Safety of High-Titer Versus Low-Titer Anti-Influenza Immune Plasma for the Treatment of Severe Influenza A

Detailed Description:

Despite antivirals and vaccines, influenza is responsible for thousands of hospitalizations and deaths each year worldwide. Because of this, additional treatments for influenza are needed. One potential treatment may be the use of high-titer anti-influenza immune plasma. The purpose of this study is to evaluate the efficacy and safety of treatment with high-titer versus low-titer anti-influenza immune plasma, in addition to standard care, in participants hospitalized with severe influenza A infection.

This study enrolled people aged 2 weeks or older who are hospitalized with severe influenza A infection. Participants were randomly assigned to receive either high-titer anti-influenza plasma or low-titer (control) anti-influenza plasma on Day 0. In addition, all participants received standard care antivirals. Participants were assessed on Day 0 (baseline) and on Days 1, 2, 3, 7, 14, and 28. 
For participants who were not hospitalized on Days 2, 14, and 28, researchers could contact participants by telephone. Study procedures included clinical assessments, blood collection, and oropharyngeal swabs.

Study Design

Study Type : Interventional (Clinical Trial)
Actual Enrollment : 138 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Double-Blind, Phase 3 Study Comparing the Efficacy and Safety of High-Titer Versus Low-Titer Anti-Influenza Immune Plasma for the Treatment of Severe Influenza A
Study Start Date: November 2015
Actual Primary Completion Date : April 26, 2018
Actual Study Completion Date : May 18, 2018
The Lancet report, with its disappointing findings, can be viewed at:
Anti-influenza immune plasma for the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial
John H Beigel, MD Evgenia Aga, MSc, Prof Marie-Carmelle Elie-Turenne, MD, Josalyn Cho, MD, Prof Pablo Tebas, MD, Carol L Clark, MD,et al.

Published:September 30, 2019
The bottom line, from the summary:
  • High-titre anti-influenza plasma conferred no significant benefit over non-immune plasma. 
  •  . . . the benefit is insufficient to justify the use of immune plasma for treating patients with severe influenza A.
The Lancet also carried a commentary on these results, where the authors discuss the likely difference between protective antibody titers ( > 1:40 or 1:80), and therapeutic levels, which may need to be an order of magnitude higher.
Passive immunity for the treatment of influenza: quality not quantity
Sanjat Kanjilal, Michael J Mina
This study isn't necessarily the last word on convalescent therapy, but it reminds us we've a long ways to go to fully understand how the human immune system works, and how best to enhance it.