key: cord-0909963-wk4qsvw9
authors: Hartog, Nicholas; Holsworth, Amanda; Rajasekaran, Surender
title: Controlled Trials Needed to Prove Efficacy and Safety of Convalescent Plasma Therapy in COVID-19
date: 2020-11-05
journal: Ann Allergy Asthma Immunol
DOI: 10.1016/j.anai.2020.11.005
sha: 807876ea4e08d420cbe2ee5f9c528c4d353a1cb6
doc_id: 909963
cord_uid: wk4qsvw9

nan

by March 2020 was recognized as a global pandemic by the World Health Organization. The 2 speed with which the disease has spread, and its sizable case fatality have led to the clinical 3 application of various therapies with at most minimal evidence of efficacy or safety. 4 Use of convalescent plasma therapy for COVID-19 was initially reported in five patients in 5 China. Its use has grown rapidly to become a mainstay of COVID-19 therapy due to the United 6 States Food and Drug Administration (FDA) expanded access and single-arm expanded access 7 coordinated through Mayo Clinic with >105,000 patients being treated prior to the program 8 closure due to the FDA approving emergency use authorization (EUA). As the pandemic 9 continues, the efficacy of convalescent plasma therapy remains to be established and has been 10 unconvincing at best in its previous use in Ebola, influenza, SARS-associated coronavirus 1, or 11 Middle East Respiratory syndrome coronaviral infections. 1 Thus far, no placebo-controlled 12 randomized controlled trial has shown efficacy for convalescent plasma in COVID-19. Despite 13 this lack of evidence trial, the FDA recently issued an EUA for convalescent plasma in COVID-14 19.

Over the last two decades, the use of blood products in critically ill patients has been discouraged 16 by multiple societies and guidelines due to inferior outcomes. The risks of convalescent plasma 17 therapy include but are not limited to transfusion-associated circulatory overload (TACO), 18 transfusion related acute lung injury (TRALI), complement-mediated tissue damage, allergic 19 reactions and antibody dependent enhancement of disease. 2 The very nature of transfusion 20 mediated injuries dictate that an " inflammatory first hit" be present thus laying the foundation 21 for virus related pulmonary manifestations to serve that role . Therefore, the adverse effects There is mounting evidence defective type I IFN response contributes to severity of disease and 35 transfer of these auto-antibodies from donor to critically ill patient via convalescent plasma 36 presents distinct potential for worsening disease with this specific therapy. The presumption that 37 the risk of convalescent plasma is low risk may not be true and remains to be proven in 38 prospective trials.

To determine the efficacy of plasma therapy we must understand the characteristics that predict a 40 favorable response; this includes the optimal donor COVID-19 antibody titer level so that the 41 dose, recipient outcome, and timing of infusion can be ascertained. Special consideration and 42 attention should be given to primary secondary immunodeficiency patients and potential benefit 43 of convalescent plasma in these patients. A properly designed study should address the 44 deficiency of data for convalescent plasma therapy. One such potential approach to further 45 studying convalescent plasma therapy that could be considered is a four-armed study that would 46 J o u r n a l P r e -p r o o f include immunologic monitoring to collect data on effectiveness, mechanism of action, 47 immunologic modulation and risks (Table 1 ). In addition to lack of data on effectiveness, there is 48 a paucity of data on dose dependent response. Stratifying treatment groups by COVID-19 49 specific antibody level present in the plasma will allow us to tease out potential differences based and transfer of these auto-antibodies from donor to critically ill patient via convalescent plasma 38 presents distinct potential for worsening disease with this specific therapy. The presumption that 39 the risk of convalescent plasma is low risk may not be true and remains to be proven in 40 prospective trials.

To determine the efficacy of plasma therapy we must understand the characteristics that predict a 42 favorable response; this includes the optimal donor COVID-19 antibody titer level so that the 43 dose, recipient outcome, and timing of infusion can be ascertained. Special consideration and 44 attention should be given to primary secondary immunodeficiency patients and potential benefit 45 of convalescent plasma in these patients. A properly designed study should address the 46 J o u r n a l P r e -p r o o f deficiency of data for convalescent plasma therapy. One such potential approach to further 47 studying convalescent plasma therapy that could be considered is a four-armed study that would 48 include immunologic monitoring to collect data on effectiveness, mechanism of action, 49 immunologic modulation and risks (Table 1 ). In addition to lack of data on effectiveness, there is 50 a paucity of data on dose dependent response. Stratifying treatment groups by COVID-19 51 specific antibody level present in the plasma will allow us to tease out potential differences based 

We strongly encourage well designed studies to evaluate risk and 71 benefit of therapies before large scale single arm expanded access and now EUA, especially now 72 that there is evidence of harm with plasma therapy