key: cord-1047523-ctizjahn
authors: Di Minno, Giovanni; Mannucci, Pier Mannuccio; Ironside, James W.; Perno, Carlo Federico; Gürtler, Lutz; Aledort, Louis
title: Convalescent plasma for administration of passive antibodies against viral agents
date: 2020-12-01
journal: Haematologica
DOI: 10.3324/haematol.2020.267427
sha: c0d777530bbb73bab32a59807ebff34a7abbe188
doc_id: 1047523
cord_uid: ctizjahn

nan

A dministration of passive antibodies through transfusion of plasma from donors recovering from a viral infection has long been employed to treat individuals infected with the same pathogen. 1 However, in studies with convalescent plasma (CP), differences and inherent limitations (e.g., sensitivity/specificity of tests to quantify neutralizing antibodies; sample size; scheduling of treatment [early/late CP administration vs. degree of disease severity], the presence of confounders [concomitant treatments]), and restricted generalizability of data argued for large-scale, randomized, controlled trials. 1, 2 The results of a multicenter proof-of-concept, observational Italian study in 46 patients with moderate or severe acute respiratory distress syndrome due to infection with the novel coronavirus, SAR-CoV-2, who needed mechanical ventilation and/or continuous positive airway pressure are reported in this issue of the Journal. 3 The interval between symptom onset and study inclusion was highly variable (2-29 days). The 7day mortality rate was 6% in patients given CP compared with an expected 15% according to Italian statistics and 30% in a small concurrent cohort not treated with CP. Weaning from continuous positive airway pressure was achieved in 26 of 30 patients, and three of the seven intubated patients were extubated. Whether those who received CP earlier improved more or faster than patients who received plasma later in the course of the disease is not clarified, nor are the reasons for administering one, two or three CP bags provided. In this larger than previous uncontrolled reports, five serious adverse events (including 1 transfusion-related acute lung injury [TRALI]) occurred in four patients. Although TRALI may be triggered by transfused antibodies, 4 CP was safe in this study as it was in #Donor selection is critical for the safety of plasma and plasma products. For SARS-CoV-2 studies; the FDA established that plasma should be collected from patients who had recovered from COVID-19 who had a negative SARS-CoV-2 polymerase chain reaction test and had been symptom-free for at least 14 days. Donors should meet the eligibility criteria for standard blood donors as set out in federal regulation 21 CFR 630. 10 . The latter studies also call for selecting convalescent donors based on the viral sequence of individual patients, a key issue for infections, such as influenza, caused by multiple strains of viruses. ^ The overall evidence that the administration of CP, serum, or H-Ig might be beneficial for the treatment of severe acute respiratory infections due to influenza or SARS-CoV-1 has been systematically reviewed and meta-analyzed (J Infect Dis. 2015;211(1):80-90). As a whole, a 75% reduction in the odds of mortality was found among patients with severe acute respiratory infections of viral etiology who were treated with convalescent plasma (or serum), together with a clinically relevant impact of the treatment on reducing the viral load. No evidence of serious adverse events or complications due to therapy were found and there was some evidence of a reduced use of critical care resources and length of hospital stay. Maximal reduction in mortality was achieved when CP was administered early after symptom onset. ^^The efficacy of CP in Ebola virus disease has been reported in two case series (Clin Infect Dis Resists conventional forms disease prion † and blood Taiwan, Saudi Arabia. diagnosis by of inactivation histopathology and western blot of brain or tonsils after onset of symptoms § The term "Emerging" denotes those pathogens whose incidence in humans has increased or may increase in the future, based on their appearance in a new host population or changes in epidemiology in an existing population. This definition includes causative agent(s) leading to a new infection, a re-emerging infection, or an infection with new attributes (e.g., drug resistance or virulence) making them pathogenic. Like SARS-CoV-2, most of these previously unknown entities are capable of quickly overcoming the original geographical boundaries and spreading among the human population. In the globalized world of the third millennium, millions of people and huge amounts of merchandise are transported every day by air from one part of the planet to another. This facilitates the 'traffic' of microbes and the diseases they cause from ecological niches in which they were confined, and their rapid spread to every corner of the earth. Unpredictable global and national events (wars, world tourism, migration) can further increase the spread of blood-borne diseases. With regards to the roles of zoonotic transmission in the introduction of an unknown pathogen into a new human host population, recombination and re-assortment (adaptation) to produce 'new' mutations that allow pathogens to acquire new biological characteristics to adapt to new ecologies and to infect new hosts (dissemination), leading to short, explosive outbreaks (e.g. Ebola virus) or slower, silent spreading (e.g. HIV-1) have been documented. Factors that influence the course of the SARS-CoV-2 disease are largely unknown. 5,000 patients in another study. 5 Also considering a risk/benefit analysis performed to improve the treatment of severe acute respiratory distress syndrome caused by SARS-CoV-2 infection, 1 the Food and Drug Administration (FDA) issued guidance on CP collection and distribution in the USA and recommended conducting clinical trials with CP in the setting of SARS-CoV-2 infection. 6 It has been proposed that, in such trials, one CP unit is used for post-expo-sure prophylaxis and one to two units for treatment of SARS-CoV-2 infection. 1 For patients who fail to meet the criteria for enrollment in clinical trials, the FDA has approved protocols for emergency use and expanded access. 4 In parallel, the plasma industry joined forces (the CoVIg-19 ALLIANCE) to increase plasma collection and produce safe and effective CP and hyperimmune immunoglobulins (H-Ig). 7,8 Beside the USA, other countries 9 Editorials haematologica | 2020; 105 (12) are collecting CP to be used in SARS-CoV-2 infections, and many studies are ongoing. 10 Parallel to the submission of the Italian study, an openlabel, multicenter, randomized trial from China appeared, in which patients with SARS-CoV-2 and severe acute respiratory distress syndrome were randomized to 4-13 mL/kg of CP plus standard treatment vs. standard treatment alone ( Table 1 ). The calculated sample size was 100 patients for each group. Due to the containment of the SARS-CoV-2 epidemic in China, the study was terminated when 103 of the 200 planned patients had been enrolled. At termination of the trial, improvement was found in 21/23 patients in the CP group vs. 15/22 in the control group (P=0.03) among those with severe disease, and in 6/29 of the CP group vs. 7/29 in the control group (P=0.83) among those with lifethreatening disease. There was no between-group difference in mortality (P=0.30) and two adverse events were detected in two patients in the CP group.

While antibody administration by means of CP is indeed a reliable strategy for conferring immediate immunity against viral agents to individuals with SARS-CoV-2 infection, there is uncertainty about whether CP or H-Ig is the more effective product to be administered. 10, 11 While CP is characterized by donor-dependent variability in antibody specificity and titers, H-Ig contains standardized antibody concentrations. On the other hand, while the IgM fraction, a key weapon against some viruses, is removed from plasma during H-Ig fractionation, CP also provides coagulation factors (to fight hemorrhagic fevers, such as Ebola). 2 Although specific antibodies hamper viral replication, the SARS-CoV spike (S) protein is the main antigenic component responsible for biological effects, e.g., host immune responses, neutralizing-antibody formation, T-cell responses and ultimately protective immunity. 12 On the whole, the proportion of anti-S protein antibodies, relationships between IgG/IgA/IgM, standardization of antibody titers and optimal dosing and scheduling of CP administration are still major unknowns from studies conducted so far in the frame of the SARS-CoV-2 pandemic.

This scenario of growing interest from clinicians, patients, policy-makers, health systems and pharmaceutical industries provides an unprecedented opportunity to exert a major imprint on the practice of medicine. 2 A concerted effort is warranted to achieve globally uniform, high-quality standards for CP or H-Ig preparations. In high-income countries, the industrial production of plasma-derived products has never been safer than nowadays both because of the guidelines produced by the FDA and European Medicines Agency on donor selection and screening and because of the availability of viral inactivation methods. Plasma is collected at plasmapheresis centers using technologies regularly inspected by governing bodies before approval for commercial use. Plasma is screened after each donation and re-screened in mini-pools for human immunodeficiency virus-1, hepatitis A, B and C viruses, and parvovirus B19, and Plasma Master Files are subject to yearly approval by regulatory agencies. 13 Once collected, plasma from single donors may be administered directly to patients or pooled to manufacture plasma-derived products such as H-Ig, coagulation factors and others. The resulting products may be treated with solvent/detergent and/or super-heated (at 80° C for 3 days), pasteurized or nano-filtered. The aforementioned approaches are highly effective in minimizing pathogen transmission, as demonstrated by the fact that no blood-borne pathogen transmission has been reported since 1987 for commercially prepared plasma products received by patients with hemophilia, the epitome of multi-transfused patients. 13 In theory, however, risks remain pertaining to emerging and re-emerging pathogens (prions, non-lipid enveloped viruses) ( Table 2) , for which diagnosis and inactivation methods are still a challenge. 14 The reasons for this caveat concerning risks include the lack of reliable screening tests for some pathogens (e.g. prions), no screening for unknown pathogens, and relative poor sensitivity/specificity of the available assay methods. 15 Furthermore, some viral mutants may escape screening, 16 which may also not pick up potential plasma contamination from infectious but not yet seropositive donors. In addition, there may be low-level chronic carriers among donors who remain undetected and yet contribute to infect the plasma pool. 17, 18 Finally, determining the prevalence of emerging pathogens may be difficult when there is a long latency between infection and symptom onset. 19 On this background and with these knowledge gaps, the adaptation of screening methods is a constant challenge, 13 and public health organizations and plasma pharmaceutical industries have combined efforts to tackle the risks. In the framework of its global perspective, the World Health Organization tries to minimize pathogen transmission through early information and public health vigilance on the emergence of regional pathogens capable of causing transfusion-transmitted infections (e.g. Zika virus in Brazil), even before local authorities manage to develop means to prevent blood-borne transmission. 20 Because 'zero risk' in terms of product safety is unlikely, governing bodies provide guidance to identify factors relevant for pathogen transmission. As an example, the presence of blood-borne hepatitis E virus may pose significant threats to some people (e.g., the elderly, immunocompromised individuals) despite being of low risk to other potential recipients. Thus, in addition to the circumstances under which blood products are collected and manufactured, the nature of the pathogen (e.g., its physical characteristics, level of virulence, prevalence) and the patients' characteristics (age, immune status, geographical location, lifestyle, treatment urgency) should be considered when choosing the individual treatment (and assessing an acceptable level of risk).

Alongside this scenario of basically satisfactory blood product safety in high-income countries, it should be considered that in most low/middle-income countries procedures for blood collection are seldom standardized, and donor selection, screening and viral inactivation often fail to meet the criteria validated and implemented by regulatory agencies in high-income countries. If insufficient anti-SARS-CoV-2 CP is available from high-income countries to meet global needs, the use of plasma from low/middleincome countries may become necessary but may also raise some issues, because the type and prevalence of infectious agents likely differ in different populations. 13 To sum up, if worldwide uniform advancements in blood-banking quality are encouraged in low/middleincome countries, there is now a global opportunity to perform clinical studies on the efficacy of CP or H-Ig in viral infections and address uncertainties on the occurrence of serious adverse events related to the administration of these products. 10 Removing regulatory barriers that limit the use of pathogen-reduction technology for CP collections would be a major help in this respect. 2 The process of obtaining informed consent requires communication of risks and benefits of treatments to patients. SARS-CoV-2 is an easily inactivated enveloped virus, 13 and strict regulations for plasma product manufacturing minimize the risk of known and unknown pathogens. Apart from emergency situations, the extent to which people should be further informed on specific risks associated with any particular product will depend on a variety of factors including availability of alternative treatments, and the patients' characteristics (e.g., age, physical/mental condition, education/level of understanding, language barriers/religious beliefs). A good understanding by health care professionals of the sources and modes of production of plasma derivatives and of pathogen-reduction/inactivation techniques might be an additional benefit of studies involving CP.

Parallel to the submission of this Editorial, a systematic review of completed (as of June 4, 2020) and ongoing (n=98) studies on the efficacy and safety of convalescent plasma or hyperimmune immunoglobulins to reduce mortality in patients with SARS-CoV-2 infection appeared (Cochrane Database Syst Rev. 2020;7(7):CD013600. Its provisional conclusions support the clinical relevance of the concepts summarized in the present report.

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