key: cord-0873641-ws573yud authors: Focosi, Daniele; Franchini, Massimo title: COVID‐19 convalescent plasma therapy: hit fast, hit hard! date: 2021-04-01 journal: Vox Sang DOI: 10.1111/vox.13091 sha: 874614cd9804f5fb9976fa204a57fd900e96caf9 doc_id: 873641 cord_uid: ws573yud nan Timeliness of treatment can be defined in various ways: median duration of symptoms before randomization or transfusion, time between hospital admission and transfusion and time between final diagnosis and transfusion, or can be inferred from the disease stage. The rationale for administering CCP as early as possible lies in the neutralization stoichiometry itself. The more actively replicating virions there are within the body, the higher the nAb dose needs to be to neutralize them all. At the very beginning, many historically or internally controlled phase II studies showed clinical benefit from CCP. The largest of them is likely the one by Joyner et al., who showed, in a post hoc analysis from the US open-label EAP (NCT04338360), that 7-day mortality in non-intubated patients younger than 80 years of age and treated within 72 h after diagnosis was 6Á3% in those receiving high-titre CCP and 11Á3% in those receiving low-titre CCP [1] . Of the 3,082 patients included in a later analysis, death within 30 days after CCP transfusion occurred in 22Á3% in the high-titre group, 27Á4% in the medium-titre group and 29Á6% in the low-titre group; no effect of CCP titre on the risk of death was observed among patients who had received mechanical ventilation [2] . In a post hoc subgroup analysis of 35,322 transfused patients from the Mayo Clinic (including 52Á3% in the intensive care unit and 27Á5% receiving mechanical ventilation), the 7-day mortality rate was 8Á7% in patients transfused within 3 days of diagnosis but 11Á9% in patients transfused ≥ 4 days after diagnosis. Similar findings were observed in 30-day mortality (21Á6% vs. 26Á7%) in the US EAP [3] . Unfortunately, the main bias of those studies is that controls were neither randomized nor PSM; hence, differences in the treatment outcome between treated and untreated groups may have been caused by a factor that predicted treatment rather than by the treatment itself. PSM studies balance treatment and control groups on a large number of covariates without losing a large number of observations. In two retrospective PSM studies from two different hospitals in New York, trends for improved outcomes were observed in non-intubated patients and in those treated within 7 days of hospitalization (hazard ratio, 0Á33) [4, 5] . These findings were later confirmed in a prospective PSM study from Houston [6, 7] . Of interest, a retrospective PSM study from Providence in which patients were treated at a median of 7 days after onset of symptoms did no show any benefit [8] . Since PSM only accounts for observed (and observable) covariates and not latent characteristics, RCTs remain the gold standard for highest level evidence (Table 1 ). In the PlasmAr RCT, the primary and secondary outcomes in the small number of early arrivals (within 72 h) were better in the CCP arm (n = 28) than in the placebo arm (n = 11), but the minimal contribution of this group to the overall cohort (228 CCP and 105 placebo) made the advantage disappear in the final outcomes at day 30 [9] . In another Argentinean RCT on 160 patients older than 65 years of age with mild COVID-19 who were treated with CCP within 72 h, progression to severe COVID-19 was halved at day 30 [10] . In another RCT from India, patients younger than 67 years of age treated at a median of 4 days after hospital admission showed superior mitigation of hypoxia and survival in the CCP arm [11] . Another RCT in Spain enrolling patients at less than 7 days of hospitalization showed benefit [12] . Many more RCTs are ongoing. 'Not assessed' means that antivirus antibodies were assessed only using high-throughput serology. *The WHO score [20] ranges from 0 to 8: 0: no clinical or virological evidence of infection; 1: no limitations of activities; 2: limitations of activities; 3: hospitalized, no oxygen therapy; 4: oxygen by mask or nasal prongs; 5: non-invasive ventilation or high-flow oxygen; 6: intubation and mechanical ventilation; 7: ventilation + additional organ support -pressors, renal replacement therapy, extracorporeal membrane oxygenation; and 8: death. Here below, an alternative layout/adaptation of n.a. Hospital stay in the CCP group was significantly longer than in the matched control group (P < 0Á0001). [27] © 2021 International Society of Blood Transfusion Vox Sanguinis (2021) COVID19 convalescent plasma therapy 5 None of these studies tittered neutralizing antibodies in either the donors or recipients using the plaque reduction neutralization test. WHO, World Health Organization; CCP, COVID-19 convalescent plasma; Refs, references; aOR, adjusted odds ratio; aHR, adjusted hazard ratio; RR, relative risk; RBD, receptor binding domain; S/CO, significant cut-off. *The WHO score [20] ranges from 0 to 8: 0: no clinical or virological evidence of infection; 1: no limitations of activities; 2: limitations of activities; 3: hospitalized, no oxygen therapy; 4: oxygen by mask or nasal prongs; 5: non-invasive ventilation or high-flow oxygen; 6: intubation and mechanical ventilation; 7: ventilation + additional organ support -pressors, renal replacement therapy, extracorporeal membrane oxygenation; and 8: death. In the previously mentioned subgroup analysis on the EAP, a gradient of mortality was seen in relation to IgG antibody levels in the transfused CCP: 7-day mortality was 8Á9% for patients who received high IgG plasma (>18Á45 signal cut-off [S/CO]), 11Á6% for recipients of medium IgG plasma (4Á62 to 18Á45 S/CO) and 13Á7% for recipients of low IgG plasma (<4Á62 S/CO). This unadjusted dose-response relationship with IgG was also observed in 30-day mortality. The pooled relative risk of mortality among patients transfused with plasma units containing high levels of antibodies was 0Á65 for 7 days and 0Á77 for 30 days compared to units containing low levels [3] . The lack of utility from low-titre (1:40) CCP in moderate COVID-19 was confirmed by the PLACID trial [13] . Similarly, the ConCOVID RCT proved that CCP units with nAb titres similar to those of the recipients (1:160) were useless [14] . Analysis of published and ongoing trials has also revealed the importance of testing the antiviral activity of CCP units within clinical trials with the standard plaque reduction neutralization test (PRNT) rather than with the surrogate highthroughput serological tests [15] . Considering that the qualitative composition of CCP is due to the nAb titre (the higher, the better), its accurate evaluation is particularly critical and could make the difference between clinical efficacy and inefficacy. Thus, although most trials perform a correlation analysis between PRNT and high-throughput serological assays, in many cases, the CCP units are tested only with the latter tests (44% in the PlasmAr trial [3]), with the risk of an incorrect evaluation of the neutralizing CCP activity. One major cause could be that, despite IgM, IgG and IgA all being capable of mediating neutralization, virus neutralization test titres correlated better with binding levels of IgM and IgA 1 than IgG [16] , which are the only class routinely measured in high-throughput serological assays. In addition, the quaternary structure of the Spike protein available on infected replication-competent cell lines is poorly replicated by recombinant antigens bound on solid substrates. For the above reason, in the ongoing Italian RCT TSU-NAMI (NCT04393727) nAb titration of CCP is mandatory. Only if and when CCP is formally shown to be an effective treatment within clinical trials, could CCP collection be driven by surrogate high-throughput serology, given the hurdles to PRNT scalability. Finally, in order to collect CCP units with an adequate nAb titre (≥1:160), CCP should preferentially be collected from older male patients who have recovered from a previous symptomatic COVID-19 that required hospitalization, in accordance with the most recent literature data [17, 18] . What are the hurdles to early treatment? There are several logistical hurdles to early initiation of CCP treatment. First, during a pandemic, there is massive accrual of severely ill patients to emergency departments, and in collapsed health systems, the turnaround time between emergency room admission and admission to a ward can be relevant. Additionally, in the absence of quick (antigenic or molecular) tests for SARS-CoV-2, the turnaround time for final confirmation of diagnosis with polymerase chain reaction tests, usually run in batches, takes from 5 to 10 h. Then, bureaucracy also takes time when it comes to preparing the papers for recruiting a patient within a clinical trial, and there are challenges associated with outpatient transfusion of known infectious individuals. Finally, ABO-compatible CCP units may not be readily available at the local blood bank, and recruited patients are therefore left on the waiting list. All these variables are likely to affect the efficacy of CCP treatment. We suggest wide deployment of quick tests within emergency departments, where CCP could be safely administered even before the patient reaches the final ward. As suggested by the recently revised European Commission guidelines on CCP, 'evidence suggests that studies should focus on early transfusion of convalescent plasma with high neutralizing antibody titres'. [19] . In conclusion, CCP is emerging as a new time-sensitive, life-saving treatment. 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D.F. designed the paper, analysed the data and wrote the first draft. M.F. revised the final version.