key: cord-0984993-n7khs38w authors: de Candia, Paola; Prattichizzo, Francesco; Garavelli, Silvia; La Grotta, Rosalba; De Rosa, Annunziata; Pontarelli, Agostina; Parrella, Roberto; Ceriello, Antonio; Matarese, Giuseppe title: Effect of time and titer in convalescent plasma therapy for COVID-19 date: 2021-07-22 journal: iScience DOI: 10.1016/j.isci.2021.102898 sha: 4f47f6bf9663c13dd14054be80e51c9313bcbcf8 doc_id: 984993 cord_uid: n7khs38w The clinical benefit of convalescent plasma for COVID-19 patients is still debated. In this systematic review and meta-analysis, we selected 10 randomized clinical trials (RCTs) and 15 non-randomized studies (total number of patients = 22,591) of convalescent plasma treatment and evaluated two different scenarios: 1- disease stage of plasma recipients and 2 - donated plasma antibody titer, considering all-cause mortality at the latest follow-up. Our results show that, when provided at early stages of the disease, convalescent plasma significantly reduced mortality (RR 0.72, p<0.00001), while provided in severe or critical conditions, it did not (RR 0.94, p=0.22). On the other hand, the benefit on mortality was not increased by using plasma with a high antibody titer compared to unselected plasma. This meta-analysis might promote convalescent plasma usage in patients with early stage COVID-19 in further RCTs to maximize its benefit in decreasing mortality, especially in less affluent countries. entailing the production of neutralizing antibodies, the collection of plasma from a convalescent 48 donor and its passive transfusion to another patient (an approach known since the beginning of However, randomized clinical trials (RCTs) and cohort studies have provided with conflicting 57 results and three meta-analysis found a consistent benefit (Klassen et al., 2020) , a low-quality 58 evidence for mortality reduction (Sarkar et al., 2021) , and no substantial benefit on a range of possible 59 outcomes (Chai et al., 2020) , respectively. A number of reasons has been proposed to explain the 60 J o u r n a l P r e -p r o o f observed differences in the outcomes of COVID-19 patients treated with convalescent plasma. In 61 particular, it has been hypothesized that time from hospital admission to convalescent plasma 62 treatment (the earlier in the course of disease, the better) and/or prior selection of plasma with high 63 antibody titer (or in vitro-tested SARS-CoV-2 neutralization activity) might be key determinants of 64 convalescent plasma efficacy (Joyner et al., 2021; Tobian and Shaz, 2020) . Since none of the previous 65 meta-analyses has directly tested this hypothesis, we have here conducted a pragmatic, rationale- The inclusion flow is presented in Figure S1 . Upon identification of 753 univocal records, we 73 selected 40 pertinent manuscripts. During the screening phase of these manuscripts, 15 were 74 excluded: three studies did not report mortality data or compared mortality rate with national Table S1 . Two studies did not have a control group; nonetheless, 88 one provided the relative mortality data upon multiple comparisons between patients receiving high 89 vs. low titer plasma and between early (≤ 3 days from hospitalization) and late treatment (Joyner et Appropriate mortality endpoints were thus extracted from these studies according to the different 97 scenarios. All the other studies did not provide data from similar subgroups. Thus, they were 98 categorized as 1 -late vs. early treatment; and 2 -use of high titer plasma vs. studies only checking 99 for the presence/absence of antibodies without further characterization. To make the first 100 classification, priority was given to disease severity of the enrolled population. If patients were not 101 on any form of mechanical ventilation and did not need supplemental oxygen, the treatment was 102 considered "early". In case of exclusive enrollment of intensive care unit or ventilated patients, the 103 treatment was instead considered "late". In case of a heterogenous population, the discriminating 104 parameter was time to treatment, measured as median days from hospitalization to treatment. Given 105 the indications provided in one study (Joyner et al., 2021) , we applied the criteria of ≤ 3 days to 106 categorize the treatment as early. As a result, we obtained 11 studies as early and 16 as late (Table 107 S1 ). We were unable to categorize one study (Gharbharan et al., 2020) , since the enrolled population (Table S1) . 112 As above, 2 studies provided internal comparisons considering treatment plasma titer (Joyner et al., 113 2021; Salazar et al., 2020a); instead, we decided not to categorize one multicenter-study (Budhiraja 114 et al., 2021), since it used either positive only or high titer plasma, depending on the specific center 115 and was thus considered heterogeneous. The assessment of bias risk inside the included studies is 116 summarized in Table S2 . 117 Overall, we collected data from 22591 patients, with a 63.8% prevalence of male sex (gender 118 information was not provided in one study (Hegerova et al., 2020) ) and a weighted age average (by 119 approximation of median to mean value in the studies for which only the former parameter was 120 reported) of 62.3 years (in three studies age was not provided as mean for each group but divided into better design this practice which, importantly, may be affordable also in developing countries. The present results should be considered exploratory, rather than conclusive. In particular, the 263 fact that the benefit in terms of mortality for RCTs enrolling patients with mild disease or providing The RR extracted from the studies were used to calculate log RR with 95% CI for every item. When RR were not provided, they were calculated from the number of crude events. We used the 374 Inverse Variance statistical method with RR as effect measure to test the effect of convalescent 375 plasma on the endpoint mortality. Fixed or random effects were applied as analysis model depending 376 on the heterogeneity across studies. Statistical heterogeneity between trials was evaluated by I 2 377 statistics. Significance for heterogeneity was set at I 2 > 50% or p < 0.1, in which case the random-378 effects model was used for analysis. At p > 0.1 and I 2 < 50%, we considered heterogeneity as 379 insignificant and the fixed-effects model was used. Different meta-analyses were performed 380 according to different scenarios with the relative, pre-specified rationale, as detailed in the results. 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