key: cord-0729542-hf9sh9vs
authors: Salazar, M. R.; Gonzalez, S. E.; Regairaz, L.; Ferrando, N. S.; Gonzalez, V.; Carrera, P. M.; Munoz, L.; Pesci, S. A.; Vidal, J. M.; Kreplak, N.; Estenssoro, E.
title: EFFECT OF CONVALESCENT PLASMA ON MORTALITY IN PATIENTS WITH COVID-19 PNEUMONIA
date: 2020-10-09
journal: nan
DOI: 10.1101/2020.10.08.20202606
sha: ffd1b0fded1c16e5096bfefe58df9493da518fea
doc_id: 729542
cord_uid: hf9sh9vs

Abstract Background Convalescent plasma, widely utilized in viral infections that induce neutralizing antibodies, has been proposed for COVID-19, and preliminary evidence shows that it might have beneficial effect. Our objective was to compare epidemiological characteristics and outcomes between patients who received convalescent plasma for COVID-19 and those who did not, admitted to hospitals in Buenos Aires Province, Argentina, throughout the pandemic. Methods This is a multicenter, retrospective cohort study of 2-month duration beginning on June 1, 2020, including unselected, consecutive adult patients with diagnosed COVID-19, admitted to 215 hospitals with pneumonia. Epidemiological and clinical variables were registered in the Provincial Hospital Bed Management System. Convalescent plasma was supplied as part of a centralized, expanded access program. Results We analyzed 3,529 patients with pneumonia, predominantly male, aged 62{+/-}17, with arterial hypertension and diabetes as main comorbidities; 51.4% were admitted to the ward, 27.1% to the Intensive Care Unit (ICU), and 21.7% to the ICU with mechanical ventilation requirement (ICU-MV). 28-day mortality was 34.9%; and was 26.3%, 30.1% and 61.4% for ward, ICU and ICU-MV patients. Convalescent plasma was administered to 868 patients (24.6%); their 28-day mortality was significantly lower (25.5% vs. 38.0%, p<0.001). No major adverse effects occurred. Logistic regression analysis identified age, ICU admission with and without MV requirement, diabetes and preexistent cardiovascular disease as independent predictors of 28-day mortality, whereas convalescent plasma administration acted as a protective factor. Conclusions Our study suggests that the administration of convalescent plasma in COVID-19 pneumonia admitted to the hospital might be associated with decreased mortality.

Convalescent plasma, widely utilized in viral infections that induce neutralizing antibodies, has been proposed for COVID-19, and preliminary evidence shows that it might have beneficial effect. Our objective was to compare epidemiological characteristics and outcomes between patients who received convalescent plasma for COVID-19 and those who did not, admitted to hospitals in Buenos Aires Province, Argentina, throughout the pandemic.

This is a multicenter, retrospective cohort study of 2-month duration beginning on June 1, 2020, including unselected, consecutive adult patients with diagnosed COVID-19, admitted to 215 hospitals with pneumonia. Epidemiological and clinical variables were registered in the Provincial Hospital Bed Management System. Convalescent plasma was supplied as part of a centralized, expanded access program.

We analyzed 3,529 patients with pneumonia, predominantly male, aged 62±17, with arterial hypertension and diabetes as main comorbidities; 51.4% were admitted to the ward, 27.1% to the Intensive Care Unit (ICU), and 21.7% to the ICU with mechanical ventilation requirement (ICU-MV). 28-day mortality was 34.9%; and was 26.3%, 30.1% and 61.4% for ward, ICU and ICU-MV patients. Convalescent plasma was administered to 868 patients (24.6%); their 28-day mortality was significantly lower (25.5% vs. 38.0%, p<0.001). No major adverse effects occurred.

Logistic regression analysis identified age, ICU admission with and without MV requirement, diabetes and preexistent cardiovascular disease as independent predictors . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020. 10 antibodies, has also been proposed [4] [5] [6] . It was used during outbreaks of severe acute respiratory disease caused by other coronaviruses, SARS-CoV-1 and MERS-CoV, with varying results and when administered early, it decreased length of hospital stay [7] [8] [9] .

Convalescent plasma utilization has an acceptable safety profile and its administration constitutes a feasible approach to implement during a pandemic, even in low-resource settings. In COVID-19, it might reduce viral burden, improve clinical status, and decrease mortality [10] [11] [12] . On March 24, 2020, the Food and Drug Administration of the United States launched an Expanded Access Program to collect convalescent plasma donated by individuals who had recovered from COVID-19, and on August 23 approved emergency use [13] . A study conducted in 20,000 patients confirmed the safety of convalescent plasma and, thereafter, in a study of 30,000 patients, the same group of researchers demonstrated a decrease in mortality when convalescent plasma was . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.08.20202606 doi: medRxiv preprint administered early in the course of COVID-19 [14] [15] .Convalescent plasma is currently being evaluated in 126 clinical trials [16] .

Early in the emergency caused by the COVID-19 pandemic, the Ministry of Health of the Province of Buenos Aires, Argentina, created the Centralized Registry of Convalescent Plasma Donors (CROCPD-BA), with the aim of collecting, processing and distributing convalescent plasma, and issuing recommendations for its use in patients with COVID-19 [17] . Accordingly, the objective of the present study is to compare the epidemiological characteristics, outcomes and independent predictors of mortality among patients who received convalescent plasma and those who did not receive it, who were admitted to hospitals in Buenos Aires Province for COVID-19 throughout the pandemic.

This was a multicenter retrospective cohort study conducted over 2 months, beginning on June 1, 2020, which included consecutive patients ≥18 years diagnosed with SARS CoV-2 with RT-PCR, admitted to hospitals with pneumonia. Data were obtained from the National Vigilance System (SNVS 2.0), the Provincial Hospital Bed Management System, and the CROCPD-BA.

Collected variables were age, gender, comorbidities [18] [19] (arterial hypertension, diabetes, preexistent cardiovascular disease, chronic obstructive pulmonary disease, immunodeficiency), requirement of mechanical ventilation, treatments, death or discharge, and convalescent plasma administration. Severe adverse events related to plasma infusion, as transfusion-related acute lung injury (TRALI) and transfusionassociated circulatory overload (TACO) were also recorded [20] .

Information about plasma collection and characteristics is available in the Supplement.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.08.20202606 doi: medRxiv preprint

The requirement of convalescent plasma was initiated by assistant physicians as part of a Program of Expanded Access [17] . The indications issued by the CROCPD-BA were presence of pneumonia, defined as of lung infiltrates, plus one of the following: were confirmed on patient death certificates.

Statistical analysis: Continuous variables were expressed as mean ± standard deviation (SD) or median, [0.25-0.75] percentiles. Categorical variables were expressed as percentages. Differences between survivors and nonsurvivors, and between patients who received plasma or not, were analyzed with chi-square, t, or Mann-Whitney U-tests, as appropriate.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.08.20202606 doi: medRxiv preprint

To identify independent predictors of 28-day mortality, variables differing between survivors and nonsurvivors with a p value <0.10 were entered into a multivariable regression model, using a forward stepwise analysis. Adjusted risks were expressed as odd ratios (OR) and confidence intervals of 95% [CI95%]

Data were analyzed with SSPS-21 (Amonk, NY, US).

A two-tailed p value <0.05 was considered significant. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.08.20202606 doi: medRxiv preprint .

During the study period, 3,529 patients with COVID-19 pneumonia were admitted to 215 hospitals. Epidemiological data of the entire group and comparisons between survivors and nonsurvivors are shown in Table 1 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. Logistic regression analysis identified age, ICU admission with and without MV, diabetes and preexistent cardiovascular disease as independent predictors of 28-day mortality, while convalescent plasma administration was associated with decreased mortality (Table 3 ).

The main finding of our study was that the administration of convalescent plasma to patients with COVID-19 pneumonia was associated with a decrease of 24.4% in adjusted mortality. This effect was consistent over all grades of severity on admission, although it was greater in less critical patients-those admitted to the general ward.

In this study, the global mortality of 34.6% was higher than the 21-28% shown in observational studies [21] [22] [23] [24] which can be ascribed to a different patient case-mix. The proportion of patients admitted to the ICU was 42.6%, of which 21.6% required mechanical ventilation on admission. These figures are notably higher than those reported by two studies from Spain (respectively for each: n=15,111 and 4,035, with ICU admission of 8.3% and 18%;and mortality of 21% and 28%); United States (n=11,721, ICU admission of 19.9%, and mortality of 21.4%), and United Kingdom (n= 20,133, ICU admission 16.8%, and mortality of 26%) [21] [22] [23] [24] .

The efficacy of convalescent plasma in COVID-19 has been subject to much debate, due to the lack of a clinical trial with sufficient power to confirm it. For example, a study . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.08.20202606 doi: medRxiv preprint carried out in Wuhan was prematurely terminated due to the end of the pandemic, although significant clinical improvement was observed in patients with severe disease [10] . Likewise, a study from The Netherlands was stopped because 79% of patients already had high titers of neutralizing antibodies before receiving convalescent plasma [25] . A recent clinical trial from India which excluded critically ill patients did not find any clinical benefit. However, these results might be ascribed to the absence of neutralizing antibodies or to titers lower than 1:80 in 27% and 45% of convalescent plasma units, respectively [26] . Moreover, 86% of patients in the plasma subgroup had detectable neutralizing antibodies on enrollment; so it is uncertain if the intervention would have been efficacious.

Conversely, two small clinical trials demonstrated a significant decrease in mortality: in a study from Spain (n=81) including severely ill patients, mortality in the convalescent plasma subgroup was 0% vs. 9.3 % in the control, and in an Iraqi study (n =49), it was 4.8% vs. 28.5%, respectively [27-28].

Many observational studies support a probable efficacy of convalescent plasma. For example, a case-control study from China (including 138 cases and 1,568 controls) reported 2.2% mortality for the convalescent plasma subgroup, versus 4.1% for the control [29] . Furthermore, in a case-control study from the US including non-ventilated patients, 14-day mortality was 12.8% in the subgroup that had received convalescent plasma, vs. 24.4% in the control [30] . Similar results were reported in a matched casecontrol study, also from the US (136 cases, 251 controls), which showed lower mortality in patients receiving early administration of convalescent plasma with high titers of antibodies: 1.2% vs 8.9% [31] . Finally, the large case-series from the Mayo Clinic . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. [15] .

Our study develops a different approach to this very relevant issue. We analyzed a cohort of 3,529 unselected, consecutive patients with COVID-19 pneumonia, of whom 868 received convalescent plasma; its administration was evaluated as any other prognostic variable for mortality. We observed an independent, favorable effect on survival, and this is a novel finding. Although the nature of our study was observational, it was carried out using a robust database composed of observations prospectively collected, within the framework of a pre-established government program. Other independent predictors of mortality were age, diabetes and cardiovascular disease, similar to current literature on the topic [23, [32] [33] [34] .

This effect of convalescent plasma was more pronounced in less severe patients -those admitted to the ward, suggesting the importance of timely administration. Even though age >65 was one inclusion criterion for receiving convalescent plasma, surprisingly, those who received it were, in fact, younger. We cannot discard selection bias of physicians prescribing a seemingly promising therapy to patients with greater chances of responding to it. Nevertheless, older age was an independent predictor of mortality, as expected [23,34]

The main limitation of this study is the lack of randomized assignment of convales cent plasma administration. Additionally, unmeasured confounders might have influenced the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.08.20202606 doi: medRxiv preprint results, such as other risk factors or treatments. Since severity of illness on admission could not be evaluated with an established score, misclassification of patients might have occurred. However, the use of severity of illness on admission as a surrogate of acuity has already been utilized [3] . A more detailed analysis of the clinical variables collected could not be done, because of the type of data recorded in the register. Finally, the reason why assistant physicians chose not to administer convalescent plasma to patients with COVID-19 pneumonia fulfilling the inclusion criteria are unknown, but we speculate that some physicians might have felt uncomfortable with prescribing an experimental treatment to their patients.

In conclusion, our study suggests that the administration of convalescent plasma in COVID-19 pneumonia might be associated with decreased mortality. Large, welldesigned clinical trials are required to confirm these findings. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.08.20202606 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 9, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 9, 2020. . https://doi.org/10.1101/2020.10.08.20202606 doi: medRxiv preprint 

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