key: cord-0875718-xs8dnn84
authors: Omrani, Ali S.; Zaqout, Ahmed; Baiou, Anas; Daghfal, Joanne; Elkum, Naser; Alattar, Rand A.; Bakdach, Dana; Abusriwil, Hatem; Mostafa, Abdalrahman M.; Alhariri, Bassem; Ambra, Naseem; Khatib, Mohamed; Eldeeb, Ali M.; Merenkov, Zeyd; Fawzi, Zeinab; Hmissi, Saloua M.; Hssain, Ali A.; Coyle, Peter V.; Alsoub, Hussam; Almaslamani, Muna A.; Alkhal, Abdullatif
title: Convalescent plasma for the treatment of patients with severe coronavirus disease 2019: A preliminary report
date: 2020-10-05
journal: J Med Virol
DOI: 10.1002/jmv.26537
sha: 996899318ab314138b0d55e3ef71300a61dc3322
doc_id: 875718
cord_uid: xs8dnn84

BACKGROUND: The role of convalescent plasma therapy for patients with coronavirus disease 2019 (COVID‐19) is unclear. METHODS: We retrospectively compared outcomes in a cohort of critical COVID‐19 patients who received standard care (SC Group) and those who, in addition, received convalescent plasma (CP Group). RESULTS: In total, 40 patients were included in each group. The median patient age was 53.5 years (interquartile range [IQR] 42–60.5), and the majority of patients required invasive ventilation (69, 86.2%). Plasma was harvested from donors after a median of 37 days (IQR 31–46) from the first positive severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) polymerase chain reaction (PCR) result and 26 days (IQR 21–32) after documented viral clearance; it was administered after a median of 10 days (IQR 9–10) from the onset of symptoms and 2.5 days (IQR 2–4) from admission to intensive care unit. The primary endpoint of improvement in respiratory support status within 28 days was achieved in 26 patients (65%) in the SC Group and 31 patients (77.5%) in the CP Group (p = .32). The 28‐day all‐cause mortality (12.5% vs. 2.5%; p = .22) and viral clearance (65% vs. 55%; p = .49) were not significantly different between the two groups. Convalescent plasma was not significantly associated with the primary endpoint (adjusted hazard ratio 0.87; 95% confidence interval 0.51–1.49; p = .62). Adverse events were balanced between the two study groups. CONCLUSION: In severe COVID‐19, convalescent plasma therapy was not associated with clinical benefits. Randomized trials are required to confirm our findings.

The total global number of individuals diagnosed with coronavirus disease 2019 , caused by the novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has surpassed 10 million, with more than 500,000 associated deaths. 1 Up to 10% of COVID-19 patients may develop organ failure and may require admission to an intensive care unit (ICU). 2 Several investigational antiviral agents are currently being evaluated for the treatment of patients with severe and critical COVID-19. 2 Thus far, hydroxychloroquine, with or without azithromycin, lopinavir-ritonavir, and remdesivir have not been shown to be associated with a clear clinical benefit in patients with severe COVID-19. [3] [4] [5] In patients with severe influenza, convalescent plasma was associated with improved viral clearance and reduced mortality. 6 Similarly, convalescent plasma therapy for patients with severe acute respiratory syndrome (SARS) shortened hospital stays and lowered overall mortality. 7 Convalescent plasma may be useful in the treatment of severe COVID-19. However, peer-reviewed clinical data are limited. 8 Using a cohort of patients with severe COVID-19, we aimed to assess the clinical benefits of convalescent plasma over and above standard care. COVID-19 is classified as severe if any one or more of the following is present: respiratory rate >30/min, oxygen saturation ≤90% while in ambient room air, partial pressure of oxygen-oxygen concentration (PaO 2 /FiO 2 ) ≤ 300 mmHg, hypotension, or any organ failure. 2 Standard care for patients with severe COVID-19 in HMC involved supportive care and antiviral therapy with hydroxychloroquine, azithromycin, and/or lopinavir-ritonavir. Tocilizumab could be added for those with evidence of significant systemic inflammation and methylprednisolone for acute respiratory distress syndrome (ARDS). Individual regimens were selected by the attending clinical teams based on patients' characteristics and needs.

From April 13, 2020, convalescent plasma derived from recovered COVID-19 patients was available for clinical use for patients with severe COVID-19. Plasma donors are adults whose COVID-19 symptoms have resolved more than 2 weeks ago, with documented negative upper airway SARS-CoV-2 RT-PCR and negative serological tests for syphilis and blood-borne viruses.

We retrospectively included patients from HMC COVID-19 database. The convalescent plasma group (CP Group) included patients who received SARS-CoV-2 convalescent plasma therapy within the first 7 days of admission to ICU, required mechanical ventilation, and completed 28 days of follow-up by June 1, 2020.

Criteria for inclusion in the comparator group, the standard care (SC Group), included laboratory-confirmed SARS-CoV-2 infection, need for mechanical ventilation in ICU, and completion of 28 days of follow-up by June 1, 2020. Starting from the earliest case of SARS-CoV-2 in Qatar, consecutive patients eligible for inclusion in the SC Group were selected until one control was identified for each individual in the CP Group.

Donor apheresis was performed using Trima Accel Automated Blood Collection System (Terumo BCT) and inactivated using Mirasol PRT System (Terumo BCT). Each recipient received a total of 400 ml of ABO-compatible convalescent plasma. Donation and receipt of plasma were subject to HMC standard clinical policies. SARS-CoV-2 antibody titers in the donated plasma were not available. The date on which a patient was admitted to ICU was designated as study day 1.

All outcomes were recorded on the basis of the patients' disposition up to study day 28. Data including outcomes and adverse events were retrieved retrospectively from the electronic healthcare records. Radiological findings were reviewed and reported by a single radiologist who was blinded to the group allocation.

The results are reported according to the recommendations of STROBE initiative. 9 The study was approved by HMC's Institutional Review Board (MRC0120191), with a waiver of informed consent.

The primary outcome was improvement in the respiratory status, defined as two-category improvement on a six-level ordinal scale. 4 The scale in a descending order was death, invasive mechanical ventilation, noninvasive ventilation (NIV) or high-flow nasal oxygen (HFNO) therapy, oxygen therapy other than NIV or HFNO, hospitalization without need for oxygen therapy, and discharge home or a community isolation facility. Secondary outcomes were as follows: discharged alive from ICU by study day 28 and viral clearance, defined as two consecutive negative RT-PCR tests on airway samples taken within a gap of more than 24 hours.

In the absence of data on treatment effect, the sample size for the study was arbitrarily set at 40 patients in each group. This sample size provides approximately 80% power to detect an increase in the primary endpoint from 30% in the SC Group to 65% in the CP Group, at a two-sided significance level of .05.

Categorical data were summarized as numbers (percentages) and compared using Fisher's exact test, whereas continuous data were presented as medians and interquartile ranges (IQR), and compared using Wilcoxon rank-sum test. Cox proportional hazard was used to identify covariables associated with time to improvement in respiratory support status. To avoid overfitting the model, given the sample size and the number of events in the study, the number of variables included in the multivariate model was limited to four. In addition to receipt of convalescent plasma therapy and need for invasive mechanical ventilation, Acute Physiology and Chronic Health Evaluation (APACHE II) score was included due to its established role as a prognostic tool in critically ill patients. 10 The fourth variable in the multivariable Cox model was receipt of systemic corticosteroid therapy, which was recently reported to be associated with survival benefit in patients with severe COVID- 19. 11 Kaplan-Meier survival curve with log-rank p value was used to compare time to improvement in respiratory status between the two study groups.

All p values were two-sided with a threshold of <.05 for statistical significance. Statistical analyses were performed using Stata Statistical Software Release 15.1 (StataCorp LLC).

Eighty individuals were included, with 40 in each group. The majority were males (69, 86.3%) and the median age was 53.5 years (IQR 42-60.5). Diabetes mellitus (40, 50%) and hypertension (32, 40%) were common, and median body mass index (BMI) was 27.4 kg/m 2 (IQR 25-32.4). The median duration between the onset of symptoms and admission to ICU was 7 days (IQR 6-9). Cough (73, 91.2%) and fever (68, 85.0%) were the most frequent presenting symptoms. The median APACHE II score was 12 (IQR 9-12), and all patients had pulmonary infiltrates on their chest radiographic images (Table 1) .

During their ICU stay, the majority of patients required invasive mechanical ventilation (69, 86.2%), and/or vasopressor support (42, 52.5%). All patients received hydroxychloroquine, azithromycin, and lopinavir-ritonavir, whereas tocilizumab was given to 73 patients (91.2%) and intravenous methylprednisolone to 66 patients (82.5%).

Compared with the CP Group, the SC Group had higher median serum creatinine at admission to ICU (90 vs. 81 µmol/L, p = .009).

There were no other significant baseline differences between the two groups ( Table 1 ).

The median donor age was 36.5 years (IQR 26.3-41). All donors had infiltrates in their chest X-rays. Seventeen donors (42.5%) required oxygen via nasal canulae, nine (22.5%) required noninvasive ventilation, and three (7.5%) required invasive mechanical ventilation. (Table 1) .

Overall, the primary endpoint of improvement in respiratory support status was achieved in 57 patients (71.3%): 26 (65%) in the SC Group and 31 (77.5%) in the CP Group (p = .32). There were no significant differences between the SC Group and CP Group in the proportions of patients who were discharged alive from ICU within 28 days (65% for both groups; p > .99), viral clearance (65% vs. 55%; p = .49), or the 28-day all-cause mortality (12.5% vs. 2.5%; p = .22; Table 1 ).

Compared with patients in whom improvement in respiratory status was documented within 28 days, patients in whom it was not achieved were significantly older (median age 60 vs. 48 years; p < .001), had higher APACHE II scores (13 vs. 11; p = .017), and were more likely to have required hemodialysis (21.7% vs. 2 (3.5%; p = .019). Convalescent plasma recipients constituted 54.4% of those patients in whom the primary endpoint was achieved, compared with 39.1% of those in whom it was not achieved (p = .32; Table 2 ).

Time to improvement in the respiratory support status was not significantly different between the two study groups (p = .99; | 5 molecular confirmation could not survive. 16 To maximize potential clinical benefit, SARS-CoV-2 convalescent plasma may need to be administered earlier in the clinical course. To facilitate patient selection, robust COVID-19 severity prediction tools are required.

Examples exist, but none of them have been widely validated. 17 A second possible explanation for the apparent lack of clinical benefit in association with SARS-CoV-2 convalescent plasma in this study is the patients' characteristics. The median patient age in this study was 53.5 years, and only 7.5% of patients died within 28 days of follow-up. This contrasts with experiences reported elsewhere.

For example, an Italian report described 1591 patients with critical COVID-19. The median age was 63 (IQR 56-70) and the overall ICU mortality was 26%. 18 Another study from the United States reported 50% all-cause mortality in 24 patients with critical COVID-19 who had a mean age of 64 years. 19 Our substantially lower mortality rate suggests that any clinical benefit with convalescent plasma, if one exists, may be too small to be detected in our setting using our relatively small sample size.

Third, we were unable to establish that our donors' plasma contained adequate SARS-CoV-2-neutralizing antibody titers, a prerequisite for effective convalescent plasma therapy. 20 20, 25 In addition, the risk of blood product-derived infections, including currently unrecognized agents, can never be completely eliminated. 26 The limitations of this study include its observational nature. We used multivariate analyses to assess independent associations with the study endpoints, but the risk of residual confounding by indication cannot be eliminated. Nonetheless, existing peer-reviewed data in this area are mostly limited to uncontrolled case series of two to ten patients and a single prematurely halted randomized trial. 12, [27] [28] [29] [30] [31] We, therefore, believe that our report, despite the limitations discussed above, provides useful insight for physicians considering the use of SARS-CoV-2 convalescent plasma for the treatment of patients with COVID-19.

In conclusion, in this retrospective cohort study of critically ill COVID-19 patients, convalescent plasma therapy was not asso- 

Open access publication of this article was funded by Qatar National

Library. No other funding was required.

The authors declare that there are no conflict of interests. 

Coronavirus disease 2019 (COVID-19) Situation report-165

Clinical management of COVID-19-interim guidance

A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State

Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection

Use of convalescent plasma therapy in SARS patients in Hong Kong

Convalescent plasma transfusion for the treatment of COVID-19: systematic review

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies

APACHE II: a severity of disease classification system

Dexamethasone in hospitalized patients with Covid-19-preliminary report

Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

The convalescent sera option for containing COVID-19

Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?

Effect of convalescent plasma therapy on viral shedding and survival in COVID-19 patients

Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19

Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area

The potential danger of suboptimal antibody responses in COVID-19

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. medRxiv

The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis

Covid-19: low dose steroid cuts death in ventilated patients by one third, trial finds

Passively acquired antibodies suppress humoral but not cell-mediated immunity in mice immunized with live attenuated respiratory syncytial virus vaccines

Prevention of transfusiontransmitted infections

Use of convalescent plasma therapy in two COVID-19 patients with acute respiratory distress syndrome in Korea

Effectiveness of convalescent plasma therapy in severe COVID-19 patients

Treatment of 5 critically ill patients with COVID-19 with convalescent plasma

Treatment with convalescent plasma for COVID-19 patients in Wuhan

Treatment with convalescent plasma for critically ill patients with severe acute respiratory syndrome coronavirus 2 infection

Convalescent plasma for the treatment of patients with severe coronavirus disease 2019: A preliminary report