Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

Convalescent Plasma as Adjunctive Therapy for Hospitalized Patients with COVID-19: The Co-CLARITY Trial.

Background and Objective: Convalescent plasma therapy (CPT) may reduce the risk of disease progression among patients with COVID-19. This study was undertaken to evaluate the efficacy and safety of CPT in preventing ICU admission among hospitalized COVID-19 patients. Methods: In this open-label randomized controlled trial, we randomly assigned hospitalized adult patients with COVID-19 in a 1:1 ratio to receive convalescent plasma as an adjunct to standard of care or standard of care alone. The primary endpoint was ICU admission within first 28 days of enrolment. Primary safety endpoints include rapid deterioration of respiratory or clinical status within four hours of convalescent plasma transfusion and cumulative incidence of serious adverse events during the study period including transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), severe allergic reactions, and transfusion-related infections. Results: A total of 22 patients were assigned to receive convalescent plasma as an adjunct to standard of care and 22 to receive standard of care alone. The median time from onset of COVID-19 symptoms to study enrolment was eight days (IQR, 4 to 10). Two patients (9.1%) in the CPT group and one patient (4.5%) in the control group were admitted to the ICU. The primary outcome measure, ICU admission, was not different between the two groups (q-value >0.9). No patient who received convalescent plasma had rapid deterioration of respiratory/clinical status within four hours of transfusion and none developed TRALI, TACO, anaphylaxis, severe allergic reactions, or transfusion-related infections. There was also no significant difference in the secondary outcomes of 28-day mortality (two patients in the CPT group and none in the control group, q-value >0.90), dialysis-free days, vasopressor-free days, and ICU-free days. Conclusions: Among hospitalized COVID-19 patients, no significant differences were observed in the need for ICU admission between patients given CPT as adjunct to standard of care and those who received standard of care alone. Interpretation is limited by early termination of the trial which may have been underpowered to detect a clinically important difference.

Seroprevalence of human adenovirus type 5 neutralizing antibodies in the Philippines.

Human adenovirus (HAdV), particularly the HAdV type 5 (HAdV-5), has been extensively utilized in the development of vector vaccines due to its high immunogenicity, good safety profile, and ease of propagation. However, one of the main challenges in its use is the presence of pre-existing immunity among vaccine recipients. Pre-existing neutralizing antibodies (NAbs) can prevent the uptake of HAdV-5 vectors and reduce vaccine efficacy. Hence, this study investigated the seroprevalence of NAbs against HAdV-5 in urban and rural regions of the Philippines. Luciferase-based neutralization assay was performed on 391 plasma/serum samples. Out of these samples, 346 or 88.5% were positive for HAdV-5 NAbs, and the majority of them (56.8%) had high titers against the virus. Among the regions included in this study, Bicol (Region V) had the highest seroprevalence rate (94.1%). Our findings show that a significant number of adults in the Philippines have pre-existing immunity against HAdV-5. This supports the recommendation that vaccination programs in the country should consider implementing vaccination techniques, such as a prime-boost regimen or addition of booster doses, to address the potential negative effects of pre-existing HAdV-5 immunity in the efficacy of adenoviral vector-based vaccines.

Validation of a Questionnaire for Distinguishing X-Linked Dystonia Parkinsonism From Its Mimics.

Objectives: X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder endemic to the island of Panay in the Philippines. We undertook a population-based prevalence study to enumerate all cases of XDP in Panay. We first developed a 4-item questionnaire to distinguish XDP suspects from the general population. In the present study we aimed to revalidate this questionnaire to distinguish XDP from similar conditions so as to give it greater utility in the clinical setting. Patients and Methods: A total of 306 subjects (114 cases and 192 controls) were screened in from the 16 towns and 1 city of Capiz province. Their responses to the previously developed 4-item questionnaire were collected and multivariable logistic regression was performed to develop a predictive model. The accuracy of the model was determined by using it on a subset of patients; then, a scoring system based on the model coefficients was established. Results: With a cut-off score of 6, the questionnaire had an accuracy of 70.7% (95% CI 0.57-0.82), a sensitivity of 84.6 % (95% CI 0.65-0.96) and a specificity of 59.4 % (95% CI 0.41-0.76). The item on "shuffling of feet" was the strongest predictor in distinguishing XDP from its common mimics. Conclusion: We were able to revalidate a simple, four-item questionnaire that could distinguish XDP from its common mimics with fair accuracy. The questionnaire along with other clinical features can be used to determine which patients need specialty evaluation and genetic testing to verify a diagnosis of XDP.

Corrigendum: Validation of a Questionnaire for Distinguishing X-Linked Dystonia Parkinsonism From Its Mimics.

[This corrects the article DOI: 10.3389/fneur.2018.00830.].