key: cord-0815169-6shr542k authors: Zuo, Ling; Ao, Guangyu; Wang, Yushu; Gao, Ming; Qi, Xin title: Bamlanivimab improves hospitalization and mortality rates in patients with COVID-19: A systematic review and meta-analysis date: 2021-09-14 journal: J Infect DOI: 10.1016/j.jinf.2021.09.003 sha: e6442a6f7debc1480c46039654350a935be529de doc_id: 815169 cord_uid: 6shr542k nan range from mild to severe, the incidence of illness and mortality is high in some vulnerable subgroup of patients. Until now, treatment option for patients to prevent progression to severe COVID-19 is limited. Although, vaccination is considered as an effective method to stop the spread of the COVID-19 pandemic, the newly emerged SARS-CoV-2 variants have led to breakthrough infections after completion of vaccination regimen 1 . The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attaches to host cells by binding its spike protein to angiotensin-converting enzyme 2 (ACE2) receptors on target cells 2 . Bamlanivimab (also knowns as LY-CoV555 or LY3819253), a recombinant human IgG1 monoclonal antibody, binds to the receptor binding domain of the spike protein of SARS-CoV-2 and blocks viral entry into host cells. Bamlanivimab(BAM) was granted emergency use authorization by the Food and Drug Administration (FDA) in November 2020 3 . Currently, there were a few studies that evaluated the effect of BAM on clinical outcomes in patients with mild-to-moderate COVID-19. Thus, we aim to perform a systematic review and meta-analysis of the available evidence to investigate the efficacy of BAM in COVID-19. An electronic search of the PubMed, Embase, and Cochrane Library databases was conducted from December 1 2019 to August 9 2021 with no language restrictions. The following key words and/or medical subject heading terms searched were used: ("COVID-19" or "novel coronavirus" or "2019-nCoV" or "coronavirus disease 2019" or "SARS-CoV-2") AND ("Bamlanivimab" or "LY3819253" or "LY-CoV555"). A manual search of possible articles that were relevant to the topic were carried out. "PROSPERO (International Prospective Register of Systematic Reviews) database" registration was done with study number as CRD42021274064. The inclusion criteria in our meta-analysis were as follows: (1) Patients with confirmed COVID-19; (2) reported information of comparison of clinical outcomes between BAM treatment (administered alone) and various control groups (no treatment, usual care according to the hospital guidelines, NIH guidelines). Studies were excluded if they were (1) case reports, conference abstracts, non-clinical studies, editorials and reviews; and (2) duplicated publications. All data from studies were extracted by independent investigators (GA and YW) onto prespecified. Any discrepancies were resolved through discussion in group conference. We also extracted baseline information of name of the first author, study design, country, the participants, number of participants, demographics data (mean/median age, male gender), dose of Bamlanivimab used, outcomes (mortality, hospitalizations, deterioration and progression to the complications). The quality of randomized controlled studies (RCTs) was evaluated using the Jadad scale. The quality of observational studies was assessed using a nine-item Newcastle-Ottawa Quality scale. High-quality studies were defined as a study with a Jadad score of ≥2 (maximum, 5), or a modified Newcastle-Ottawa score (NOS) of ≥6 (maximum, 9) . The analysis was done using Review Manager and Stata software version 15.1. Reported odd ratios (ORs) and 95% CIs were extracted from each study. We selected OR as an effect estimate. The heterogeneity of outcomes was calculated using Cochran's Q test and the I 2 statistic. The I 2 value of 25%, 50%, and 75% represented low, moderate, and high degrees of heterogeneity, respectively. If I 2 ≤ 50%, the meta-analysis was performed using the fixed effect model (Mantel-Haenszel). If I 2 > 50%, the random-effect model (DerSimonian and Laird) was preferred. Sensitivity or subgroup analyses were performed to identify potential sources of heterogeneity. Sensitivity analysis was performed to evaluate the stability of the results by sequentially omitting one study at a time. P < 0.05 was considered to be statistically significant. The search strategy yielded 263 potentially eligible literatures. Among them, 47 literatures were excluded due to duplicated searches. 168 studies were subsequently screened and regarded as absolute irrelevant studies by examining titles and abstracts. 48 studies were identified for full-text review and 40 studies were excluded because they had no comparison groups between Bamlanivimab treatment and control or outcomes were not available. A total of 8 studies 4-11 comprising of 13573 adult patients with COVID-19, including 4191 in the BAM (administered alone) and 9382 in the control group arm, were included in this meta-analysis. The study characteristics of the included RCT, cohort studies and case-controls are shown in Table 1 . All studies were from America. Four studies were retrospective cohort, two studies were case-control and only one study was RCT. Most studies included mild to moderate COVID-19 nonhospitalized patient and used a dosage of 700 mg to 7000 mg infusion of Bamlanivimab. All of the eligible studies were published in 2021 with different sample patient sizes that ranged from 46 to 6117 patients with COVID-19. The details of quality assessment are presented in the Supplemental Table 1 and Table 2 . All studies included in our meta-analysis were considered as high quality (RCT with a Jadad score of ≥2 and observational studies with a modified NOS score of ≥6). The meta-analysis showed the overall mortality was lower in the BAM group (Fig.1E ). In addition, sensitivity analyses by excluding each study at a time did not significantly alter the overall results. COVID-19 remains a public health emergency. Although people have taken many measures to control the virus, the treatment of COVID-19 remains a challenge. Until now, vaccines are still the primary option for COVID-19 prevention 12 . Unlike vaccine-derived immunity that develops over time, the use of neutralizing monoclonal antibodies is an immediate and passive immunotherapy. In the current meta-analysis, our results demonstrated that patients received BAM treatment had a better outcome in hospitalization and mortality. With limited therapeutic options for COVID-19, BAM provide an effective treatment option. Prevention of hospitalization is an important part of COVID-19 management. High patient volumes in the hospital from COVID-19 strain medical resources and supplies. The shortage of personal protective equipment and air isolation wards will bring greater risks to health care workers. As for mild-to-moderate COVID-19, treatments administered in outpatient is a more reasonable approach to preserver hospital supplies and reduce overcrowding. Our study affirmed the efficacy of BAM in the treatment of mild-to-moderate COVID-19, which was consistent with previous clinical trials (BLAZE-1 and -2) 9,13 . Before monoclonal antibodies treatment, there was no strategies to reduce the rates of hospitalization or death in outpatients with COVID-19. Several limitations of our study should be noted. Most of the studies included were retrospective in design and had relatively small sample size, which were subject to potential confounders that may weaken the overall results. Moreover, all studies were conducted in America, which may not provide sufficient statistical power to explore accurate correlations. Furthermore, lack of data of individual patient, it is uncertain which patients will benefit most when treated with BAM. Therefore, large clinical RCTs are needed to overcome these limitations Despite these limitations, there were advantages of our meta-analysis. First, to our best knowledge, this is the first meta-analysis assess the clinical impact of Bamlanivimab monoclonal antibody monotherapy on mortality and disease severity in patients with COVID-19. In addition, the heterogeneity across the studies was low, which enhances the reliability of our results. In conclusion, our meta-analysis provide evidence that BAM is effective in the treatment in COVID-19 patients. There is an urgent need for well-designed randomized trials to determine the effectiveness and safety of BAM in severe COVID-19. Table 1 and Table 2 Study quality assessment using the Newcastle-Ottawa Scale Dominance of alpha and Iota variants in SARS-CoV-2 vaccine breakthrough infections in New York City SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor A narrative review of the clinical practicalities of Bamlanivimab and Etesevimab antibody therapies for SARS-CoV-2 Clinical impact of the early use of monoclonal antibody LY-CoV555 (Bamlanivimab) on mortality and hospitalization among elderly nursing home patients: A multicenter retrospective study Impact of Bamlanivimab monoclonal antibody treatment on hospitalization and mortality among nonhospitalized adults 7 with severe acute respiratory syndrome coronavirus 2 infection The efficacy of Bamlanivimab in reducing emergency department visits and hospitalizations in a real-world setting Bamlanivimab use in mild-to-moderate COVID-19 disease: A matched cohort design Association of intravenous Bamlanivimab use with reduced hospitalization, intensive care unit admission, and mortality in patients with mild to moderate COVID-19 Effect of Bamlanivimab as monotherapy or in combination with Etesevimab on viral load in patients with mild to moderate COVID-19: A randomized clinical trial Bamlanivimab use in a military treatment facility Real-world experience of Bamlanivimab for COVID-19: A case-control study