Efficacy and safety of casirivimab and imdevimab for preventing and treating COVID-19: a systematic review and meta-analysis

Introduction

Ever since its initial identification in 2019, the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly escalated into a global pandemic, leading to the deaths of millions of lives worldwide (1). The SARS-CoV-2 virus has gradually evolved into new strains, such as Omicron and Delta variants, concurrently generating diverse subvariants (2), characterized by their potent virulence and widespread transmission. Current treatments include vaccination, employment of monoclonal antibodies (anti-SARS-CoV-2 monoclonal antibodies), convalescent plasma therapy, antiviral drugs, and cellular therapy (3). Nevertheless, some studies have underscored the limited efficacy of convalescent plasma therapy, cellular therapy, and antiviral medications in effectively treating COVID-19 (3-6). Challenges surrounding vaccination efforts stem from the persistent mutational shifts of the virus, coupled with the constraints imposed on immunocompromised individuals and patients afflicted with cardiac, pulmonary, and renal conditions, among others. Such individuals constitute a notably higher-risk demographic for developing COVID-19 (7,8). Moreover, hospitalization and mortality rates among these groups after infection are also higher when compared to the healthier population (9). Consequently, an urgent imperative arises to identify universally effective and safe therapies for managing SARS-CoV-2 infections. Research findings have indicated the potential of monoclonal antibodies to serve as a dual-purpose tool—both for preemptive application in uninfected individuals and for treatment across varying degrees of COVID-19 severity (10,11). Furthermore, they offer a viable treatment avenue for patients grappling with chronic medical conditions, without giving rise to safety concerns. The timely administration of COVID-19 antibodies has been shown to mitigate infection rates and enhance recovery rates in those already afflicted (12,13). The isolation of the novel coronavirus monoclonal antibody (anti-SARS-Cov-2 mAb) from the blood of infected patients or its laboratory synthesis (14) has facilitated large-scale production. Working by binding to free viral molecules and neutralizing virus-infected host cells (15), monoclonal antibodies specifically target the SARS-CoV-2 spike protein, which interacts with the angiotensin-converting enzyme 2 receptor on host cell surfaces (16). This interaction triggers an anti-spike effect (17,18), playing a pivotal role in antiviral defense (19,20). Notably, the utilization of monoclonal antibody cocktails can mitigate the risk of viral drug resistance, a common phenomenon associated with the employment of individual antibodies (21). Consequently, the adoption of monoclonal antibody combinations has gained considerable traction in clinical settings. Specifically, the combination of casirivimab and imdevimab has garnered approval from the European Medicines Agency (EMA) for treating severe COVID-19 cases (15). Recent meta-analyses have demonstrated that this combination correlates with reduced hospitalization, mortality, and virus load (3,22,23).

One such meta-analysis (23), investigating the efficacy and safety of casirivimab and imdevimab, revealed their ability to lower mortality rates in patients who were seronegative at baseline, diminish hospitalization rates among the general population, and curtail the incidence of adverse events, while their usage had no impact on mechanical ventilation. Another meta-analysis (22) highlighted that casirivimab and imdevimab brought about decreased mortality in the general population, along with reduced hospitalization rates and viral load. Nonetheless, individuals treated with casirivimab and imdevimab faced comparable risks of encountering adverse events as those receiving the placebo. A distinct meta-analysis (3) indicated a drop in mortality among individuals initially seronegative to SARS-CoV-2 upon receiving the combination of casirivimab and imdevimab. However, this effect did not extend across the entirety of the study population, failing to improve viral clearance and avert adverse events. Consequently, consensus remains elusive regarding the efficacy and safety of casirivimab and imdevimab. Adding to this complexity, preceding studies predominantly concentrated on specific cohorts, such as the preventive effects in healthy people (13), or the therapeutic efficacy of casirivimab and imdevimab in confirmed COVID-19 cases (12), or in individuals who were seronegative or seropositive at baseline (11). Against this backdrop, the current study undertook a comprehensive meta-analysis of recent randomized controlled trials (RCTs) to evaluate the efficacy and safety of casirivimab and imdevimab within diverse subgroups of individuals. We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1604/rc).

Methods

Literature search strategy

The review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO), CRD42023475640. The comprehensive search spanned databases including PubMed, Web of Science, Embase, and the Cochrane Library, up until September 10, 2022. Keywords used for the literature search were as follows: (imdevimab [Title/Abstract]) AND (Casirivimab [Title/Abstract]) AND (covid-19 [Title/Abstract]). To ensure thoroughness, reference lists of important studies and reviews were also reviewed. In cases of duplication or multiple articles emanating from the same trial exploring an identical population, priority was given to studies yielding the most complete and up-to-date data.

Eligibility criteria

Studies were included in this meta-analysis if they met the following criteria: (I) study subjects encompassed confirmed COVID-19 cases, individuals close to those affected by COVID-19, or individuals in good health; (II) interventions entailed administering casirivimab and imdevimab to subjects in the treatment group, juxtaposed with the delivery of a placebo or alternative medications to subjects in the control group; (III) outcome measures encompassed viral load, deaths, and the need for mechanical ventilation, all-cause mortality, adverse events, infection rates, discharge rates, and the need for additional interventions after treatment; (IV) the study design adhered to the principles of a RCT; (V) publications were available in English.

Exclusion criteria were as follows: (I) reviews, meta-analyses, consensus reviews, conference abstracts, animal experiments, case reports, letters, and so on were excluded; (II) studies devoid of sufficient data for outcome analysis were excluded; (III) studies from which data pertaining to outcome measures were excluded; (IV) duplicate publications were excluded.

Two researchers independently screened, assessed, and extracted data from studies obtained from databases. Disagreements were resolved through deliberation with a third reviewer, eventually arriving at a consensus.

Data extraction

The following information was extracted from each eligible study: first author, year of publication, country, study design, study subjects, information about the treatment group (sample size, drug dosage, and drug administration protocol), details of the control group (sample size, drug dosage, and drug administration protocol), gender distribution, age, duration of follow-up, and trial registration identification. Primary outcome measures encompassed COVID-19 viral load, mortality and the need for mechanical ventilation, all-cause mortality, and adverse event rates. Secondary outcome measures were infection rates, discharge rates, and the need for additional interventions after treatment, including hospitalization, emergency room visits, and mortality.

Quality assessment for the included studies

The Cochrane risk-of-bias tool for randomized trials was utilized to evaluate the quality and potential risk of bias across the incorporated studies. The following seven parameters were considered for quality assessment: (I) random sequence generation; (II) allocation concealment; (III) blinding of participants and personnel; (IV) blinding of outcome reviewers; (V) incomplete outcome data; (VI) selective outcome reporting; and (VII) other sources of bias (24). Each study was rated as having a “high”, “low”, or “uncertain” risk of bias. The RevMan software (version 5.4) was used for the summary of the risk of bias assessment.

Statistical analysis

Data analysis was conducted using the Stata SE64 software (version 15.1). Continuous variables were expressed as weighted mean differences (WMDs) alongside their corresponding 95% confidence intervals (CIs). Dichotomous variables were summarized as odds ratios (ORs) accompanied by their corresponding 95% CI. Q test and I² statistic were used to assess statistical heterogeneity across the incorporated studies, where I²>50% indicated a significant degree of heterogeneity, warranting the adoption of a random-effects model for data analysis. Otherwise, a fixed-effects model was employed. Subgroup analyses were performed regarding mortality, the need for mechanical ventilation, and discharge rates. Sensitivity analyses were executed to ascertain the stability of the results. The threshold for statistical significance was defined as P<0.05. Funnel plots were used to assess publication bias.

Results

A total of 851 articles were obtained from databases, and 360 of them were removed for duplicate publication. Subsequently, upon a thorough review of titles and abstracts, 451 articles were excluded. Finally, 12 studies were deemed suitable for incorporation into the meta-analysis, following an assessment of full-text articles. Among them, one study (25) was prematurely halted, while another two articles (by Portal-Celhay) were drawn from the same trial (26,27). To ensure the utmost precision in data representation, preference was accorded to the latest and most comprehensive study outcomes (Figure 1).

Figure 1 Flow chart of literature screening.

Study and patient characteristics

Twelve RCTs (11-13,15,27-34) were analyzed, involving 27,179 participants in total. Among them, 15,704 participants were administered the combination of casirivimab and imdevimab, whereas 12,105 were given a placebo or alternative medications. Of the twelve studies, nine focused on confirmed COVID-19 cases, while the remaining three centered on healthy people or healthy contacts of SARS-CoV-2-infected individuals. Table 1 presents the fundamental characteristics of these studies.

Quality assessment

Upon assessment, a substantial portion of the studies exhibited a low risk of bias. Eight studies (11-13,28,30-32,34) had an uncertain risk of bias regarding allocation concealment. Notably, three studies bore a high risk of bias with regard to the blinding of participants and personnel (15,30,33), and four studies had a high risk of bias regarding the blinding of outcome evaluators (15,30,31,33) (Figure 2A,2B).

Figure 2 Risk of bias graph across included studies. (A) Risk of bias graph across included studies; (B) risk of bias summary across included studies. RCG, RECOVERY Collaborative Group.

Efficacy outcomes

The analysis of data extracted from the encompassed studies was stratified based on primary and secondary outcome measures. Subgroup analyses were performed in light of the baseline SARS-CoV-2 serology results, which included seropositivity, seronegativity, and uncertain results. Subgroup analyses of patients with or without COVID-19 and patients with or without hospitalization were performed to explore the effectiveness and safety of the drug in patients with different clinical statuses.

Primary outcome measures

Viral load

Five studies reported data on viral load alterations. A random-effects model was used due to the pronounced heterogeneity detected across the dataset (I²=91.5%, P<0.001). Compared with the placebo, casirivimab and imdevimab administered together significantly reduced viral load in confirmed COVID-19 cases and decreased the increase in the viral load among individuals with no initial infection (WMD: −0.73, 95% CI: −1.09 to −0.38, P<0.01). Subgroup analyses showed that casirivimab and imdevimab were effective in reducing viral load in COVID-19 patients, non-COVID-19 patients, and in seronegative and seropositive patients at baseline, independent of whether they were hospitalized or not. Regarding the drug dosage, we found that the use of 2.4 g drug was poorly effective (WMD: −0.49, 95% CI: −0.99 to 0.01, P=0.06), and the rest of the therapeutic doses were effective (Figure 3A-3D).

Figure 3 Forest plots of viral load and all-cause mortality. (A) Forest plot of viral load by serological properties. (B) Forest plot of viral load by patients with or without COVID-19 at baseline. (C) Forest plot of viral load by patients with or without need for hospitalization. (D) Forest plot of viral load by dose of antibodies. (E) Forest plot of all-cause mortality by serological properties. (F) Forest plot of all-cause mortality by patients with or without COVID-19 at baseline. (G) Forest plot of all-cause mortality by patients with or without need for hospitalization. (H) Forest plot of all-cause mortality by dose of antibodies. *, seronegative; **, seropositive; ***, other. WMD, weighted mean difference; CI, confidence interval; RCG, RECOVERY Collaborative Group; CAS, casirivimab; IMD, imdevimab; COVID-19, coronavirus disease 2019; OR, odds ratio.

All-cause death rates

Seven studies investigated all-cause death rates. A fixed-effects model was used due to the significant heterogeneity across the studies (I²=46.7%, P=0.04). We found that all-cause death rates decreased in participants who were either confirmed COVID-19 cases or in healthy conditions at baseline. All-cause death rates were treated with the casirivimab and imdevimab antibody cocktail during clinical trials (OR =0.90, 95% CI: 0.82–0.99, P=0.03). However, subgroup analysis results showed that in patients with and without COVID-19, the antibody reduced all-cause mortality (OR =0.90, 95% CI: 0.82–0.99, P=0.03), independent of whether they were hospitalized or not and the specific dose of the drug administered. The mitigation of all-cause death rates owing to casirivimab and imdevimab was evident solely in patients who were seronegative at baseline (OR =0.73, 95% CI: 0.63–0.85, P<0.01) (Figure 3E-3H).

Death and mechanical ventilation rates

Three studies provided data on death and mechanical ventilation rates. A random-effects model was used due to the significant heterogeneity across the studies (I²=72.5%, P=0.001). There was no evidence supporting that casirivimab combined with imdevimab could reduce death and mechanical ventilation rates (OR =0.88, 95% CI: 0.71–1.10, P=0.26). Likewise, subgroup analyses showed that casirivimab and imdevimab did not reduce the death and mechanical ventilation rates of patients with either serologic nature, without statistically significant difference (Figure 4A).

Figure 4 Forest plots of death and mechanical ventilation rates, infection rates, discharge rates and clinical outcomes of special interest. (A) Forest plot of death and mechanical ventilation rates. (B) Forest plot of infection rates. (C) Forest plot of discharge rates. (D) Forest plot of clinical outcomes of special interest. *, seronegative. OR, odds ratio; CI, confidence interval; RCG, RECOVERY Collaborative Group; CAS, casirivimab; IMD, imdevimab.

Secondary outcome measures

Infection rates

Four studies investigated infection rates. A random-effects model was used due to the significant heterogeneity across the studies (I²=81.8%, P=0.001). Casirivimab combined with imdevimab significantly lowered the risk of SARS-CoV-2 infection in healthy individuals and those in close contact with infected cases (OR =0.24, 95% CI: 0.13–0.45, P<0.01) (Figure 4B).

Discharge rates

Two studies reported discharge rates and a random-effects model was used due to the significant heterogeneity across the studies (I²=78.6%, P<0.001). The results indicated that casirivimab combined with imdevimab did not increase the discharge rate in individuals with confirmed or suspected COVID-19 (OR =1.15, 95% CI: 0.91–1.46, P=0.23), without significant difference between the treatment group and the control group. Subgroup analyses also found no statistically significant differences between patients with different serological properties (Figure 4C).

Clinical outcomes of special interest

Six studies reported several clinical outcomes of special interest, including hospitalization, emergency room visits, and mortality. A random-effects model was used due to the significant heterogeneity across the studies (I²=84.4%, P<0.001). The combination of casirivimab and imdevimab reduced the rate of hospitalization, emergency room visits, and mortality among confirmed COVID-19 cases and healthy individuals (OR =0.54, 95% CI: 0.32–0.93, P=0.03). Subgroup analysis demonstrated that casirivimab and imdevimab reduced the occurrence of these clinical outcomes among people who were seronegative at baseline (OR =0.06, 95% CI: 0.01–0.47, P=0.01) (Figure 4D).

Safety outcomes

Adverse events

Nine studies reported the incidence of severe adverse events. A random-effects model was used due to the significant heterogeneity across the studies (I²=62.6%, P=0.003). The results indicated that the incidence of adverse events was significantly reduced among confirmed COVID-19 patients, close contacts, or healthy individuals after treatment with casirivimab and imdevimab compared to the control group, with statistical significance (OR =0.80, 95% CI: 0.67–0.95, P=0.01). Subgroup analyses found that the antibody significantly reduced the rate of any serious adverse events in COVID-19 patients who were not hospitalized (OR =0.64, 95% CI: 0.46–0.87, P=0.01) and those without clear serologic classification (OR =0.69, 95% CI: 0.60–0.81, P<0.01). The drug with a dose of 2.4 g significantly reduced the rate of any serious adverse events (OR =0.80, 95% CI: 0.65–0.98, P=0.03) (Figure 5A-5D). Grade 3 or more severe adverse events were reported in six studies. Due to the significant heterogeneity across the studies (I²=0.0%, P=0.57), a random-effects model was used, and the analysis results showed that casirivimab combined with imdevimab reduced the incidence of these adverse events among confirmed COVID-19 patients and healthy people (OR =0.76, 95% CI: 0.62–0.92, P=0.01). In subgroup analyses, the drug significantly reduced the incidence of ≥ grade 3 serious adverse events (OR =0.70, 95% CI: 0.56–0.89, P<0.01) in hospitalized COVID-19 patients (OR =0.79, 95% CI: 0.64–0.98, P=0.03) and those without clear serologic classification, and the drug with a dose of 2.4 g also markedly reduced the risk of ≥ grade 3 serious adverse events (OR =0.74, 95% CI: 0.58–0.95, P=0.02) (Figure 5E-5H).

Figure 5 Forest plots of adverse events. (A) Forest plot of severe adverse events by serological properties. (B) Forest plot of severe adverse events by patients with or without COVID-19 at baseline. (C) Forest plot of severe adverse events by patients with or without need for hospitalization. (D) Forest plot of severe adverse events by dose of antibodies. (E) Forest plot of Grade 3 or more severe adverse events by serological properties. (F) Forest plot of Grade 3 or more severe adverse events by patients with or without COVID-19 at baseline. (G) Forest plot of Grade 3 or more severe adverse events by patients with or without need for hospitalization. (H) Forest plot of Grade 3 or more severe adverse events by dose of antibodies. *, seronegative; **, seropositive; ***, other. OR, odds ratio; CI, confidence interval; CAS, casirivimab; IMD, imdevimab; COVID-19, coronavirus disease 2019; RCG, RECOVERY Collaborative Group.

Publication bias and sensitivity analysis

Sensitivity analysis was conducted by removing each study in turn, and it was found that the recalculated combined effect size did not change significantly, indicating that the results of this study were relatively stable and the overall outcomes remained largely unaffected by the exclusion of any particular study. As for the assessment of the risk of bias in the included studies, the funnel plot presented a relative symmetry, indicating the absence of significant publication bias (P>0.05).

Discussion

This meta-analysis delved into 12 RCTs to compare the efficacy and safety profiles of casirivimab and imdevimab against those of placebo or alternative medications. The outcomes indicated a significant reduction in viral load among confirmed COVID-19 cases when casirivimab and imdevimab were administered jointly. Furthermore, this antibody combination prevented the increase in viral load among newly infected individuals. Remarkably, the reduction in viral load exhibited heightened significance in individuals who were seronegative at baseline. Notably, a decrease in all-cause mortality was seen across the broader population receiving casirivimab and imdevimab treatment, and this reduction was more significant in those who were seronegative at baseline. Furthermore, the application of this antibody combination was associated with a reduction in infection rates among both healthy people and close contacts, as well as decreased incidence of clinical outcomes of particular interest among subjects who were confirmed COVID-19 cases or in healthy condition at baseline. In contrast, in a subgroup analysis of patients with or without COVID-19 and hospitalized patients, we found that the drug was statistically significant in improving all-cause mortality in COVID-19 patients, independent of whether they were hospitalized or not. Casirivimab and imdevimab were ineffective in reducing mortality and mechanical ventilation rates and improving hospital discharge rates, regardless of serologic properties. In light of adverse events, compared with the control group, the combination of casirivimab and imdevimab was capable of reducing the incidence of any severe adverse event, irrespective of whether applied to confirmed COVID-19 patients, the close contacts of COVID-19 cases, or the healthy population. Additionally, compared with the control group, the incidence of severe adverse events of grade 3 or higher was lower in the infected COVID-19 population and the normal population receiving the treatment, affirming the safety of casirivimab and imdevimab. Based on the above outcome indicators, we believe that casirivimab and imdevimab have obvious strengths in both COVID-19 patients and non-COVID-19 individuals, and in both outpatients and inpatients. Seronegative patients benefit more from this antibody in terms of all-cause mortality, hospitalizations, emergency room visits, and fatal events. COVID-19 patients benefit from this drug in terms of all-cause mortality. Therefore, in clinical practice, we recommend early use of this drug for the prevention and control of COVID-19.

The above findings indicate that casirivimab and imdevimab, which were generally well-tolerated, hold the potential to mitigate the incidence of SARS-CoV-2 infection and increase recovery rates, a pattern previously observed in certain prior studies (23,35). A retrospective cohort study by Cicchitto et al. (36) provided evidence that the application of casirivimab and imdevimab led to a reduction in viral load, accompanied by a high level of safety and minimal adverse events. Hegazy et al. (37-39) did several studies on COVID-19 antibodies and found that casirivimab and imdevimab had significant advantages over the COVID-19 antibodies Remdesivir and Favipravir in terms of reducing mortality and adverse events, as well as lower oxygen requirements and less invasive mechanical requirements in patients. Casirivimab and imdevimab led to less case progression (presented by lower World Health Organization scale) and better multi-organ functions (presented by lower Sequential Organ Function Assessment score) than remdesivir and favipiravir. Moreover, four additional retrospective cohort studies (40-43) reported a decline in hospitalization and death rates among the broader population treated with casirivimab and imdevimab, and this efficacy was particularly pronounced in individuals who initiated treatment with a seronegative baseline. This heightened efficacy is closely tied to viral load clearance, with individuals exhibiting high viral loads experiencing the most substantial benefits after treatment (15). Notably, the ability of the anti-spike monoclonal antibody to clear viral load is intricately linked to patients’ serological status at baseline (44). Individuals initiating treatment with a seronegative status, lacking an established immune response, might possess higher viral loads compared to those with seropositive status, resulting in more pronounced viral load clearance in the seronegative cohort.

The evaluation of the efficacy and safety of casirivimab and imdevimab across diverse demographic groups remains an unexplored area. Existing studies, whether RCTs or meta-analyses have consistently centered on specific population subsets, leading to a lack of consensus. A prime example is the meta-analysis conducted by Siemieniuk et al. (3), which revealed that casirivimab and imdevimab reduced hospitalization rates for less severe COVID-19 cases, yet failed to reduce virus clearance, whereas they increased mortality in severe COVID-19 cases, which is not consistent with the results of the present meta-analysis. This disparity may be related to different study subjects and varying sample sizes. The absence of subgroup analysis in the study by Siemieniuk et al. may also lead to these discrepant findings. The current study, in contrast, included a comprehensive spectrum of study subjects encompassing uninfected persons, close contacts, confirmed cases, those seropositive or seropositive at baseline, and individuals with uncertain serostatus. This breadth facilitated robust subgroup analyses. Another meta-analysis (45) with limited study populations only studied the efficacy of casirivimab and imdevimab in COVID-19 patients and showed that the drug reduced the hospitalization rate and mortality rate of COVID-19 patients, consistent with our study. However, the study indicators were more homogeneous, and our study also studied the viral load, death and mechanical ventilation rate, all-cause mortality rate, infection rate, discharge rate, and emergency room visits on this basis. Thus, our study is more comprehensive and more credible. Furthermore, the present study drew upon the latest RCTs for its meta-analysis, enhancing the accuracy of the results compared with previous studies.

Nonetheless, this study does come with certain limitations. Each outcome measure analyzed in this meta-analysis was based on a relatively small number of RCTs, potentially introducing bias to the results. For instance, only three RCTs reported data on death and mechanical ventilation. Moreover, significant differences in serostatus were apparent across the 12 RCTs, and some studies did not provide data on the serostatus of participants, affecting the results of subgroup analyses. Additionally, the predominant ethnic background of study participants in the included RCTs was European and American Caucasians, which may limit the generalizability of findings to other populations. Further research encompassing larger and more diverse samples is imperative. For the subgroup analysis of the dosage, we found that the 2.4 g dose resulted in a small possibility of adverse events, but was poorly effective in clearing viral load, while all other doses were effective in reducing viral load, which was contrary to conventional knowledge. We considered that the conclusions might be biased due to the small number of dose-related studies included and the lack of sufficient sample data. Additional large sample-size studies are needed to further explore the effectiveness and safety of antibody doses in COVID-19 patients.

While preparing this article, China experienced a sharp spike in SARS-CoV-2 cases in 2022, underscoring the urgency of curbing infections, hospitalizations, and fatalities. This outbreak in China is mainly due to the Omicron strain and its subvariants (mainly BA. 5 and BF. 7). A previous meta-analysis of Omicron strains (46) indicated that casirivimab and imdevimab were not so effective for COVID-19 due to their diminished neutralizing activity against these variants. The diverse mutations in the spike receptor-binding domains of the Omicron strain, the main target of monoclonal antibodies have posed challenges to the effectiveness of casirivimab and imdevimab. In light of the rapid revolution of Omicron strains, it is crucial to obtain more comprehensive evidence to ascertain the effectiveness of casirivimab and imdevimab against these variants.

Conclusions

In conclusion, casirivimab and imdevimab demonstrate efficacy in reducing viral load and all-cause mortality compared to conventional treatments or placebos. This efficacy is particularly pronounced in patients seronegative to SARS-CoV-2 at baseline. The safety of casirivimab and imdevimab is affirmed by their association with a lower incidence of severe adverse events compared to the control group. This study holds implications for COVID-19 prevention and treatment, spanning various infection statuses, with a particular recommendation for patients seronegative to SARS-CoV-2 at baseline.

Acknowledgments

We would like to thank the researchers and study participants for their contributions.

Funding: The study was supported by Jiaxing Fight Novel Coronavirus Pneumonia Emergency Technology Attack Special Research in 2020 (No. 2020GZ30001), Jiaxing Key Laboratory of Precision Treatment for Lung Cancer, Scientific Technology Plan Program for Healthcare in Zhejiang Province (No. 2021KY1100), Jiaxing Science and Technology Plan Project (No. 2022AD30055), The Key Discipline of Jiaxing General Practice Medicine Construction Project (No. 2019-fc-03), and Key Construction Disciplines of Provincial and Municipal Co-construction of Zhejiang (No. 2023-SSGJ-002). The funder was not involved in any study design, data collection, analysis and interpretation, report writing, or article submission for publication.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1604/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1604/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1604/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1604/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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