Introduction

The novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was first reported in Wuhan, China, at the end of 2019. It rapidly spread worldwide, leading the World Health Organization (WHO) to declare it a pandemic in March 2020 [1]. Most COVID-19 infections in children are asymptomatic or mild. However, severe and critical diseases may also occur, especially in children with pre-existing medical comorbidities [2, 3]. Children with severe disease may present with acute respiratory distress syndrome (ARDS), myocarditis, shock, and multiple organ failure that often require admission to the pediatric intensive care unit (PICU) and mechanical ventilation, and sometimes lead to death [4].

A majority of children with mild COVID-19 can be managed at home by conservative and symptomatic therapy [5, 6]. Most consensus recommends hospital admission in children with medical complexity, moderate to severe infection, lack of a reliable caregiver, and very young age [5]. Many efforts have been made so far to find an effective and safe medication for the disease. Among pharmacological medications, corticosteroids and remdesivir (RDV) are promising agents for hospitalized children with COVID-19 under specific circumstances [6, 7]. RDV is a nucleotide analog that converts to its active metabolite and inhibits the activity of RNA polymerases, a key enzyme for the replication of many RNA viruses, including SARS-CoV-2. The FDA has approved RDV for hospitalized patients aged ≥ 12 years (≥ 40 kg), with pediatric use authorized under Emergency Use Authorization for children aged < 12 years and weighing ≥ 3.5 kg [8, 9].

Many trials have tested the efficacy of RDV in hospitalized adults with COVID-19. Some studies suggest potential benefits on mortality and oxygen requirements, mainly when prescribed early. Additionally, RDV appears generally well-tolerated with no major safety concerns reported [10,11,12]. In contrast, there is a lack of high-quality, pediatric-specific evidence regarding both the efficacy and safety of remdesivir in children. Only one phase 2/3, open-label trial and one randomized clinical trial have evaluated RDV use in children [13, 14], while the remaining evidences consists of retrospective observational studies. Consequently, most recommendations for RDV use in children are extrapolated from adult studies and expert consensus. For example, the Infectious Disease Society of America (IDSA) guideline recommends using RDV for hospitalized children with COVID-19, following the recommendation of the expert panel of infectious disease specialists [15]. Available pediatric safety data are also limited, with the most commonly reported adverse events including acute kidney injury, increased liver enzyme levels, and sinus bradycardia [16]. Therefore, we aimed to conduct a systematic review and meta-analysis of all available studies that addressed the use of RDV in children hospitalized with COVID-19, with an emphasis on the safety of RDV. Clinical outcomes were also summarized to provide contextual information regarding RDV efficacy in this population.

Method

The current research adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement as the basis for the systematic review and meta‐analysis [17]. This review was registered in the International Prospective Register of Systematic Reviews database (PROSPERO registration number: CRD420251022664).

Search method

We systematically explored relevant studies on PubMed, Scopus, and Web of Science (WOS) up to August 31, 2024. Only English-language articles were enrolled. The following medical subject headings (MeSH) were searched:

((RDV[Title/Abstract]) AND (((((((((((covid[Title/Abstract]) OR (covid19[Title/Abstract])) OR (sars cov[Title/Abstract])) OR (2019 ncov infection[Title/Abstract])) OR (2019 ncov infections[Title/Abstract])) OR (2019 novel coronavirus disease[Title/Abstract])) OR (2019 novel coronavirus infection[Title/Abstract])) OR (coronavirus disease 2019[Title/Abstract])) OR (coronavirus disease 19[Title/Abstract])) OR (severe acute respiratory syndrome coronavirus 2 infection[Title/Abstract])) OR (sars coronavirus 2 infection[Title/Abstract]))) AND ((((pediatrics[Title/Abstract]) OR (pediatric[Title/Abstract])) OR (child[Title/Abstract])) OR (children[Title/Abstract]))

All search results were exported and transferred to EndNote. We also explored references of the selected papers. Relevant studies were also added for analysis. Duplicate records were identified and removed using EndNote, with subsequent manual verification to ensure accuracy.

Study selection

We first reviewed the titles and abstracts of the studies; irrelevant papers were excluded. Then, two reviewers (MO and SM) independently assessed the full texts of the remaining articles for eligibility. Any discrepancies were discussed, and the reviewers finally reached an agreement. All the final included studies had ethical approval from the local committee.

Observational and clinical trial studies, with or without a control group, that met these inclusion criteria were included:

  1. (1)

    Administration of RDV to hospitalized children with COVID-19,

  2. (2)

    Confirmation of COVID-19 with positive SARS-CoV-2 real-time polymerase chain reaction (RT-PCR), or a COVID-19 antigen test.

  3. (3)

    The age range of participants between 0 and 19 years old,

  4. (4)

    The included study provided comprehensive details of RDV administration and addressed at least three outcomes of interest (outcomes are explained later in the manuscript).

We excluded narrative reviews, case reports, case series, editorials, and letters-to-the-editor type of articles. We also did not include preprints, conference abstracts, or unpublished data in our search strategy. Multisystem inflammatory syndrome (MIS-C) cases were also excluded.

Data extraction and outcomes

Data extraction was performed independently by two reviewers, and any discrepancies were resolved through discussion and consensus.

First, general and demographic characteristics, including the country of study and year of publication, age and sex distribution of participants, comorbidities, details on dose and course of RDV administration, severity of the disease, and concomitant medications were extracted.

The primary outcomes were all-cause in-hospital mortality and baseline and highest respiratory support. We also studied ICU and inotrope requirements, hospital and ICU length of stay, and time to defervescence. The secondary outcome was the safety profile of RDV, identified by adverse events and subsequent discontinuation of the medication.

The timing of outcome assessment varied by outcome. Respiratory support was reported either at admission or as the highest level required during hospitalization. Mortality was assessed during hospitalization, with some studies additionally reporting 30-day and 60-day mortality. ICU admission and inotrope use were assessed during hospitalization. Adverse events were recorded during the period of remdesivir administration.

Quality assessment

To assess the quality of the included studies, we used the Joanna Briggs Institute Critical Appraisal tool checklist for included studies [18].

Risk of bias assessment and quality of evidence

The risk of bias in the studies included in this analysis was independently assessed by two reviewers using the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool [19]. Any disagreements between the two reviewers were first addressed through discussion; if consensus could not be reached, a third reviewer was consulted to resolve discrepancies. This instrument evaluates multiple bias domains, including confounding, selection bias, measurement bias, and reporting bias, thereby enabling a comprehensive appraisal of the methodological quality of each study. Each domain was systematically reviewed to identify potential sources of bias that could affect the validity of the findings.

In addition, the quality of evidence for each outcome was appraised using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. GRADE provides a structured approach for rating the certainty of evidence and the strength of recommendations. Evidence is categorized into four levels—high, moderate, low, and very low—based on criteria such as study design, risk of bias, inconsistency, indirectness, and imprecision [20].

Data analysis

The metaprop command in Stata 12.0 was used to calculate pooled proportions and 95% confidence intervals for each parameter. Only parameters reported in at least three studies were included, and results were presented in tables and forest plots. Forest plots were generated using a random-effects model. Study heterogeneity was assessed using the I² statistic, with values of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively. Publication bias was evaluated using Egger’s test, where each dot in the plot represents an individual study. A p-value < 0.05 was considered indicative of statistically significant publication bias.

Results

General characteristics of the included studies

We found 1298 articles by searching electronic databases. After removing duplications, 984 articles were screened by title and abstract. Then, the full texts of 379 articles were reviewed. Finally, 16 studies, including one randomized clinical trial [14], one phase 2/3 open-label trial [13], and 14 observational studies, met the inclusion criteria in the systematic review and meta-analysis [21,22,23,24,25,26,27,28,29,30,31,32,33,34]. Figure 1 shows the selection process. The indication for RDV treatment differed between studies and is shown in Table 1. Table 1 summarizes the general characteristics of the included studies.

Fig. 1
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PRISMA flow chart

Table 1 General characteristics of articles included in the systematic review
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The total number of study participants was 1203, of which 722 received RDV and 481 received supportive care alone or with other treatments. In all included studies, the treatment group received a loading dose of RDV of 5 mg/kg/dose on day 1 (maximum dose: 200 mg) followed by 2.5 mg/kg/dose (maximum dose: 100 mg) once daily on subsequent days. The total duration of therapy differed between studies and ranged from 3 to 10 days.

Fifteen studies reported the sex distribution of participants [21,22,23,24,25,26,27,28,29,30, 32,33,34]. In most studies, males were more dominant than females in both case and control groups.

Most of the participants had chronic underlying comorbidities, including neurologic, cardiologic, respiratory, oncologic and immunologic diseases or genetic/chromosomal/congenital abnormalities. Obesity was also reported in some studies, and was reported in nearly 40% of participants in two studies [13, 31].

Eight studies categorized patients according to the severity of COVID-19 [21, 23,24,25, 27, 29, 33, 34]. The classification was based on local guidelines/protocols that varied across studies, making it impossible to combine the data. Some studies categorized patients from mild to severe, while others categorized them from mild to critical. According to these articles, among the patients who received RDV, only 8 patients had a history of receiving at least two doses of the COVID-19 vaccine (Table 2) [33, 34].

Table 2 Severity of illness and history of vaccination
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There was variability of supportive care across studies and included steroids, antibiotics or antivirals in some cases. Some studies provided data on concomitant medications used with RDV and supportive care [13, 21,22,23,24, 26,27,28, 30,31,32,33,34]. Corticosteroids, anticoagulants, and antibiotics were the most commonly used medications, followed by antivirals, anticoagulants, immunosuppressive drugs, and IVIG.

Dexamethasone was the most commonly used corticosteroid. In the Seah et al. study, all patients treated with RDV also received corticosteroids [33]. In Hammed et al. study, all patients received low-dose methylprednisolone for 7 days [23]. In the study by Mendez-Echevarria et al., azithromycin was prescribed to 75% of patients [28]. Further details are described in Table 3.

Table 3 Other applied treatments in addition to remdesivir
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Primary outcomes

Twelve studies provided data on the level of respiratory support required on admission and/or the highest level during hospitalization [14, 22, 23, 25,26,27,28, 30,31,32,33,34]. Based on available data, we categorized the level of respiratory support as follows: no supplemental oxygen (breathing at room air), low-flow oxygen, high-flow oxygen, non-invasive ventilation (NIV), mechanical ventilation (MV), and extracorporeal membrane oxygenation (ECMO) (Figs. 2 and 3; Table 4).

Fig. 2
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Forest plot of the level of respiratory support at baseline. a: room air, b: low-flow oxygen, c: high-flow oxygen, d: non-invasive ventilation, e: mechanical ventilation

Fig. 3
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Forest plot of the highest level of respiratory support during hospitalization. a: room air, b: low-flow oxygen, c: high-flow oxygen, d: non-invasive ventilation, e: mechanical ventilation

Table 4 Respiratory support of patients at baseline and the highest level
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Six studies reported data on the level of respiratory support needed on admission [14, 22, 26, 31, 32, 34]. The pooled analysis of these studies showed that 28% of patients did not require oxygen (95% CI: 0.07, 0.55, I2 = 95.46%, p < 0.001), 23% needed low-flow oxygen (95% CI: 0.08, 0.38, I2 = 91.70%, p < 0.001), 21% needed high-flow oxygen (95% CI: 0.09, 0.36, I2 = 85.25%, p < 0.001), 11% required NIV (95% CI: 0.00, 0.41, I2 = 96.45%, p < 0.001), and 9% were intubated and treated with MV (95% CI: 0.00, 0.30, I2 = 95.12%, p < 0.001). Goldman et al. stated that one patient required venovenous ECMO at baseline [22].

Eight studies provided data on the highest level of respiratory support during hospitalization [23, 25, 27, 28, 30,31,32,33]. The pooled data showed that 27% of patients did not require oxygen until the end of hospitalization (95% CI: 0.08, 0.51, I2 = 88.72%, p < 0.001), 33% required low-flow oxygen (95% CI: 0.19, 0.47, I2 = 80.01%, p < 0.001), 32% required high-flow oxygen (95% CI: 0.25, 0.39, I2 = 0.00%, p = 0.40), 5% required NIV (95% CI: 0.00, 0.22, I2 = 90.01%, p < 0.001), and 19% needed MV (95% CI: 0.08, 0.31, I2 = 76.04%, p < 0.001). Five patients ultimately required ECMO, two in the Romani et al. study and one in the Goldman et al. study [22, 30].

Only two studies reported details of the level of respiratory support, both at baseline and at the highest level [31, 32]. In the Samuel et al.. study, 86% of patients did not require oxygen on admission, while only 16.7% remained in this situation. No patient needed MV on admission, while three patients were eventually intubated and required MV. In Schulz et al.’s study, the percentage of patients breathing on room air decreased from 45% at baseline to 34% in the following days, and 6% ultimately required MV.

“Shift in distribution of status on ordinal scale” is somewhat mentioned in the Goldman et al. study [22]. The modified ordinal scale was a clinical severity scale that categorizes patients based on disease progression and level of respiratory support, ranging from no symptoms to invasive mechanical ventilation or death. They declared that 88% improved by at least 1 category in clinical support, 6% did not change status, and 5% had worsened status.

The median duration of oxygen therapy in patients treated with RDV was 3–5 days.

Eight studies provided data on the number of ICU admissions [21, 25, 27, 28, 30,31,32,33]. Pooled data indicated that 30% of participants needed ICU care (95% CI: 0.18, 0.43) (I2 = 77.87%, p < 0.001). Inotrope administration was addressed by three studies [26, 28, 33]. Pooled data revealed that 25% of participants needed inotrope medications (95% CI: 0.05, 0.52) with low heterogeneity (I2 = 59.51%, p = 0.08). Mendez-Echevarria et al. study reported the highest rates of ICU admission (75%) and inotrope administration (50%) [28]. All studies published data on mortality rates except for one study. No deaths occurred among participants of the six studies [24, 27, 29, 31,32,33]. Mortality rates varied across other studies, ranging from 2.6% to 15.5% in patients receiving RDV. The pooled analysis showed that only 2% of patients expired (95% CI: 0.00, 0.04) with low heterogeneity (I2 = 59.81%, p < 0.001). 30-day mortality was reported by some studies, and all were zero (Fig. 4; Table 5).

Fig. 4
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Pooled outcome with 95% CIs for COVID-19 pediatric patients treated with Remdesivir. “a”: ICU admission, “b”: inotrope need, “c”: death"left"

Table 5 Severity-related outcome
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The median hospital and ICU stay in patients who received RDV varied considerably between studies and is reported in Table 5.

The median time to resolution of fever was reported by three studies and was approximately three days [27, 29, 33] (Table 5).

Secondary outcomes and safety endpoints

Twelve studies reported data on the safety profile of RDV (Fig. 5; Table 6). Three studies reported no RDV-related adverse events [28, 29, 33].

Fig. 5
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Forest plot of safety endpoints of remdesivir. Figure a-g shows patients with different side effects. a: any side effects, b: bradycardia, c: hypertension, d: increased creatinine, e: unspecified elevated liver enzymes (AST and/or ALT), f: high AST, g: high ALT

Table 6 Adverse events reported during remdesivir therapy
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Bradycardia was seen in none of the patients in the Manabe et al., Seah et al., and Kautsch et al.. studies [25, 27, 33], while 12.5%, 8%, and 4% of patients in the Samuel et al., Schulz et al., and Romani et al. studies experienced bradycardia, respectively [30,31,32]. The pooled analysis showed bradycardia in 3% of patients (95% CI: 0.00, 0.08) with moderate heterogeneity (I2 = 62.56%, p = 0.02).

In Samuel et al. study, 54.2% of patients experienced hypertension (HTN) [31], while no patients in the other two studies discussing HTN had it [27, 32]. The pooled analysis showed HTN in 10% of patients (95% CI: 0.00, 0.58) with high heterogeneity (I2 = 97.16%, p < 0.001).

Elevated ALT and/or AST were reported in nine studies. The findings about increased AST were pooled from five studies [22, 26, 28, 31, 33]. Overall, 10% of patients had elevated AST related to RDV (95% CI: 0.00, 0.41) (I2 = 94.56%, p < 0.001). Elevated ALT was significantly seen in Goldman et al. (48%) and Khalil et al. (34.2%) studies [22, 26]. In contrast, no patients in the Méndez-Echevarría et al., Samuel et al., and Seah et al. studies experienced this adverse event [28, 31, 33]. Pooled data from these five studies showed increased ALT in 11% of patients (95% CI: 0.00, 0.42) (I2 = 94.02%, p < 0.001) [22, 26, 28, 31, 33]. Three studies reported increased LFT (AST/ALT) in up to 44% of the patients and did not specify the details [27, 30, 32]. The pooled analysis showed increased LFT in 8% of patients (95% CI: 0.01, 0.20) (I2 = 81.84%, p < 0.001). We could not integrate these data with previous studies because a patient may have elevated AST and ALT simultaneously. Almost all studies reported no drug-related serious adverse events. The studies did not clearly define what constituted “serious”; however, in general, serious adverse events are those resulting in death or life-threatening conditions (such as severe hypersensitivity reactions, life-threatening arrhythmias, or clinically significant elevations of liver enzymes or creatinine). An exception was the study by Goldman et al. which reported serious adverse events in 16% of patients. However, the authors stated that these adverse events were largely attributable to COVID-19, underlying comorbidities, or their combination, and were not considered to be drug-related [22].

Increased Cr level was assessed by eight studies [22, 23, 25, 27, 30,31,32,33]. Six of them reported no RDV-related nephrotoxicity. Only one patient in the Hammed et al. study had an increased Cr level versus 39% of patients in the Goldman et al. study [22, 23]. The pooled data showed that an increased Cr level was seen in 2% of patients (95% CI: 0.00, 0.11) with high heterogeneity (I2 = 91.98%, p < 0.001). Although hepatic and renal events were observed, these might reflect the severity of critical illness rather than being directly attributable to remdesivir toxicity.

Less common side effects, reported in two or fewer studies, are described in Table 6. Arrhythmia was reported in one patient in the study done by Schulz et al. [32]. The patient had structural heart disease and developed PVCs while receiving RDV. The arrhythmia resolved after correcting concomitant hypokalemia.

The median duration of RDV therapy was 5 days in most studies (Table 7). Important intervals for RDV administration are described in Table 7. RDV was discontinued in 8 patients due to adverse events (in three distinct studies): five patients for elevated liver enzymes [22], and one patient each for skin rash, relapse of leukemia, and arrhythmia [13, 32].

Table 7 Important intervals and points about remdesivir administration
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Publication bias

Egger’s test was applied to the pooled outcome of any remdesivir-related adverse events (12 studies, Table 6).The test indicated a significant intercept (bias = -2.69, 95% CI: -5.12 to -0.27; p = 0.033), suggesting possible funnel plot asymmetry and the presence of small-study effects. The funnel plot shows slight asymmetry, with smaller studies tending to lie on one side of the pooled effect estimate. This pattern, consistent with the significant Egger’s test, suggests the presence of potential publication bias or small-study effects in the meta-analysis (Fig. 6).

Fig. 6
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Funnel plot for publication bias

Most of the included studies were judged to have a serious overall risk of bias, primarily due to confounding. In contrast, the classification of interventions was consistently rated as low risk, and the handling of missing data was generally rated as moderate risk. A low risk of bias was identified for deviations from the intended interventions, and the measurement of outcomes. Overall, the cumulative assessment across domains indicated a serious risk of bias (Supplementary Table 1).

The certainty of evidence for pooled outcomes, including respiratory support at baseline and during hospitalization, mortality, ICU admission, inotrope requirement, and remdesivir-related adverse events, was rated as very low according to the GRADE approach. Most included studies were retrospective and uncontrolled, with a serious risk of bias. One phase 2/3 open-label trial and one clinical trial were also included; however, their contribution to the overall body of evidence was limited due to relatively small sample sizes and heterogeneity. Most outcomes showed substantial variability between studies (moderate to very high heterogeneity) and, in many cases, wide confidence intervals, leading to further downgrading for inconsistency and imprecision. Therefore, the pooled estimates across outcomes should be interpreted with caution.

Discussion

We conducted a systematic search for the best available data on the clinical benefits and safety profile of RDV in hospitalized children with COVID-19. Due to conflicting findings in existing research, we aimed to comprehensively assess its efficacy and safety in the pediatric population for the first time. However, in the absence of randomized clinical trials involving children, our meta-analysis was restricted to observational data, limiting our ability to draw firm conclusions about the true effectiveness of RDV—unlike the more robust evidence available in adult studies. Nevertheless, the pooled data did offer relatively valuable insights into the drug’s safety profile and some other key clinical outcomes in children. To the best of our knowledge, this is the first systematic review and meta-analysis addressing RDV treatment in children.

This paper utilizes meta-analysis to summarize evidence pooled from 16 studies involving 1203 children. Among these children, 722 received RDV, while 481 received supportive care alone or in combination with other treatments. While both RDV and non-RDV groups are presented in our tables, the meta-analysis was restricted to patients who received RDV.

We observed a male predominance among hospitalized children with COVID-19, which is consistent with prior reports suggesting sex-based differences in COVID-19 susceptibility or outcomes. Genetic factors, hormonal influences, and gender-related behavioral differences may contribute to this observed disparity [35].

A majority of patients had underlying comorbidities. Due to inconsistencies in the reports, we were unable to pool data. Neurologic, cardiologic, respiratory, oncologic, and immunologic diseases, as well as genetic/chromosomal/congenital abnormalities, were frequently reported. Obesity was another prevalent comorbidity, reported by some authors. This is consistent with established data identifying obesity as a major risk factor for severe COVID-19 outcomes in children [36]. The high prevalence of comorbidities in the study populations must be considered when interpreting the efficacy and safety outcomes of RDV, as these factors may act as confounders, influencing both disease progression and therapeutic response. Many adverse events (e.g., elevated liver enzymes, hypertension, bradycardia) were considered to be related to remdesivir, although contributions from the underlying illness or concurrent therapies cannot be excluded.

We found a significant heterogeneity in the classification of disease severity across studies. This inconsistency reflects the broader challenges in standardizing disease severity definitions in pediatric COVID-19 research, which complicates efforts to compare outcomes between different studies. Furthermore, data on COVID-19 vaccination status were scarce. While this could be due to underreporting, it is more likely due to low vaccination rates among children [37], potentially influencing disease severity patterns, as vaccination coverage may significantly influence clinical course and treatment response. This underscores the urgent need for a standardized severity definition and improved vaccination coverage.

The concomitant use of corticosteroids, anticoagulants, antibiotics, and other supportive therapies alongside RDV was common. This factor could potentially confound the evaluation of RDV’s independent effects. Dexamethasone was the most frequently used corticosteroid, in line with international guidelines [15]. A systematic review of placebo-controlled RCTs conducted on adults with COVID-19 suggested that oral or intravenous corticosteroids may improve severe disease outcomes, including reducing mortality [38].

Based on a pooled analysis of studies reporting baseline respiratory support, 28% of hospitalized children did not require oxygen on admission, approximately 20% required low/high flow oxygen, and about 10% required invasive or non-invasive ventilation. These findings indicate considerable variability in disease severity at presentation, where a subset of hospitalized children present with significant respiratory compromise. Unfortunately, studies reporting the highest level of respiratory support were largely distinct from those reporting baseline data. However, based on pooled analysis of studies that did report the highest level of respiratory support during hospitalization, we observed a progression in respiratory support requirements: 27% remained without oxygen requirements, about 30% required low/high flow oxygen, 5% required non-invasive ventilation, and 19% required invasive ventilation during hospitalization. While the observed trend toward increased respiratory support may reflect disease progression, the lack of a comparator arm and the absence of longitudinal follow-up within a single, consistent population preclude attribution of this trend to RDV. It is also possible that, without RDV, a more pronounced deterioration might have occurred. A retrospective cohort study published by Nives et al. in 2025 supports this hypothesis [39]. They reported a significant decrease in respiratory support in children who received RDV, from 57% before initiation of the drug to 23% by the end of treatment, and even to 12% at the time of discharge.

Based on the pooled estimate, we found that 30% of RDV-treated patients required intensive care, 25% required inotropes, and 2% of patients died.

A systematic review by Beckerman et al. found that in adult patients requiring supplemental oxygen at baseline, use of RDV compared to supportive care was associated with lower mortality, faster recovery, and reduced oxygen requirements [12]. Altogether, the relatively short median duration of oxygen therapy (3–5 days), as well as a considerably low mortality rate, may indicate some clinical benefit in our patients.

Based on pooled analysis, the most common adverse events related to RDV were elevated ALT (11%), elevated AST (10%), HTN (10%), increased hepatic enzymes (non-specified by authors) (8%), bradycardia (3%), and increased creatinine (2%). Almost all studies reported no drug-related serious adverse events. However, RDV was discontinued in 8 patients. Our findings almost align with the data in adults. Based on the WHO database report early in the pandemic, increased hepatic enzymes (32.1%) and renal injury (14.4%) were the most common adverse drug events, followed by increased Cr, respiratory failure, tachy or bradyarrhythmia, hypotension, rash, and drug cessation [40]. Among cardiovascular adverse events, transient asymptomatic sinus bradycardia is described by several authors in all age groups [41,42,43]. An important observation is that hypertension was reported in a notable proportion of patients in Samuel et al. study, even though it is not generally recognized as a common side effect of RDV in adults. Conversely, hypotension is more frequently observed when used. This finding may be explained by several factors, such as inflammatory responses or fluid and electrolyte shifts in children; however, no other study in our review reported it, and a direct causal link has not yet been established, so its clinical significance should be further investigated.

Taken together, most clinical trials in adults have confirmed the tolerability of RDV and reported few serious adverse events among patients who received RDV, even in those with severe kidney impairment [44, 45]. Nevertheless, reported cases of hypertension, bradycardia, and other observed adverse events warrant attention.

Given the overall tolerability profile observed in our review and general alignment with adult safety data, we recommend that RDV be considered a treatment option for pediatric patients with COVID-19, particularly those at risk of progression to severe disease, provided that close monitoring is ensured. Special attention should be paid to cardiovascular parameters such as blood pressure and heart rate, as well as liver and kidney function, at baseline and during treatment. However, until more robust pediatric-specific data—particularly from randomized controlled trials—become available, its use should remain cautious and guided by individual risk-benefit assessments under careful clinical supervision.

The major limitation of this study was the insufficiency of RCTs about the efficacy of RDV in children. This limitation significantly lowered our ability to draw definite conclusions, especially about the effect of RDV on recovery, respiratory support requirements, duration of hospitalization, and mortality rate. Additionally, we could not stratify patients based on disease severity due to variations in classification criteria outlined in local guidelines/protocols across different studies. This inconsistency made it impossible to combine the data. The lack of vaccination status reporting may limit the interpretation of outcomes, as vaccination can influence disease severity, treatment response, and the incidence of adverse events. Moreover, the inclusion of only English-language studies may have introduced selection bias, potentially excluding relevant data published in other languages.

To address these gaps, future research should prioritize well-designed multicenter pediatric randomized controlled trials in children and adopt standardized severity classification to enable meaningful data synthesis and clear conclusions regarding RDV efficacy and safety in children.

Conclusion

In conclusion, this meta-analysis suggests that RDV has an acceptable safety profile in pediatric patients with COVID-19 and is generally well-tolerated. The most commonly reported drug-related adverse events were elevated hepatic enzymes (AST and/or ALT) and hypertension. Less frequently, bradycardia and increased creatinine levels were also observed. However, this study was inconclusive regarding the impact of RDV on mortality or respiratory support requirements, as a very limited number of well-designed randomized controlled trials have been conducted to date, which are insufficient to draw firm conclusions.