Most of the randomized clinical trials (RCTs) of remdesivir therapy in COVID-19 patients were conducted in adults, and there is a lack of studies involving children and adolescents.

The WHO Solidarity Therapeutics Trial was a multinational, open-label, adaptive RCT of repurposed drugs in hospitalized adult patients with COVID-19. In this study, 2,743 patients receiving a 10-day course of remdesivir and 2,708 receiving local standard of care were analyzed [12]. The mortality rate was 11.0% in remdesivir group and 11.2% in standard of care group; there was no significant difference between the 2 groups (rate ratio, 0.95; 95% confidence interval [CI], 0.81–1.11; P=0.50). The proportion of patients who initially did not but eventually required mechanical ventilation was 11.9% (295 of 2,489) and 11.5% (284 of 2,475) in remdesivir and standard of care groups, respectively.

The Adaptive COVID-19 Treatment Trial (ACTT-1), a multinational, placebo-controlled, double-blinded RCT of remdesivir in hospitalized adult patients with COVID-19 pneumonia. A total of 541 and 521 patients were assigned to the remdesivir and placebo groups, respectively, for 10-day treatment [13]. Remdesivir significantly shortened the recovery time (10 days vs. 15 days; rate ratio for recovery, 1.29; 95% CI, 1.12–1.49; P<0.001). Furthermore, the benefit of remdesivir was the greatest in patients who were randomized within the first 10 days of symptom onset (rate ratio for recovery, 1.37; 95% CI, 1.14–1.64) and those who required supplemental oxygen therapy at the time of enrollment (rate ratio for recovery, 1.45; 95% CI, 1.18–1.79). However, there was no difference in time to recovery for patients who required high-flow oxygen therapy, noninvasive mechanical ventilation, mechanical ventilation, or ECMO. Patients in the remdesivir group were found to be more likely than those in the placebo group to have clinical improvement at day 15 (odds ratio [OR], 1.5; 95% CI, 1.2–1.9; P<0.001). The estimated mortality by day 29 was 11.4% in the remdesivir group and 15.2% in the placebo group, indicating no significant difference between the 2 groups (hazard ratio [HR], 0.73; 95% CI, 0.52–1.03). However, the subanalysis of the patients requiring supplemental oxygen therapy showed that the estimated mortality was 4.0% in the remdesivir group, which differed significantly from the 12.7% in the placebo group (HR, 0.30; 95% CI, 0.14–0.64). The proportion of serious adverse events was 25% in the remdesivir and 32% in the placebo group.

In a multinational, open-label RCT of the 5-day or 10-day remdesivir compared with standard of care in hospitalized adult patients with moderate COVID-19 pneumonia, patients in the 5-day remdesivir group had better clinical status on day 11 than those in standard of care group (OR, 1.65; 95% CI, 1.09–2.48; P=0.02); however, there was no difference between the 10-day remdesivir and standard care groups [14]. In another open-label RCT of adult patients with severe COVID-19 pneumonia, by day 14, clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day remdesivir group and in 54% in the 10-day remdesivir group. After adjustment for the baseline clinical status, there was no significant difference in the distribution of clinical status between the 2 groups at day 14. This study showed that in hospitalized adult patients with severe COVID-19 pneumonia who were not receiving mechanical ventilation or ECMO, using remdesivir for 5 or 10 days had similar clinical benefit [15].

In a double-blind, placebo-controlled RCT of remdesivir for 3 days in nonhospitalized patients aged ≥12 years with COVID-19, patients who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (aged ≥60 years, obesity, certain coexisting medical conditions) were enrolled. The proportion of COVID-19-related hospitalization or death from any cause was 0.7% (2 of 279) in the 3-day remdesivir group, which differed significantly from the 5.3% (15 of 283) in the placebo group (HR, 0.13; 95% CI, 0.03–0.59; P=0.008) [16].

As of April 2022, there are no comparative clinical data evaluating the efficacy or safety of remdesivir in children and adolescents with COVID-19. However, there is an ongoing clinical trial to evaluate the safety, pharmacokinetics, and efficacy of remdesivir in children with COVID-19 under the age of 18 (ClinicalTrials.gov identifier: NCT04431453) [17]. In the early stages of the pandemic, studies were conducted on the compassionate use of remdesivir in children and adolescents [18,19]. Goldman et al. [18] analyzed data from 77 patients from 6 countries who were administered remdesivir through the compassionate use program during the period March 21, 2020 to April 22, 2020. Approximately 79% (61 patients) of the participants had at least one underlying disease. Their median age was 14 years (interquartile range, 7–16 years), and 47% (36 patients) were younger than age 12, including 4 patients under the age of 2 months. A total of 90% (69 patients) required supplemental oxygen, and 51% (39 patients) needed invasive mechanical ventilation. By day 28 of follow-up, 83% (64 patients) recovered, and 73% (56 patients) were discharged. In patients who required invasive mechanical ventilation, 67% (26 of 39) were discharged by day 28, and 13% (5 of 39) and 5% (2 of 39) did not require oxygen or required low-flow oxygen, respectively. Sixteen percent of patients (12 of 77) had any serious adverse events. Twenty-six (34%) had grade 3 or 4 elevations of serum creatinine levels (higher than 1.8 times the upper limit of normal) or transaminase levels (higher than 5 times the upper limit of normal).

In the WHO living guideline, an initial conditional recommendation was made on November 20, 2020, suggesting not to use remdesivir for patients with COVID-19 regardless of illness severity. A new recommendation on using remdesivir for patients with nonsevere illness was published on April 22, 2022 (10th version). The WHO guidelines suggest treatment with remdesivir for patients with nonsevere COVID-19 at highest risk of hospitalization (conditional recommendation). Remdesivir should be administered as soon as possible after onset of symptoms, ideally within 7 days [9].

The Australian guidelines conditionally recommend the use of remdesivir in adult COVID-19 patients who require oxygen therapy but not mechanical ventilation [20]. However, they recommend that the use of remdesivir in children and adolescents (under the age of 16) should not be routinely considered (conditional recommendation against) [1].

The National Institute for Health Care and Excellence (NICE) recommends considering a 3-day course of remdesivir for adult or young people aged ≥12 years and weight of at least 40 kg with COVID-19 who do not supplemental oxygen and are within 7 days of symptom onset and are at high risk of progression to severe COVID-19 (conditional recommendation). A 5-day course of remdesivir is considered for adults or young people aged ≥12 years and weight of at least 40 kg who have COVID-19 pneumonia and are in hospital and need low-flow supplemental oxygen (oxygen delivered by a simple face mask or nasal cannula at a flow rate usually up to 15 L/min) (conditional recommendation) [7].

The IDSA guidelines suggest that among patients with mild to moderate COVID-19 at high risk for progression to severe disease, a 3-day treatment with remdesivir is initiated within 7 days of symptom onset rather than no remdesivir (conditional recommendation). In patients on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA suggests remdesivir over no antiviral treatment and treatment with 5 days of remdesivir rather than 10 days of remdesivir (conditional recommendation). It is suggested against the routine initiation of remdesivir in patients with COVID-19 on invasive mechanical ventilation and/or ECMO [10]. On April 25, 2022, the U.S. Food and Drug Administration (FDA) extended the approval of the use of remdesivir to include pediatric patients 28 days of age and older weighing at least 3 kg [21].

The National Institutes of Health (NIH) guidelines suggest that remdesivir can be considered for children of all ages with COVID-19 who have an emergent or increasing need for supplemental oxygen in consultation with a pediatric infectious specialist [8].

Remdesivir is available in 2 formulations for intravenous administration, a concentrated solution and a lyophilized powder. The concentrated solution should only be used in adults and pediatric patients weighing ≥40 kg, while the lyophilized powder can be used in adults and pediatric patients weighing ≥3 kg. Remdesivir contains the excipient sulfobutylether-beta-cyclodextrin sodium, which accumulates in patients with renal dysfunction. Remdesivir should not be administered to patients with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min. Remdesivir is administered intravenously over 30–120 minutes. Remdesivir should be administered in a setting where severe hypersensitivity reactions, such as anaphylaxis, can be managed and the emergency medical system can be activated. Patients should be monitored during the infusion and observed for at least 1 hour after the infusion as clinically appropriate [8]. During the treatment with remdesivir, liver function tests, renal function tests, and prothrombin time must be monitored. Remdesivir may need to be discontinued if a patient’s alanine transaminase (ALT) level increases to >10 times the upper limit of normal, and it should be discontinued if increases in ALT levels and signs or symptoms of liver inflammation are observed [8].

The recommended dose for persons weighing between 3 kg and 40 kg is 5 mg/kg/dose on the first day, followed by 2.5 mg/kg/dose once daily on subsequent days. For those weighing over 40 kg, the recommendation is 200 mg on the first day, followed by 100 mg once daily on subsequent days [10,22].

As of May 9, 2022, remdesivir is available for children and adolescents in Korea in following cases [23]: (1) patients weighing at least 3.5 kg with COVID-19 pneumonia or severe COVID-19 requiring supplemental oxygen therapy, excluding mechanical ventilation and/or ECMO; a 5-day treatment of remdesivir, and (2) patients aged ≥12 years and weight of at least 40 kg with mild to moderate COVID-19 who do not supplemental oxygen and are within 7 days of symptom onset and have at least one underlying medical conditions such as chronic lung disease, hypertension, cardiovascular or cerebrovascular disease, diabetes, obesity, active malignancy, immunosuppressive disease or receipt of immunosuppressive therapies, chronic kidney disease, chronic liver disease, or sickle cell disease; a 3-day treatment of remdesivir.

In July 2020, the Korean Ministry of Food and Drug Safety (MFDS) authorized the use of remdesivir for patients with COVID-19 weighing at least 3.5 kg who met the following criteria: radiologically identified pneumonia (either by chest x-ray or computed tomography), oxygen saturation of less than 94%, and supplementary oxygen requirement. Based on the clinical trial data for remdesivir reported in other countries, on January 7, 2022, the Korean MFDS revised the approval of the use of remdesivir to limit hospitalized adults and adolescents aged ≥12 years and weight of at least 40 kg with COVID-19 pneumonia or severe COVID-19. However, since there were no antiviral drugs available for pediatric patients under 12 years of age in Korea, remdesivir was authorized for emergency use in these patients [24]. On January 20, 2022, the Korean MFDS also approved the emergency use of remdesivir in adults and adolescents with mild to moderate COVID-19 who are at high risk for progression to severe disease [25].

Currently, there are no clinical data on the treatment of children and adolescents with COVID-19 using corticosteroids only. However, several RCTs involving adults showed that systemic corticosteroid therapy improved clinical outcomes and reduced mortality in hospitalized COVID-19 patients requiring supplemental oxygen therapy [32-37]. The RECOVERY trial is the largest multicenter, open-label RCT of dexamethasone in hospitalized patients with COVID-19 in the United Kingdom. A total of 6,425 patients underwent randomization; 2,104 received dexamethasone 6 mg intravenously or orally once daily plus standard care for up to 10 days or until discharge and 4,321 received standard care only [36]. The overall mortality rate at day 28 was 22.9% in the dexamethasone group and 25.7% in the standard care group (age-adjusted rate ratio, 0.83; 95% CI, 0.75–0.93; P<0.001). In patients with severe COVID-19 who required supplemental oxygen, dexamethasone reduce mortality at day 28, with greatest benefit in those with mechanical ventilation at randomization: patients requiring mechanical ventilation or ECMO at randomization, 29.3% in the dexamethasone group versus 41.4% in the standard care group (rate ratio, 0.64; 95% CI, 0.51–0.81); patients requiring supplemental oxygen but not mechanical ventilation at randomization, 23.3% in the dexamethasone group versus 26.2% in the standard care group (rate ratio, 0.82; 95% CI, 0.72–0.94). However, no survival benefit of dexamethasone who did not require supplemental oxygen at baseline (17.8% in the dexamethasone group vs. 14.0 % in the standard care group; rate ratio, 1.19; 95% CI, 0.92–1.55).

In the CoDEX (COVID-19-associated ARDS treated with DEXamethasone) trial, a multicenter, open-label RCT of dexamethasone in patients with acute respiratory distress syndrome (ARDS) in Brazil, patients who received mechanical ventilation within 48 hours of meeting criteria for moderate to severe ARDS were randomized to the dexamethasone group (20 mg intravenously daily for 5 days, then 10 mg for 5 days or until intensive care unit discharge; 151 patients) or the standard care group (148 patients) [35]. Although the CoDEX trial was early terminated after the release of data from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, the mean number of days alive and free from mechanical ventilation by day 28 was significantly longer in the dexamethasone group (6.6 days in the dexamethasone group vs. 4.0 days in standard care group; P=0.04). Several RCTs of hydrocortisone [32] or methylprednisolone [37] in patients with severe COVID-19 showed the clinical benefits in the treatment failure or mortality rate. However, there were insufficient data to evaluate the efficacy of hydrocortisone and methylprednisolone because enrollment stopped after release of data from the RECOVERY trial.

The WHO, IDSA, NIH, NICE, and Australian guidelines strongly recommend the use of corticosteroids in adult patients with severe and critical COVID-19 who require supplemental oxygen [7-10,20]. However, the use of corticosteroids is not recommended for patients with nonsevere COVID-19.

Although there is a lack of evidence for the use of corticosteroids in children and adolescents with severe COVID-19, several guidelines recommend the use of corticosteroids in pediatric patients with severe or critical COVID-19 based on clinical data from adult patients. The NIH guidelines recommend using dexamethasone for hospitalized children who require high-flow oxygen therapy, noninvasive ventilation, invasive mechanical ventilation, or ECMO [22]. The Australian guidelines recommend using dexamethasone daily intravenously or orally for up to 10 days (or acceptable alternative regimen) in children and adolescents with COVID-19 who are receiving oxygen including those requiring mechanical ventilation (conditional recommendation) [1].

Corticosteroids are not routinely recommended for pediatric patients who require only low levels of oxygen support but could be considered on a case-by-case basis. The use of dexamethasone for the treatment of severe COVID-19 in children who are profoundly immunocompromised has not been evaluated; therefore, such use should be considered only if the benefit is perceived to outweigh the risks [8]. Dexamethasone is administered orally or intravenously 0.15 mg/kg/dose (maximum dose 6 mg) once daily for up to 10 days. If dexamethasone is unavailable, equivalent total daily doses of alternative corticosteroids may be used. Equivalent total daily doses of alternative corticosteroids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg [10]. During systemic corticosteroid administration, hyperglycemia, secondary infections, and risk of fungal opportunistic infection should be monitored.

To date, there are no data from the clinical trials on tocilizumab treatment in children and adolescents with COVID-19. In the RECOVERY trial, severe COVID-19 patients with hypoxia (oxygen saturation <92% on room air or requiring oxygen therapy) and evidence of systemic inflammation (CRP≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone (2,094 participants) versus usual standard of care plus tocilizumab (2,022 participants) [39]. In the tocilizumab group, the 28-day all-cause mortality was significantly lower (31% vs. 35%; rate ratio, 0.85; 95% CI, 0.76–0.94; P=0.003). The proportion of patients discharged alive within 28 days was greater in the tocilizumab group (57%) than the usual care group (50%) (rate ratio, 1.22; 95% CI, 1.12–1.33; P<0.0001).

The WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group conducted a prospective meta-analysis to estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. In 19 trials that randomized 4,299 patients to tocilizumab (960 deaths) and 3,749 patients to usual care or placebo (1,023 deaths), compared with usual care or placebo, administration of tocilizumab was associated with lower 28-day all-cause mortality (OR, 0.83; 95% CI, 0.74–0.92; P<0.001). Concurrent administration of tocilizumab and corticosteroids was associated with lower mortality (OR, 0.77; 95% CI, 0.68–0.87). Secondary infections by 28 days occurred in 21.8% of patients treated with tocilizumab versus 19.2% of patients treated with usual care or placebo (OR, 0.95; 95% CI, 0.77–1.16) [40].

The WHO guidelines strongly recommend treatment with IL-6 receptor blockers such as tocilizumab or sarilumab for patients with severe and critical COVID-19. The WHO guidelines recommend patients meeting severe and critical severity criteria should receive both corticosteroids and IL-6 receptor blockers [9]. Among hospitalized adults with progressive severe or critical COVID-19 who have elevated markers of systemic inflammation, the IDSA guidelines suggest tocilizumab in addition to standard of care (corticosteroids) rather than standard of care alone [10].

In the NIH guidelines, the position on the use of tocilizumab in pediatric patients with COVID-19 is undetermined due to insufficient evidence [22]. On the other hand, the Australian guidelines conditionally recommend using tocilizumab in children and adolescents who require supplemental oxygen, particularly where there is evidence of systemic inflammation; the guidelines specify the use of combined tocilizumab and corticosteroids [1].

Administration of tocilizumab may cause serious and fatal infections (active tuberculosis, invasive fungal infection, and opportunistic bacterial, viral, or protozoan infections). Most of these infections are observed when other immunosuppressive agents are administered simultaneously. Therefore, prior to administering tocilizumab, the risks and benefits of treatment must be considered in patients with a history of chronic or recurrent infections.

The FDA has authorized the emergency use of tocilizumab in patients 2 years of age and older with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation, or ECMO [38]. The recommended dose and regimen are as follows: 12 mg/kg for persons weighing less than 30 kg and 8 mg/kg (maximum 800 mg) for persons weighing over 30 kg for a single intravenous administration over 60 minutes. If no clinical improvement is observed after the first administration, repeat dose may be administered every 8 hours for up to 3 additional doses. Tocilizumab administration is not recommended for patients with an absolute neutrophil count of <1,000/mm³, platelets <50,000/mm³, or for those with active liver disease or hepatic insufficiency [38].