Remdesivir Use in Pediatric Patients for SARS-CoV-2 Treatment: Single Academic Center Study

Abstract

Background: 

Millions of children in the United States have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with many infections leading to hospitalization. For pediatric patients, especially younger children, treatment options are limited. Remdesivir has demonstrated a positive safety and efficacy profile in adults, but little data is published regarding remdesivir use in pediatric patients. Additional data for SARS-CoV-2 treatments in pediatric patients is required to prevent further SARS-CoV-2–related morbidity and mortality. At a single pediatric academic medical center, the safety and efficacy of remdesivir was evaluated.

Methods: 

A retrospective review of patients admitted to a pediatric academic medical center who received remdesivir over a 17-month period was completed. All pediatric patients who received at least 1 dose of remdesivir were included. Safety and efficacy were assessed using national organization’s definitions of clinical improvement, bradycardia, hypertension, acute kidney injury and drug-induced liver injury.

Results: 

There were 48 pediatric patients included in this study with 29% of patients admitted to the pediatric intensive care unit. Less than one-third of patients received the full treatment course of remdesivir, with over half of patients not completing therapy due to symptomatic improvement or hospital discharge. Majority of patients required some level of supplemental oxygen support. The median World Health Organization score was consistent throughout all 5 days of therapy. No patients experienced significant bradycardia, hypertension, acute kidney injury, or drug-induced liver injury.

Conclusions: 

Remdesivir may correlate with clinical stability or improvement and demonstrates safety when used in pediatric patients. A randomized controlled trial is needed to confirm these findings.

As of May 2022, over 13 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been reported in children in the United States, with 3% of those cases leading to hospitalization.¹ Infection with SARS-CoV-2 can be deadly and treatment options are limited for children, especially younger children.² Remdesivir, a SARS-CoV-2 ribonucleic acid polymerase inhibitor, is effective in decreasing recovery time and mortality in adult patients with SARS-CoV-2 infection.³ In October 2020, remdesivir was approved by the Food and Drug Administration (FDA) for the treatment of SARS-CoV-2 infection in patients 12 years of age or older weighing at least 40 kg, and for Emergency Use Authorization if less than 12 years of age and at least 3.5 kg.^4,5

While an adult safety study showed a mortality benefit with the use of remdesivir for SARS-CoV-2 infections, the study also demonstrated increased serum alanine aminotransferase, increased serum creatinine and bradycardia associated with remdesivir.^3,6 Data regarding safety and efficacy of remdesivir use in pediatric patients is limited.⁷ A case series of children admitted to the intensive care unit in 2020 with SARS-CoV-2 infection found that the majority of children received therapies targeting the SARS-CoV-2 virus despite minimal available data regarding use of novel agents in pediatric patients, including remdesivir.⁸ A multicenter review of inpatient pediatric remdesivir use in 77 patients with severe SARS-CoV-2 infection published in May 2021 found that 83% of patients had clinically recovered by the 28-day follow-up period.⁹ Of these, 25 patients experienced adverse effects, which included but were not limited to elevated transaminases, renal impairment and rash. Interim data from another multicenter study of 52 patients report remdesivir is generally well-tolerated; a high proportion of pediatric patients have shown clinical improvement based on a clinical 7-point ordinal scale and an 82% hospital discharge rate.¹⁰ A total of 21 patients experienced the following adverse events: acute kidney injury, pyrexia, increased serum alanine aminotransferase, constipation, hyperglycemia and hypertension. These studies included mostly intensive care unit patients with an overall high proportion of patients receiving oxygen supplementation at the start of remdesivir treatment. It remains unclear how remdesivir may impact clinical improvement and hospital length of stay in a lower-acuity patient population.

SARS-CoV-2 infection can result in serious morbidity and mortality in patients of all ages and there is a minuscule amount of data or recommendations available regarding treatment options for pediatric patients, which necessitates further investigation into treatment options for this patient population.¹¹ This retrospective review describes remdesivir use in general care and intensive care unit pediatric patients at a single academic children’s hospital.

MATERIALS AND METHODS

This Institutional Review Boards-exempt retrospective study included all pediatric patients admitted to American Family Children’s Hospital who received remdesivir from October 2020 to February 2022. Patients were eligible for inclusion if they were 18 years of age or less at the time of admission and received at least 1 dose of remdesivir during admission. Eligible patients could have either symptomatic SARS-CoV-2 infection or were asymptomatic but SARS-CoV-2-positive upon admission. Methodology for SARS-CoV-2 infection detection at the institution is through polymerase chain reaction testing. There were no exclusion criteria.

Patients were stratified using a data analytics platform based on documented remdesivir administrations during admission. Depending on the patient’s age and weight, remdesivir was ordered either through the Emergency Use Authorization study protocol order set or the FDA-approved medication order set. At the time of this study, remdesivir was restricted for use only in patients who were requiring respiratory support. Data were obtained from the analytics platform when able, and remaining data were collected with manual chart review.

Efficacy was assessed based on the 9-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement.¹² A score of 0 indicates no clinical evidence of infection, and a score of 8 represents death; as the score gets higher, the patient has a higher burden of clinical signs of infection. See the footnote of Figure 1 for further details regarding the WHO scale score descriptions.

Bradycardia was defined per the pediatric advanced life support algorithm.¹³ Hypertension was defined based on the American Academy of Pediatrics guideline.¹⁴ The 2012 Kidney Disease Improving Global Outcomes guideline for acute kidney injury was used to define renal toxicity, and the 2021 American College of Gastroenterology guideline for diagnosis and management of drug-induced liver injury was used to define hepatotoxicity.^15,16

RESULTS

A total of 48 pediatric patients received remdesivir during their admission between October 2020 and February 2022 (Table 1). Over the 17-month period included in this review, there were a total of 211 patients who tested positive for SARS-CoV-2 infection at the institution; of all patients positive for SARS-CoV-2 infection, only 23% of them received treatment with remdesivir. The most common comorbidities were pulmonary, obesity and cardiac. There were 10 patients with no comorbidities and 10 patients with at least 3 comorbidities. Services that patients were admitted to most commonly were pediatric hospitalist, pediatric critical care and pediatric pulmonary services. Two patients had proven co-bacterial infections and received antibiotics along with remdesivir. Additionally, there were 36 patients (75%) who received dexamethasone with remdesivir and 1 patient who received baricitinib during their admission. Length of admission and length of pediatric intensive care unit stay are shown in Table 2.

TABLE 1. - Baseline Characteristics (n = 48 Patients)

Baseline Characteristics	Result	IQR
Median age (years)	12.5	(7.5–16)
Patient age, % (n)
<5 years old	17 (8)
5–11 years old	31 (15)
12+ years old	52 (25)
Common comorbidities, % (n)
Pulmonary	52 (25)
Obesity	37.5 (18)
Cardiac	25 (12)
Number of comorbidities per patient (n)
0	10
1	14
2	14
3+	10
Median number of comorbidities per patient	1.5	(1–2)
Immunocompromised, % (n)	15% (7)
Oxygen requirement at baseline, % (n)
Room air	86 (41)
Low flow	4 (2)
High flow	10 (5)
Proven co-viral infection, % (n)	0
Proven co-bacterial infection, % (n)	4% (2)
Nosocomial SARS-CoV-2 infection (n)	1
Mortality from SARS-CoV-2 (n)	0
All-cause mortality (n)	1
Median days of symptoms before initiating remdesivir	4	(2–6.75)
Initiation of remdesivir, % (n)
Day of admission	21 (10)
Day after admission	46 (22)
Two or more days after admission	33 (16)

IQR indicates interquartile range.

TABLE 2. - Admission Characteristics of Pediatric Patients Treated With Remdesivir for SARS-CoV-2 Infection

Admission Characteristic	Result	IQR
Median length of admission (days)
<5 years old	5.5	(3–12.25)
5–11 years old	4	(2–5)
12+ years old	5	(3–8.25)
All patients	4.5	(3–8)
Median length of pediatric intensive care unit stay (days)
<5 years old	4.5	(2.5–7.75)
5–11 years old	2	(1.25–2.75)
12+ years old	3.5	(3–6.5)
All patients	3	(2–5.5)
Admitting service
Pediatric hospitalist	18
Pediatric critical care	14
Pediatric pulmonary	10
Other	6
Additional SARS-CoV-2 therapies received during admission, % (n)
Baricitinib	2 (1)
Dexamethasone	75 (36)
Highest level of oxygen support required, % (n)
Room air	16.7 (8)
Low flow	37.5 (18)
High flow	39.6 (19)
Mechanical ventilation	6.3 (3)
Completed course of remdesivir (%)
<5 years old	37.5
5–11 years old	33.3
12+ years old	28
All patients	31.3

IQR indicates interquartile range.

Most patients were started on remdesivir the day after admission. The next most frequent time point that patients started remdesivir was 2 or more days into their admission; the least number of patients were started on remdesivir on the day of admission (Table 1). Less than one-third of patients who were started on remdesivir completed 5 days of therapy. Over half of patients (54%) received less than 5 days of therapy because of either symptomatic improvement or patient was ready for hospital discharge. Other reasons for premature discontinuation of remdesivir were transaminitis, concern for arrhythmia, decrease in supplemental oxygen requirements, loss of intravenous access and other undocumented reasons.

The median WHO score on first day of therapy was 4, indicating patients required some supplemental oxygen via mask or nasal prong (Table 3 and Fig. 1). The median WHO score was consistent at 4 throughout all 5 days of remdesivir therapy for patients who remained in the hospital. Overall, relative WHO scores for all patients combined, inpatient and discharged, improved in the subsequent days after the initial remdesivir dose due to patient improvement and clinical readiness for hospital discharge. The median WHO score at the time of discharge was 1.

TABLE 3. - Patient Safety and Efficacy Findings During Remdesivir Treatment

Result	Result	IQR
Oxygen requirement escalation while on remdesivir (number of patients [%], median duration of escalation [days])
<5 years old	25 (4)	(1.5–11)
5–11 years old	26.7 (2)	(1–4.5)
12+ years old	20 (3)	(1–3.25)
All patients	22.9 (3)	(1–4)
Median WHO score
Day 1 of therapy (n = 48)	4	(4–5)
Day 2 of therapy (n = 39)	4	(4–5)
Day 3 of therapy (n = 34)	4	(3–5)
Day 4 of therapy (n = 22)	4	(3–5)
Day 5 of therapy (n = 12)	4.5	(3.75–5)
Day of discharge (n = 48)	1	(1–1.25)
Bradycardia (%)
<5 years old	0
5–11 years old	6.7
12+ years old	20
All patients	12.5
Hypertension (%)
<5 years old	37.5
5–11 years old	53.3
12+ years old	60
All patients	54.2

IQR indicates interquartile range.

FIGURE 1.: Median WHO score by day after remdesivir dose (n = 48 patients)^a,b. ^aNumbers within the columns of the figure represent the number of patients with the corresponding WHO score on each day of remdesivir treatment. ^bWHO Score Clinical Description: 0 = no clinical or virological evidence of infection; 1 = ambulatory with no limitation of activities; 2 = ambulatory with limitations of activities; 3 = hospitalized with no oxygen therapy; 4 = hospitalized with oxygen by mask or nasal prongs; 5 = hospitalized with noninvasive ventilation or high-flow oxygen; 6 = intubation and mechanical ventilation; 7 = ventilation with additional organ support such as vasopressors, renal replacement therapy and/or extracorporeal membrane oxygenation; 8 = death.¹²

Less than 20% of patients were stable on room air throughout the entirety of their admission. Seven patients received remdesivir without having any supplemental oxygen requirement, which went against institutional guidance and medication restriction criteria. Three patients required mechanical ventilation for oxygen support while receiving remdesivir; they required 5, 6 and 17 ventilator days before extubation. There were no patients who required extracorporeal membrane oxygenation. Most patients (77%) required high-flow or low-flow oxygen support. The level of oxygen support was escalated for 23% of patients while they were receiving remdesivir, whether that was transitioning from room air to some level of oxygen requirement or escalating their oxygen support. The median duration of escalated oxygen support for all patients was 3 days. One patient was discharged with higher oxygen support compared with their baseline support before admission; on the day of admission, the patient was admitted to the pediatric intensive care unit, placed on high-flow oxygen and started on remdesivir and dexamethasone. The patient continued to worsen after completing remdesivir and dexamethasone therapies and was administered baricitinib for 12 days; the total length of admission was 25 days and the patient was discharged home with oxygen support via nasal cannula.

Approximately 20% of patients experienced bradycardia, and approximately half of patients experienced hypertension while receiving remdesivir. None of the patients who experienced bradycardia or hypertension required discontinuation of remdesivir. There were no patients who experienced hepatic or renal toxicity from remdesivir. One patient experienced bilateral arm tremors while receiving a remdesivir infusion with no other known cause or contributing factors to the tremors. The patient remained neurologically intact with normal mental status throughout the event, the tremors resolved with no intervention, and there were no subsequent tremor-like events during the remainder of the hospitalization.

One patient died 7 months after the hospitalization during which they received remdesivir for SARS-CoV-2 treatment. The patient had an extensive medical history including but not limited to seizure disorders and chronic aspiration. They were admitted to the hospital for a planned procedure and tested positive for SARS-CoV-2 on postoperative day 2. The patient received 5 days of remdesivir therapy, and at the time of discharge was back to their baseline status. Seven months after discharge, the patient was found pulseless and not breathing by their caregiver and was pronounced dead at an outside hospital after attempting resuscitation. There is no known determination of whether this cardiac event was related to his hospitalization or receipt of remdesivir, but due to remdesivir’s potential cardiac adverse effects, this case is noteworthy.

DISCUSSION

Remdesivir may be safe for treatment of pediatric SARS-CoV-2 infections as evidenced by the lack of adverse effects directly linked to the medication. One-eighth of patients and approximately half of patients developed bradycardia and hypertension, respectively, but none of those incidences were significant enough to lead to discontinuation of therapy. Confounding factors included disease burden, comorbidities, oxygenation status, fluid status and other medications that could also contribute to bradycardia and hypertension while hospitalized. With no patients experiencing hepatic or renal toxicity during their course of remdesivir, this finding suggests that organ damage did not occur in this patient population when using remdesivir for treatment of SARS-CoV-2 infection.

Notably, the majority of patients did not receive treatment with remdesivir within the first 24 hours of admission. While a definitive reason regarding why there was a delay in starting treatment cannot be found due to the retrospective nature of this review, the delay could have been due to the patient's oxygen requirements at the time of admission. Approximately 1 in 5 patients never required any oxygen support throughout admission, but remdesivir may have been started after the first day of admission if the patient's clinical status worsened. Remdesivir did not require prior approval from the pediatric infectious diseases consult service to start therapy, so waiting for approval for use was not the reason for delay.

In this retrospective review of the efficacy and safety of remdesivir usage at a single children’s academic medical center, remdesivir use correlated with improvement in clinical status in pediatric patients with SARS-CoV-2 infection. As seen in Figure 1, patients that received more doses of remdesivir had decreased symptoms and decreased median WHO Ordinal Scale for Clinical Improvement scores. Nearly all patients were discharged with a WHO score of 1 except for 7 patients with chronic oxygen requirements, 1 patient discharged with a new oxygen requirement and 2 patients requiring outpatient therapies to gain baseline strength back. In these patients, oxygen requirements were increased at the time of discharge as well as one other patient who was discharged with a new oxygen requirement. Therefore, remdesivir use generally may have contributed to clinical improvement in this patient population. Remdesivir use also correlated with decreased use of more invasive mechanisms of oxygen support as only 3 patients were mechanically ventilated and none required extracorporeal membrane oxygenation. Less than one-fourth of patients required escalation of oxygen support while receiving remdesivir, indicating that the medication may have either aided in recovery or assisted with clinical stability.

Some patients included in this study received remdesivir treatment after the results of the PINETREE study were published in December 2021. (superscript reference number 17) The PINETREE study demonstrated that a three-day course of remdesivir in the outpatient setting significantly lowered the risk of death and hospitalization due to SARS-CoV-2 infection. None of the patients in this study were asymptomatic but high risk and received remdesivir for prevention of disease progression, as was indicated in the PINETREE study.

As stated, the findings of this study are significant for numerous reasons. A major strength of this study is that it is the largest, single-center study describing the use of remdesivir as treatment for SARS-CoV-2 infection in pediatric patients. However, treatment options for SARS-CoV-2 infection in pediatric patients remain limited compared with adult patients, with remdesivir as the only FDA-approved treatment.¹⁸ With very limited outpatient treatment options available for pediatric patients with SARS-CoV-2 infection during the time of this study, some patients in this study were admitted to the hospital solely to receive remdesivir treatment as they were high risk for severe disease progression. In April 2022, FDA approval of remdesivir was expanded to allow SARS-CoV-2-positive pediatric patients at high risk of progressing to severe disease, at least 28 days old and weighing at least 3 kg to receive remdesivir in the inpatient or outpatient setting.¹⁹ If the most current indications for use were approved earlier, more patients may have been eligible to receive remdesivir for treatment of their SARS-CoV-2 infection and could have been included in this study or had their hospitalization prevented.

A challenge of identifying treatment options for patients throughout the SARS-CoV-2 pandemic is efficacy of treatment for each different SARS-CoV-2 variant. Throughout the SARS-CoV-2 pandemic, there have been multiple variants—beta, alpha, delta, gamma, omicron and BA.2—and it remains unknown how efficacious remdesivir is as a treatment option for each.²⁰ The severity of the infection for the pediatric patients in this study based on the infecting variant is unknown. Additionally, it is unknown how much, if any, remdesivir improved the disease course for the patients in this study based on the infecting variant. These virus variants create a limitation in any study of treatment options for SARS-CoV-2 that partake over a longer duration of time due to virus mutations and possible differences in virus susceptibility to remdesivir.

A large case series published recently examined the effect of remdesivir in pediatric patients admitted to the intensive care unit with severe SARS-CoV-2 infections.⁸ This retrospective review provides additional information compared with the previously published case series as this review evaluates patients in both intensive care units and general care units. Additionally, this review adds information to literature regarding remdesivir treatment only, because all patients in this review received remdesivir; the previous case series evaluated multiple therapies pooled together and not all patients received remdesivir. Conclusions of the prior case series are similar to this retrospective review as many patients received remdesivir for SARS-CoV-2 treatment despite a lack of data available regarding the safety and efficacy of remdesivir.

The first published study of remdesivir use in children who were enrolled in the compassionate-use program evaluated the safety of remdesivir but not efficacy.⁹ This single-center study adds knowledge compared with the previous published study as it shows better rates of clinical recovery, which could be due to containing a patient population that was relatively less severely ill. Patients in the previous study received a longer duration of therapy with remdesivir compared with this review. With this study containing more data regarding efficacy and oxygen requirements compared with the previous study, information regarding remdesivir’s effect on oxygen requirements can be gained. Lastly, the previous study had multiple patients who experienced significant elevations in liver enzymes, whereas this study had none. Possible improved safety and efficacy of remdesivir in the pediatric population is demonstrated in this study compared with the prior study.

The phase 2/3 CARAVAN study has preliminary results with a similar number of patients; however, the patient population differs slightly as it contains a higher number of patients who required oxygen support at the start of remdesivir treatment.¹⁰ Contrastingly compared to this study, the CARAVAN study includes patients with both SARS-CoV-2 infection and multisystem inflammatory syndrome who received remdesivir, which does not allow results about remdesivir treatment for only SARS-CoV-2 infection to be determined. Additionally, the CARAVAN study enabled patients to receive remdesivir for up to 10 days, whereas all patients in this review received only 5 days of therapy or less. Multiple patients in the CARAVAN study had their remdesivir treatment discontinued due to laboratory abnormalities. Compared with the interim data published from the CARAVAN study, this review allows more information to be gathered regarding the safety and efficacy of a shorter duration of remdesivir therapy in pediatric patients with SARS-CoV-2 infection.

A limitation of this study is that statistical significance or causation are unable to be determined by descriptive data, and therefore definitive conclusions are unable to be drawn. The nature of the study being a retrospective chart review is another limitation, as all pertinent data was likely unable to be collected. Due to confounding factors such as concomitant treatment with dexamethasone, broad conclusions are unable to be drawn regarding the side effect profile and efficacy of remdesivir alone. Lastly, the patient population in this study was relatively small. Future randomized controlled studies evaluating remdesivir use in pediatric patients for the treatment of SARS-CoV-2 infection are needed to determine the true effects of remdesivir treatment.

CONCLUSIONS

In this retrospective study of pediatric patients who received remdesivir for treatment of SARS-CoV-2 infection, remdesivir may have correlated with clinical stability or clinical improvement based on oxygenation status. Remdesivir was found to be a safe medication in this patient population as no significant adverse effects were noted to be caused by remdesivir.