Safety of Remdesivir in 20 Children with COVID-19—Case Series—

Abstract

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus, has spread worldwide since 2019. Several studies report that adult patients hospitalized with severe COVID-19 can be treated successfully with remdesivir (RDV). However, few studies report the safety and efficacy of RDV for children. This study included 20 hospitalized patients who were diagnosed with COVID-19 and received RDV at Kobe Children’s Hospital, Japan, between February and June, 2022. The median age was 2 years (IQR, 1–11 years; range, 5 months to 19 years). Twelve (60%) patients were male. Three (15%) patients were previously healthy, whereas the other 17 had at least one underlying medical condition: five (25%) patients had respiratory disease, four (20%) had cardiac disease, three (15%) had central nervous system disease, four (20%) had hematologic or oncologic disease, and two (10%) had a chromosomal abnormal. All patients recovered without any sequelae, and no serious adverse events were reported. The adverse events were elevated liver enzymes in 4 children (20%), leukopenia (5%), neutropenia (5%), and hypokalemia (5%). Our study may show that the use of RDV for COVID-19 in children led to no serious adverse events.

INTRODUCTION

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus, has spread worldwide since 2019. Most hospitalized patients are adults, with elderly patients tending to have more severe disease. Young patients with COVID-19 usually have mild symptoms. Since the emergence of the Omicron variant in Japan, COVID-19 clusters have occurred at schools and within families. From August 1 to December 1, 2021, 1241 children were infected by the Delta variant of SARS-COV-2 COVID-19. By contrast, 1058 children were infected with the Omicron variant from January 1 to February 20, 2022 (in less than 2 months).¹⁾ Since January, 2022, the Omicron variant has become predominant worldwide, including in Japan.²⁾ Outbreaks at schools and in families means that more children with underlying diseases will be at risk of more serious COVID-19 infection, which may lead to get poor outcomes. Even if patients do not experience severe symptoms, treatment of their underlying disease will be delayed due to infection by COVID-19.

Remdesivir (RDV) first showed efficacy against SARS-COV-2 both in vitro and in vivo. RDV is an investigational nucleoside analog that acts as a competitive inhibitor of viral RNA-dependent RNA polymerase (RdRp). In a previous study, RDV showed antiviral activity against Ebola virus, Middle East Respiratory Syndrome-associated coronavirus, Severe-Acute-Respiratory-Syndrome-coronavirus, and other coronaviruses such as coronavirus-OC43, coronavirus -229E, and porcine Delta coronavirus.³⁾ Several studies report that hospitalized adult patients with severe COVID-19 were treated effectively with RDV. Randomized controlled trials in adults show that RDV shortens time to recovery of patients hospitalized with COVID-19, and decreases the risk of hospitalization or death among non-hospitalized patients at high risk for COVID-19 progression.^4–6) In Japan, RDV was approved for use in adults and children in May 2020; however, few studies have examined the safety and the efficacy of RDV in children. Here we report clinical outcomes of 20 children who received RDV.

PATIENTS AND METHODS

This study included hospitalized patients who were diagnosed with COVID-19 and received RDV at Kobe Children’s Hospital, in Japan, between February and June 2022. The patients were identified through a retrospective review. COVID-19 infection was defined as a positive SARS-COV-2 quantitative or qualitative antigen test, or PCR test. No patients were excluded.

All patients received RDV intravenously. Children weighting > 40 kg at screening received a single dose of 200 mg on Day 1, followed by a daily dose of 100 mg from Day 2 up to the last day. Children who weighting < 40 kg received, a single dose of 5 mg/kg on Day 1, followed by a daily dose of 2.5 mg/kg from Day 2 up to the last day. Patients received RDV for 3–10 d depending on their condition and clinical course. RDV was not given to patients with poor creatinine clearance, as determined by an age-appropriate estimated glomerular filtration rate of < 30 mL/minute, and serum levels of alanine aminotransferase (ALT) > 5 times the upper limit of the normal range.

We assessed clinical outcomes based on the following: (1) patients background: age, sex, underlying disease, and medications; (2) time from onset of COVID-19 symptoms, or a positive SARS-COV-2 test, to the start of RDV administration; (3) duration of treatment with RDV; (4) other treatments; (5) clinical course: symptoms, duration from RDV administration to alleviation of fever day, duration of additional oxygen, duration of hospital stay, and/or Pediatric Intensive Care Unit (PICU), and (6) adverse events: Common Terminology Criteria for Adverse Events (CTCAE) grade greater than I. Alleviation of fever was defined as an axillary temperature < 37.5 °C for 24 h. Day 0 was defined as the day of symptom onset or a positive COVID-19 test. The study was reviewed and approved by the Ethical Committee of the Kobe Children’s Hospital (No. R4-10). Informed consent was obtained from the patients or their parents/guardians.

RESULTS

Twenty patients were included. The clinical characteristics are listed in Tables 1, 2.

Table 1. Main Clinical Characteristics of the Patients Treated with RDV with Adverse Events

Age, sex	Underlying disease	The day of RDV start	Duration of RDV (d)	Severity	Alleviation of fever (d)	Hospital stay (d)	Respiratory support	Adverse event	Before remdesivir	Adverse event detail
15F	Hydrocephalus, ventriculoperitoneal shunt	3	10	Moderate I	4	13	Oxygen	Elevated liver enzymes	AST 39 U/L ALT 33 U/L (d5)	AST69 U/LALT142 U/L (d15)
2M	Cerebral palsy, cerebral hypoxia, CPAP	0	4	Mild	6	7	HFNC	Elevated liver enzymes	AST 17 U/L ALT 17 U/L (d0)	AST 92 U/L ALT 64 U/L (d9)
11M	Common atrioventricular valve plasty	1	3	Moderate I	2	4	Oxygen	Leukopenia, neutropenia, hypokalemia	WBC 5400 µ/L, (Neu 4400 μ/L) AST 39 U/L, ALT 27 U/L, K 4.3 mEq/L (d0)	WBC 2600 µ/L, (Neu 1250 μ/L) AST 50 U/L, ALT 30 U/L, K 4.8 mEq/L (d4)
5M	leukemia	0	7	mild	2	7	room air	Elevated liver enzymes	AST 27 U/L ALT 25 U/L (d0)	AST44 U/L ALT41 U/L (d4)

M, Men; W, women; RDV, remdesivir; WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CPAP, Continuous Positive Airway Pressure; HFNC, High Flow Nasal Cannula.

Table 2. Summaries of Main Clinical Characteristics of the Patients Treated with RDV

Age		2 years (IQR, 1–11 years; range, 5 months to 19 years)
Sex	Men	12 (60%)
	Women	8 (40%)
Underlying disease	Respiratory	5 (25%)
	Cardiac	4 (20%)
	Central nervous system	3 (15%)
	Hematologic or oncologic	4 (20%)
	Chromosomal abnormal	2 (10%)
Severity	Mild	11
	Moderate I	2
	Moderate II	1
	Severe	6
The day of RDV start		1 d (IQR, 0–2 d; range, 0–10 d)
Duration of RDV (d)	3	8 (40%)
	4	1 (5%)
	5	7 (35%)
	7	1 (5%)
	10	3(15%)
Dexamethasone		7 (35%)
Antibiotics		7 (35%)
Symptoms	Fever	17(85%)
Alleviation of fever (d)		3 (IQR, 2–5; range, 1–12)
Completion of oxygen (d)		5 (IQR, 4–10; range, 1-21)
Hospital stay (d)		7 (IQR, 6–8; range, 4–22)
PICU		7 (35%)
Adverse event*	Total	4 (20%)
	Elevated liver enzymes (II)	1 (5%)
	Elevated liver enzymes (I)	3 (15%)
	Leukopenia (I)	1 (5%)
	Neutropenia (I)	1 (5%)
	Hypokalemia (I)	1 (5%)

*CTCAE: Common Terminology Criteria for Adverse Events, IQR: Interquartile range.

Patient Background

The median age was 2 years (IQR, 1–11 years; range, 5 months to 19 years). Twelve (60%) patients were male. Three (15%) patients were previously healthy, whereas the other 17 had at least one underlying medical condition: five (25%) patients had respiratory disease, four (20%) had cardiac disease, three (15%) had central nervous system disease, four (20%) had hematologic or oncologic disease, and two (10%) had a chromosomal abnormal.

One (5%) patient received cyclosporin A and prednisolone due to frequent relapses of nephrotic syndrome, and one (5%) patient received tacrolimus due to a prior liver transplant. One (5%) patient received hydrocortisone due to pituitary adrenocortical insufficiency.

RDV

The median duration from COVID-19 onset or a positive SARS-COV-2 test to the start of RDV was 1 d (IQR, 0–2 d; range, 0–10 d). The duration of RDV therapy was 3–10 d. Eight (40%) patients received RDV for 3 d, one patient received it for 4 d, seven (35%) patients received it for 5 d, one (5%) patient received it for 7 d, and three (15%) patients received it for 10 d.

Other Treatments

Seven (35%) patients received dexamethasone. Additional antibiotic treatments were as follows: seven (35%) patients received cefotaxime, one (5%) patient received ampicillin, one (5%) patient received sulbactam/ampicillin, one (5%) patient received vancomycin, and three (15%) patients received sulfamethoxazole/trimethoprim. One (5%) patient received cefmetazole, micafungin, and sulfamethoxazole/trimethoprim as prophylactic antibiotics.

Clinical Course

Fever was the most common symptom: 17 (85%) patients came to hospital complaining of fever. (Patient No.6 had no symptom on admission, she started to have high fever and respiratory disorders.) Twelve (60%) presented with hypoxemia. Eight (40%) of them required admission to the PICU, five (25%) of whom required mechanical ventilation. The severity of the eleven patients was mild on admission. Two patients’ severity was moderate I, one patient’s severity was moderate II, and The other six patients’ severity was severe.

The median day on which fever was alleviated was Day 3 (IQR, 2–5; range, 1–12). The median day of completion of additional oxygen was Day 5 (IQR, 4–10; range, 1–21). The median duration of hospital stay was 7 d (IQR, 6–8; range, 4–22). Seven (35%) patients were admitted to the PICU.

Adverse Events

All patients recovered without any sequelae. Overall, four (20%) patients experienced a mild adverse event. No serious adverse events were reported. The mild adverse events were elevated liver enzymes: one (5%) patient’s liver enzymes elevated CTCAE grade II level and three (15%) patients’ liver enzymes elevated CTCAE grade I level. One (5%) patient experienced leukopenia (CTCAE grade I level), neutropenia (CTCAE grade I level), hypokalemia (CTCAE grade I level), but had no episode of infection or arrhythmia. No renal or cardiac adverse events, or allergic reactions were attributed to RDV.

DISCUSSION

The current study shows that RDV may be used safety for children. Only few patients developed mild to moderate liver dysfunction, leukopenia, hypokalemia but no serious adverse events were reported.

Previous clinical trials show that RDV may cause liver dysfunction (increased aminotransferase) in adults.⁶⁾ Goldman et al. reported that five out of 77 children had liver dysfunction.⁷⁾ In our study, hepatic dysfunction, which was defined as CTCAE grade greater than I was seen in three out of 20 patients. In these patients, serum ALT levels were less than five times the upper limit of normal, and improved spontaneously. Since some reports show that COVID-19 itself can cause liver dysfunction, it is unclear in our cases whether the cause was RDV therapy or COVID-19. The prevalence of ALT elevation among patients in adults with COVID-19 ranged from 4% to 33% in Chinese cohorts (weighted average: 19%), and was as high as 39% in a large cohort from the New York City area.^8,9)

It is possible that RDV causes renal dysfunction.⁶⁾ Goldman et al. reported that 1 out of 77 children suffered renal dysfunction.⁷⁾ RDV contains an excipient: 3g of sulfobutylether-beta-cyclodexirin sodium salt (SBECD) per 100 mg of RDV. More SBECD may accumulate in children with renal risk, which trigger renal impairment.¹⁰⁾ However, none of our patients had renal dysfunction, and none had serum creatinine levels greater than the upper limit of the age-appropriate normal range.

This study includes three patients with hematologic or oncologic disease. Some studies report that COVID-19 infection delayed chemotherapy for underlying disease by more than 2 weeks.^11,12) In our study, initiation of chemotherapy in these three patients was delayed for 7, 9, and 12 d. All had mild COVID symptoms but may have improved more quickly due to RDV, resulting in only a short delay in receiving chemotherapy.

The strength of this study is that to the best of our knowledge, it includes the largest number of pediatric patients who received RDV in Japan. Few previous studies have reported the safety and efficacy of RDV in children.^7,13,14) This study also reported no serious adverse events.

However, some limitation should be noted. First, each physician was able to choose the use of antibiotics. The use of antibiotics may be associated with the result of the safety and efficacy of RDV. Second, since each physician was able to choose the duration of treatment with RDV, and long-term treatment of RDV may be associated with adverse events. Actuary, one of our patients (patient No. 2) with treatment with RDV for 10 d developed Grade II liver dysfunction. Third, otherwise this study was done when the Omicron variant was predominant worldwide, we did not check whether the patients had the Omicron variant or the Delta variant. Fourth, since this report is 20 patients’ case series and this study does not have control, it is difficult to determine whether RDV is effective for children. Further study will be needed.

In conclusion, this single center retrospective study shows that the use of RDV for COVID-19 in children led no serious adverse events. Further work should be done to determine whether RDV is safe and effective for children with COVID-19.

Author Contributions

Dr. MANABE conceptualized the study, collected data, analyzed and interpreted the data, drafted the initial manuscript, and critically reviewed and revised the manuscript. Dr. MIZUNO and Dr. KASAI drafted the initial manuscript. Ph. JINDA collected data, - and reviewed and revised the manuscript. All authors approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

Conflict of Interest

The authors declare no conflict of interest. No funding was received by any of the authors for the work reported in this manuscript.

REFERENCES

• 1) Japanese Pediatric Academic Society. “Interim Report of “Study on clinical course of pediatric coronavirus disease 2019 (COVID-19) cases with domestic incidence using a database”: report 3: changes in clinical symptoms and severity of pediatric COVID-19 cases associated with omicron variant outbreaks.”: ‹http://www.jpeds.or.jp/modules/activity/index.php?content_id=385›, accessed 28 March, 2022.
• 2) Shoji K, Akiyama T, Tsuzuki S, Matsunaga N, Asai Y, Suzuki S, Iwamoto N, Funaki T, Ohmagari N. Clinical characteristics of COVID-19 in hospitalized children during the Omicron variant predominant period. J. Infect. Chemother., 28, 1531–1535 (2022).
• 3) Frediansyah A, Nainu F, Dhama K, Mudatsir M, Harapan H. Remdesivir and its antiviral activity against COVID-19: a systematic review. Clin. Epidemiol. Glob. Health, 9, 123–127 (2021).
• 4) Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19—final report. N. Engl. J. Med., 383, 1813–1826 (2020).
• 5) Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs. standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA, 324, 1048–1057 (2020).
• 6) Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe Covid-19 in outpatients. N. Engl. J. Med., 386, 305–315 (2022).
• 7) Goldman DL, Aldrich ML, Hagmann SHF, et al. Compassionate use of remdesivir in children with severe COVID-19. Pediatrics, 147, e2020047803 (2021).
• 8) Bertolini A, van de Peppel IP, Bodewes FAJA, Moshage H, Fantin A, Farinati F, Fiorotto R, Jonker JW, Strazzabosco M, Verkade HJ, Peserico G. Abnormal liver function tests in patients with COVID-19: relevance and potential pathogenesis. Hepatology, 72, 1864–1872 (2020).
• 9) Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area. JAMA, 323, 2052–2059 (2020).
• 10) Adamsick ML, Gandhi RG, Bidell MR, Elshaboury RH, Bhattacharyya RP, Kim AY, Nigwekar S, Rhee EP, Sise ME. Remdesivir in patients with acute or chronic kidney disease and COVID-19. J. Am. Soc. Nephrol., 31, 1384–1386 (2020).
• 11) Müller J, Szűcs-Farkas D, Szegedi I, Csóka M, Garami M, Tiszlavicz LG, Hauser P, Kriván G, Csanádi K, Ottóffy G, Nagy B Jr, Kiss C, Kovács G. Clinical course of COVID-19 disease in children treated with neoplastic diseases in Hungary. Pathol. Oncol. Res., 28, 1610261 (2022).
• 12) Węcławek-Tompol J, Zakrzewska Z, Gryniewicz-Kwiatkowska O, et al. COVID-19 in pediatric cancer patients is associated with treatment interruptions but not with short-term mortality: a Polish national study. J. Hematol. Oncol., 14, 163 (2021).
• 13) Méndez-Echevarría A, Pérez-Martínez A, Gonzalez Del Valle L, Ara MF, Melendo S, Ruiz de Valbuena M, Vazquez-Martinez JL, Morales-Martínez A, Remesal A, Sándor-Bajusz KA, Cabañas F, Calvo C. Compassionate use of remdesivir in children with COVID-19. Eur. J. Pediatr., 180, 1317–1322 (2021).
• 14) Yalçın N, Demirkan K. COVID-19 and remdesivir in pediatric patients: the invisible part of the iceberg. Pediatr. Res., 89, 1326–1327 (2021).