Use of Remdesivir in children with COVID-19: report of an Italian multicenter study

doi:10.21203/rs.3.rs-2507826/v1

Introduction

COVID-19 is generally milder in children than in adults, however severe infection has been described in some patients. Few data are available on use of Remdesivir (RDV) in children, as most clinical trials focused on adult patients. We report a multicenter study to investigate the safety of RDV in children affected by COVID-19.

Methods

We collected the clinical data of children with COVID-19 treated with RDV between March 2020 and February 2022 in 10 Italian hospitals. Clinical data were compared according to the duration of RDV therapy. Linear and logistic regression models were used to determine the association of significant variables from the bivariate analysis to the duration of RDV therapy.

Results

A total of 50 patients were included, with a median age of 12.8 years. Many patients had at least one comorbidity (78%), mostly obesity. Symptoms were fever (88%), cough (74%) and dyspnea (68%). Most patients were diagnosed with pneumonia of either viral and/or bacterial etiology. Blood test showed leukopenia in 66% and increased C-reactive protein (CRP) levels in 63% of cases. Thirty-six patients received RDV for 5 days, nine patients up to 10 days. Most children who received RDV longer were admitted to the PICU (67%). Treatment with RDV was well tolerated with rare side effects (Table 1): bradycardia was recorded in 6% of cases, solved in less than 24 hours after discontinuation. A mild elevation of transaminases was observed in 26% of cases, however for the 8%, it was still detected before the RDV administration. Therefore, in these cases, we could not establish if it was caused by COVID-19, RDV o both. Patients who received RDV for more than 5 days waited longer for its administration after pneumonia diagnosis. The presence of comorbidities and the duration of O2 administration significantly correlated with the duration of RDV therapy at the linear regression analysis.

Conclusion

Our experience indicates that RDV against SARS-CoV-2 is safe and well-tolerated in pediatric populations at high risk of developing severe COVID-19. Our data suggest that delaying RDV therapy after diagnosis of pneumonia may be associated with a longer duration of antiviral therapy, especially in patients with comorbidities.

COVID-19

remdesivir

pediatric intensive care unit

trial

SARS-CoV-2 infection predominantly occurs in children with less severe clinical aspects than in adults, requiring hospitalization only in 5–10% of cases [1–4]. The majority of children with COVID-19 is asymptomatic or has mild symptoms, most commonly fever, cough, pharyngitis, gastrointestinal symptoms, and changes in sense of smell or taste [5–8]. Although the course of COVID-19 disease is generally mild, cases of severe infection have been described in a small proportion of children: in these, therapeutic options such as dexamethasone, antivirals or convalescent plasma may be considered [9, 10]. To date, the optimal therapy for children with severe COVID-19 is unknown, but expert guidance suggested the use of antiviral therapy with Remdesivir (RDV) [9, 15]. RDV has received emergency approval for treating COVID-19, although few data in children are available and most clinical trials have focused on adult patients [11, 12]. RDV is a nucleotide analog that inhibits RNA-dependent RNA polymerase of several viruses, including SARS-CoV-2 [13]. In May 2020, Goldamn et al. published the results of the SIMPLE study, showing that a 10-day course of RDV was superior to placebo in reducing recovery time in hospitalized adults with severe COVID-19 and that the 5-day and the 10-day-course were similar in terms of outcomes [14].

To date, RDV is recommended for the treatment of severe COVID-19 in hospitalized children, based on adult data and studies that demonstrated a shorter time to clinical recovery, especially in those requiring supplemental oxygen, without the need for mechanical ventilation [16, 17]. Recently, on November 2022, the European Medicines Agency and the Italian Medicines Agency extended the approval of treatment for COVID-19 with RDV to pediatric patients aged 28 days or older and weighing ≥ 3 kilograms with positive SARS-CoV-2 viral test results, whether hospitalized or not, with mild-to-moderate COVID-19 and at high risk of progression to severe disease, including hospitalization or death [18, 32].

To date, few studies and case reports have described the use of RDV in children [19–22].

We hereby report the results of a nationwide multicenter study promoted by the Italian Society of Pediatric Infectious Diseases to investigate the safety and tolerability of RDV in children and the clinical characteristics of treated pediatric patients.

We retrospectively analyzed the clinical data of 50 pediatric patients with COVID-19 treated with RDV between March 2020 and February 2022 in 10 Italian hospitals.

All subjects under 18 years with documented SARS-CoV-2 infection treated with RDV were included. Diagnosis of infection was established with the presence of at least one respiratory specimen positive for SARS-CoV-2 nucleic acid using a validated Real-Time reverse-transcriptase Polymerase-Chain-Reaction (RT-PCR) assay. Molecular tests analyzed the envelope protein gene (E), the nucleocapsid protein gene (N) and the RNA-dependent RNA polymerase gene (RdRp) and all fulfilled performance criteria established by the European Commission [23]. RDV was administered at a dose of 5 mg/kg on day 1 and 2.5 mg/kg from day 2 in children less than 40 kg, at a dose of 200 mg on the first day and 100 mg from the second day in those weighing more than 40 kg. Liver enzymes were monitored every 2 to 3 days in all patients who received the drug. Renal function was monitored during and after treatment. COVID-19-related complications were defined as follows: (a) clinical and/or radiological pneumonia; (b) severe acute respiratory illness (SpO2 < 92% associated with tachypnea and/or other signs of respiratory failure); (c) acute respiratory distress syndrome; (d) neurological disturbances; (e) dehydration requiring intravenous rehydration; (f) severe bacterial supra-infection; (g) specific involvement of a single organ/apparatus requiring hospitalization (i.e., myocarditis, pericarditis, pancreatitis, etc.); (h) multisystem inflammatory syndrome temporarily related to COVID-19 (MIS-C) according to CDC criteria [24].

The following clinical data were collected from each patient's medical records: sex; weight; age; hospitalization; comorbidities; concomitant therapies; reported contact with SARS-CoV-2 infected individual; symptoms and complications of COVID-19; type and length of oxygen (O2) therapy; clinical outcome (full recovery without sequelae or death); laboratory workup, including transaminase and creatinine levels; dose, length and timing of RDV administration; side effects.

Statistical analysis

Statistical analysis was performed with IBM SPSS Statistics software version 23.0 (IBM Corp. Armonk, NY). A two-tailed p value < 0.05 was set for statistical significance. All continuous variables were expressed as means with standard deviations (SDs) or medians with interquartile ranges (IQRs), and compared by Student’s t test or Mann-Whitney’s U test according to the data distribution. All categorical variables were expressed as absolute numbers and relative percentages (taking into account missing data) and compared by chi-square test and Fisher's exact test, as appropriate. Linear regression analysis was performed adopting the duration of RDV therapy in days as the dependent variable and the clinically or statistically significant variables from previous analyses as the independent variables.

A total of 50 patients were included in the study. The clinical characteristics of the patients are detailed in Table 1.

Most patients were males (n = 32, 64%). The median age was 12.8 years (range 0.02–17.5). Among them, only one was a neonate. Most of the patients included in the study had at least one comorbidity (78%), mainly obesity (28%). The clinical presentation of SARS-CoV-2 infection was characterized by fever (88%), cough (74%), dyspnea (68%), sore throat (22%) and rhinorrhea (20%). Forty-eight patients (96%) were diagnosed with pneumonia of viral (63%), bacterial (5%) and viral plus bacterial (33%) etiology (based on serology and culture analysis). When necessary (78%), oxygen was administered via a nasal mask/cannula (63%), high-flow nasal cannulae (38%), noninvasive ventilation (25%) or mechanical ventilation (14%). Two patients required extracorporeal membrane oxygenation (ECMO), one child with primary immunodeficiency and autoimmune vasculitis, the other one with drepanocytosis. None of the patients recruited in the study had any viral respiratory co-infection while bacterial coinfection was reported in nine children (18%), mainly accompanied by bacteremia. Laboratory workup showed leukopenia in 66% and increased C-reactive protein (CRP) levels in 63% of cases.

The median time from symptoms onset to RDV administration was 6 days (range 0–15), while the median time from diagnosis of pneumonia to RDV administration was 2 days (range 0–8). Thirty-two patients (68%) received RDV for 5 days, nine patients (22%) for more than 5 days (max 10 days). For several patients the length of treatments was not reported. The decision to extend the treatment was based on clinical judgment and the severity of the clinical picture (34% were admitted to PICU). After RDV administration, the median maximum aspartate amino-transferase (AST) value was 43 U/l (range 19–164) and the median maximum alanine amino-transferase (ALT) value was 57 U/l (range 6–350). Of these, thirteen children (26%) had an AST value between 50 and 200 U/l, but four of them (8%) had an AST value above 100 U/l already before RDV treatment (data not shown). Sixteen patients (32%) had a maximum ALT value after RDV administration between 50 and 350 U/l, but four patients (8%) had an ALT value above 200 U/l already before RDV treatment. None of the patients recorded an increase in creatinine value. Bradycardia was reported in 6% of cases; for all of these, RDV therapy was discontinued. Two children died, both with severe comorbidities, namely gangliosidosis and ADA deficiency. RDV administration, safety measures and other therapies are reported in Table 2.

All variables were compared between patients undergoing RDV therapy for more than 5 days or for 5 days or less. This analysis is reported in Table 3.

The comparison showed a more frequent admission to the pediatric intensive care unit (PICU) in patients treated with RDV for more than 5 days than in children treated for 5 days or less (67% vs 22%, p = 0.010). Acute respiratory distress syndrome (ARDS) was also more frequent in the former (56% vs 7%, p = 0.003). Not surprisingly, patients treated with RDV for longer also more frequently required mechanical ventilation (44% vs 3%, p = 0.007). Interestingly, patients who were given RDV for more than 5 days also waited longer for its administration after the detection of COVID-19-associated pneumonia (3 vs. 1 median days, p = 0.010). Regarding the safety of RDV therapy, no differences were found between the two groups in terms of the frequency and degree of adverse events.

The linear regression analysis showed that the presence of comorbidities (p = 0.027) and the duration of O2 administration (p = 0.020) significantly correlated with the duration of RDV therapy. Male sex also approached significance in the correlation with RDV therapy (p = 0.052).

The logistic regression analysis is outlined in Table 4.

Adopting a duration of RDV administration > 5 days as the dependent variable, we found that the none of the selected variables significantly correlated with the chosen outcome.

We report data from a cohort of children with severe COVID-19 disease treated with RDV. To date, only one US retrospective study of 77 pediatric patients with SARS-CoV-2 treated with RDV reported good tolerance to the drug with a low incidence of serious adverse events (16%) [19]. In Spain, a nationwide multicenter observational study of 8 children with confirmed SARS-CoV-2 infection treated with RDV had a positive clinical outcome of 80% [20]. This is therefore the second largest dataset on the use of RDV for the treatment of pediatric COVID-19: in this cohort, the majority of children were treated with RDV because they had a severe form of COVID-19 and and serious comorbidities, as widely reported in literature [25, 10]. In fact, the children with comorbidities, including cardiac disease, neurologic disorders, diabetes, obesity (particularly severe obesity), chronic lung disease, feeding tube dependence, malignancies, sickle cell anemia, and immunocompromised status are often associated to severe form of COVID-19 [2, 26–31].

Recently, obesity has been recognized as a significant risk factor for COVID-19 related prognosis. Brambilla et al. described how obesity increases the risk of hospitalization, intensive care unit admission, need for mechanical ventilation, and death among children and adolescents with COVID-19 [32]. Indeed, the chronic inflammation, nutritional, cardiac, respiratory, and immunological impairment characterizing obesity contribute to the risk of severe COVID-19 [32]. The second common comorbidity in our cohort was neurological disorder. These data are in line with pediatric epidemiologic studies of SARS-CoV-2 infection and are consistent with those reported by Centers for Disease Control and Prevention surveillance data on children hospitalized with COVID-19, highlighting the potential role of these conditions in predisposing patients to severe illness [25].

Expert groups recommend the use of RDV mainly in children with "severe COVID-19" defined as a new or increased demand for supplemental oxygen compared with baseline [16, 17, 36]. However, in our study we administered RDV also in a proportion of children diagnosed with severe pneumonia before the actual need for supplemental oxygen, with few side effects. Therefore this can be considered as an additional criterion for the use of RDV in children with severe COVID-19.

Overall, RDV was well tolerated in our cohort. Therapy was discontinued in 3 cases because of bradycardia, a side effect also reported by Eleftheriou et al. in 3 of 4 children treated with RDV. After drug discontinuation, the heart rate was back to normal within 24 hours [21]. Therefore, we suggest to perform an ECG monitoring before and during RDV treatment in order to highlight this adverse effect as soon as possible. Regarding the mild elevation of liver transaminases observed in our study (47%), it is not possible to define if it is attributable to COVID-19 disease, RDV, or both as 1/3 of patients shows an increase before treatment. A recent review on the use of RDV in children reported hypertransaminasemia in 32.1% of cases [33]. However, the highest level of ALT and AST observed in our population was 350 U/L e 164 U/L respectively. Furthermore, we found a statistically significant difference, with higher incidence of hypertransaminasemia in patients treated with RDV for 5 or less days, suggesting the role of agents other than RDV in the occurrence of this finding. However, the presence of hypertransaminasemia may have influenced the choice of a more restrained use of the drug, thus no more than 5 days of standard treatment.

Recently, interim data were released from a phase 2/3 study: a single-arm, open-label clinical trial that assessed the safety, tolerability and pharmacokinetics of RDV in 53 paediatric patients. Children enrolled were at least 28 days of age and weighing at least 3 kilograms with confirmed SARS-CoV-2 infection and mild, moderate or severe COVID-19 [37]. Patients in this pediatric phase 2/3 trial received RDV for up to 10 days. Adverse events included acute kidney injury (11%) and an increase in alanine transaminase levels (8%). However, this study had no placebo group, thus limiting the possibility to draw conclusions regarding the significance of these adverse events [34].

Interestingly, the analysis of the different variables and the duration of treatment for more or less than 5 days, showed that patients who were administered RDV for more than 5 days waited longer before RDV administration after the detection of COVID-19-associated pneumonia. This might suggest that patient diagnosed with pneumonia need to start antiviral treatment promptly, to avoid getting critically ill.

Our study has some limitations: it is a descriptive analysis and the results have been clinically interpreted. This happened because it was not a clinical study designed for the collection of data. Without comparative data from a randomly assigned control group, it is not possible to say if the high level of recoveries observed in these patients was due to the effects of RDV, the natural course of the disease, or other therapeutic interventions. Another limitation is the absence of a follow up and of SARS-CoV-2 viral load data on nasal swab during treatment: the lack of this data prevents us from evaluating the real effect of RDV on virus clearance. Nevertheless our results highlight and support the safety and tolerability of RDV administration in pediatric patients, even if the absence of a control arm prevents us from determining how much RDV really contributed to recovery. This confirms the need for pediatric clinical trials on the efficacy of RDV in children with severe COVID-19, and to improve the limited data available on pharmacokinetic and pharmacodynamics of RDV.

In conclusion our data suggest that RDV against SARS-CoV-2 is safe and well-tolerated in pediatric populations at high risk of developing severe COVID-19; a delayed administration of RDV therapy after diagnosis of pneumonia may be associated with a longer duration of antiviral therapy, especially in patients with comorbidities.

Acknowledgments

We would like to acknowledge all patients and guardians who decided to participate to the study.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Romani L, Roversi M, Venturini E, Garazzino S, Donà D, Montagnani C, Funiciello E and Calò Carducci FI. The first draft of the manuscript was written by Lorenza Romani and Bernardi S, Krzysztofiak A, Marabotto C, Castagnola E, Salvini F, Lancella L, Galli L and Castelli Gattinara G commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval

Informed consent was obtained from all individual participants included in the study.

Garazzino S, Montagnani C, Donà D, Meini A, Felici E, Vergine G, et al. (2020). Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020. Euro Surveill 25. doi:10.2807/1560-7917.ES.2020.25.18.2000600.
Götzinger F, Santiago-García B, Noguera-Julián A, Lanaspa M, Lancella L, Calò Carducci, FI, et al. (2020). COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study. Lancet Child Adolesc Health 4, 653–661. doi:10.1016/S2352-4642(20)30177-2
Ludvigsson JF (2020). Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr 109, 1088–1095. doi:10.1111/apa.15270.
Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. (2020b). SARS-CoV-2 Infection in Children. N Engl J Med 382, 1663–1665. doi:10.1056/NEJMc2005073.
Romani L, Chiurchiù S, Santilli V, Bernardi S, Haywood Lombardi, M., Scarselli, A., et al. (2020). COVID-19 in Italian paediatric patients: The experience of a tertiary children’s hospital. Acta Paediatr 109, 2311–2312. doi:10.1111/apa.15465.
Zachariah P, Johnson CL, Halabi KC, Ahn D, Sen AI, Fischer A, et al. (2020). Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York. JAMA Pediatr. doi:10.1001/jamapediatrics.2020.2430
Zimmermann P, and Curtis N. (2021). Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections. Arch Dis Child 106, 429–439. doi:10.1136/archdischild-2020-320338.
Zimmermann P, and Curtis N. (2022). Why Does the Severity of COVID-19 Differ With Age?: Understanding the Mechanisms Underlying the Age Gradient in Outcome Following SARS-CoV-2 Infection. Pediatr Infect Dis J 41, e36–e45. doi:10.1097/INF.0000000000003413.
Venturini E, Montagnani C, Garazzino S, Donà D, Pierantoni L, Lo Vecchio A et al. Treatment of children with COVID-19: Update of the Italian Society of Pediatric Infectious Diseases position paper. Ital. J. Pediatr. 2021;47:139
Shane Al, Sato AI, Kao C, Adler- Shohet FC, Vora BS, Auletta JJ et al., A Pediatric Infectious Diseases Perspective of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Novel Coronavirus Disease 2019 (COVID-19) in Children. J. Pediatr. Infect. Dis. Soc. 2020;9:596–608.
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. June 11, 2020; N Engl J Med 2020; 382:2327–2336 DOI: 10.1056/NEJMoa2007016
Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020; 395: 1569–78
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269–271
Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. Clinical Trial N Engl J Med. 2020 Nov 5;383(19):1827–1837. doi: 10.1056/NEJMoa2015301. Epub 2020 May 27.
Management Strategies in Children and Adolescents with Mild to Moderate COVID-19. https://www.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/outpatient-covid-19-management-strategies-in-children-and-adolescents/
Beigel JH, Tomashek KM, Dodd LE. Remdesivir for the Treatment of Covid-19 - Preliminary Report. Reply. N Engl J Med. 2020 Sep 3;383(10):994. doi: 10.1056/NEJMc2022236. Epub 2020 Jul 10. PMID: 32649078.
Chiotos K, Hayes M, Kimberlin DW, Jones SB, James SH, Pinninti SG, Yarbrough A, Abzug MJ, MacBrayne CE, Soma VL, Dulek DE, Vora SB, Waghmare A, Wolf J, Olivero R, Grapentine S, Wattier RL, Bio L, Cross SJ, Dillman NO, Downes KJ, Oliveira CR, Timberlake K, Young J, Orscheln RC, Tamma PD, Schwenk HT, Zachariah P, Aldrich ML, Goldman DL, Groves HE, Rajapakse NS, Lamb GS, Tribble AC, Hersh AL, Thorell EA, Denison MR, Ratner AJ, Newland JG, Nakamura MM. Multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2. J Pediatric Infect Dis Soc. 2021 Feb 13;10(1):34–48. doi: 10.1093/jpids/piaa115. PMID: 32918548; PMCID: PMC7543452.
Coronavirus (COVID-19) Update: FDA Approves First COVID-19 Treatment for Young Children. https://www.fda.gov/coronavirus-covid-19-update-fda-approves-first-covid-19-treatment-young-children
Goldman DL, Aldrich ML, Hagmann SHF, Bamford A, Camacho-Gonzalez A, Lapadula G, Lee P, Bonfanti P, Carter CC, Zhao Y, Telep L, Pikora C, Naik S, Marshall N, Katsarolis I, Das M, DeZure A, Desai P, Cao H, Chokkalingam AP, Osinusi A, Brainard DM, Méndez-Echevarría A. Compassionate Use of Remdesivir in Children With Severe COVID-19. Pediatrics. 2021 May;147(5):e2020047803. doi: 10.1542/peds.2020-047803. PMID: 33883243
Méndez-Echevarría A, Pére Martínez A, Gonzalez del Valle L, Ara MF, Melendo S, Ruiz de Valbuena M et al. Compassionate use of remdesivir in children with COVID-19 European Journal of Pediatrics (2021) 180:1317–1322
Eleftheriou I, Liaska M, Krepis P, Dasoula F, Dimopoulou D, Spyridis N, Tsolia M. Sinus Bradycardia in Children Treated With Remdesivir for COVID-19. Pediatr Infect Dis J. 2021 Sep 1;40(9):e356. doi: 10.1097/INF.0000000000003214. PMID: 34285169.
Cursi L, Calo Carducci FI, Chiurchiu S, Romani L, Stoppa F, Lucignani G, Russo C, Longo D, Perno CF, Cecchetti C, Lombardi MH, D'Argenio P, Lancella L, Bernardi S, Rossi P. Severe COVID-19 Complicated by Cerebral Venous Thrombosis in a Newborn Successfully Treated with Remdesivir, Glucocorticoids, and Hyperimmune Plasma. Int J Environ Res Public Health. 2021 Dec 15;18(24):13201.
European Commission (EC). Current Performance of COVID-19 Test Methods Devices Proposed Performance Criteria (16 Apr 2020) Brussel: EC. (2020). Available online at: https://ec.europa.eu/docsroom/documents/40805 (accessed February 15, 2021).
Centers for Disease Control and Prevention. Emergency Preparedness and Response: Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19). (2020). Available online at: https://emergency.cdc.gov/han/2020/han00432.asp (accessed February 15, 2021).
Kim L, Whitaker M, O'Halloran A, Kambhampati A, Chai SJ, Reingold A, Armistead I, Kawasaki B, Meek J, Yousey-Hindes K, Anderson EJ, Openo KP, Weigel A, Ryan P, Monroe ML, Fox K, Kim S, Lynfield R, Bye E, Shrum Davis S, Smelser C, Barney G, Spina NL, Bennett NM, Felsen CB, Billing LM, Shiltz J, Sutton M, West N, Talbot HK, Schaffner W, Risk I, Price A, Brammer L, Fry AM, Hall AJ, Langley GE, Garg S; COVID-NET Surveillance Team. Hospitalization Rates and Characteristics of Children Aged < 18 Years Hospitalized with Laboratory-Confirmed COVID-19 - COVID-NET, 14 States, March 1-July 25, 2020. MMWR Morb Mortal Wkly Rep. 2020 Aug 14;69(32):1081–1088. doi: 10.15585/mmwr.mm6932e3. PMID: 32790664; PMCID: PMC7440125.
Preston LE, Chevinsky JR, Kompaniyets L, Lavery AM, Kimball A, Boehmer TK, Goodman AB. Characteristics and Disease Severity of US Children and Adolescents Diagnosed With COVID-19. JAMA Netw Open. 2021 Apr 1;4(4):e215298. doi: 10.1001/jamanetworkopen.2021.5298. PMID: 33835179; PMCID: PMC8035649.
Cianferoni A, Votto M. COVID-19 and allergy: How to take care of allergic patients during a pandemic? Pediatr Allergy Immunol. 2020 Nov;31 Suppl 26(Suppl 26):96–101. doi: 10.1111/pai.13367. PMID: 33236431; PMCID: PMC7753363.
Oualha M, Bendavid M, Berteloot L, Corsia A, Lesage F, Vedrenne M, Salvador E, Grimaud M, Chareyre J, de Marcellus C, Dupic L, de Saint Blanquat L, Heilbronner C, Drummond D, Castelle M, Berthaud R, Angoulvant F, Toubiana J, Pinhas Y, Frange P, Chéron G, Fourgeaud J, Moulin F, Renolleau S. Severe and fatal forms of COVID-19 in children. Arch Pediatr. 2020 Jul;27(5):235–238. doi: 10.1016/j.arcped.2020.05.010. Epub 2020 Jun 4. PMID: 32518045; PMCID: PMC7269941.
Shekerdemian LS, Mahmood NR, Wolfe KK, Riggs BJ, Ross CE, McKiernan CA, Heidemann SM, Kleinman LC, Sen AI, Hall MW, Priestley MA, McGuire JK, Boukas K, Sharron MP, Burns JP; International COVID-19 PICU Collaborative. Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units. JAMA Pediatr. 2020 Sep 1;174(9):868–873. doi: 10.1001/jamapediatrics.2020.1948. PMID: 32392288; PMCID: PMC7489842.
Licari A, Votto M, Brambilla I, Castagnoli R, Piccotti E, Olcese R, Tosca MA, Ciprandi G, Marseglia GL. Allergy and asthma in children and adolescents during the COVID outbreak: What we know and how we could prevent allergy and asthma flares. Allergy. 2020 Sep;75(9):2402–2405. doi: 10.1111/all.14369. Epub 2020 May 28. PMID: 32418233; PMCID: PMC7276841.
De Filippo M, Votto M, Brambilla I, Castagnoli R, Montagna L, Caffarelli C, Cardinale F, Miraglia Del Giudice M, Tosca M, Caimmi S, Licari A, Marseglia GL. Allergy and COVID-19. Acta Biomed. 2021 Nov 29;92(S7):e2021522. doi: 10.23750/abm.v92iS7.12402. PMID: 34842592.
Brambilla I, Delle Cave F, Guarracino C, De Filippo M, Votto M, Licari A, Pistone C, Tondina E. Obesity and COVID-19 in children and adolescents: a double pandemic. Acta Biomed. 2022 Jun 6;93(S3):e2022195. doi: 10.23750/abm.v93iS3.13075. PMID: 35666114.
La Tessa A, Motisi M, Marseglia GL, Cardinale F, Licari A, Manti S et al. Use of remdesivir in children with COVID-19 infection: a quick narrative review. Acta Biomed 2021; Vol. 92, Supplement 7: e2021524. doi: 10.23750/abm.v92iS7.12396
Ahmed A, Rojo P, Agwu A, Kimberlin D, Deville J, Mendez-Echevarria A, Sue- P, Galli L, Shang Z, Juneja K, Hulter HN, Hedskog C, Kersey K, Muller W, Munoz F. Remdesivir treatment for COVID-19 in hospitalized children: CARAVAN interim results. 2022. Available at: https://www.croiconference.org/abstract/remdesivir-treatment-for-covid-19-in-hospitalized-children-caravan-interim-results/. (accessed november 2022)
Agenzia italiana del farmaco AIFA. Available at: https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_004796_048854_RCP.pdf&sys=m0b1l3 (accessed november 2022)
NIH COVID treatment guideline: Special Considerations in Children (Last Updated: August 8, 2022) - https://www.covid19treatmentguidelines.nih.gov/management/clinical-management-of-children/special-considerations-in-children/
Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Remdesivir (GS-5734™) in Participants From Birth to < 18 Years of Age With Coronavirus Disease 2019 (COVID-19) (CARAVAN) https://www.clinicaltrials.gov/ct2/show/NCT04431453 (accessed november 2022)

Table 1 Characteristics of study sample

Total

50

Males - no. (%)

32 (64)

Weight (kg) - median ± IQR (range)

65.5 ± 47.5 (3.2 – 130)

Age (years) - median ± IQR (range)

12.8 ± 5.2 (0.02 – 17.5)

Hospitalization (days) - median ± IQR (range)

PICU admission - no. (%)

PICU admission (days)

12 ± 14 (2 – 63)

16 (34)

15 ± 18 (2 – 27)

Comorbidities - no. (%)

Obesity

Neurological disorder

Immunodeficiency

Pulmonary or thoracic condition

Congenital disorder

Other

39 (78)

11 (28)

9 (23)

8 (21)

3 (8)

4 (10)

Concomitant therapies - no. (%)

13 (30)

Symptoms - no. (%)

Fever

Temperature (°C, max value) - median ± IQR (range)

Cough

Dyspnea

Rhinorrhea

Sore throat

Chest pain

Diarrhea

Abdominal pain

Vomiting

Fatigue

Anorexia

Headache

Joint/muscle pain

Dysgeusia/anosmia

Hypotonia

Rash

Seizures

Conjunctivitis

44 (88)

39 ± 1.0 (36.0 – 40.8)

37 (74)

34 (68)

10 (20)

11 (22)

7 (14)

6 (12)

5 (10)

4 (8)

3 (6)

2 (4)

1 (2)

Complications - no. (%)

Pneumonia

Viral

Bacterial

Mixed

Acute respiratory failure

ARDS

MIS-C

32 (76)

48 (96)

25 (63)

2 (5)

13 (33)

29 (58)

10 (21)

3 (6)

Administration of O2 - no. (%)

Mask/nasal cannulae

Mask/nasal cannulae (days)**

High-flow nasal cannulae - HFNC

High-flow nasal cannulae - HFNC (days)**

Non-invasive ventilation - NIV

Non-invasive ventilation - NIV (days)**

Mechanical ventilation

Mechanical ventilation (days)**

Extra-Corporeal Membrane Oxygenation - ECMO

Extra-Corporeal Membrane Oxygenation - ECMO**

Total duration of O2 administration/ventilation (days)**

38 (78)

31 (63)

4 ± 3

15 (38)

6 ± 8 (1 - 25)

12 (25)

4.5 ± 6 (1 - 14)

7 (14)

16 ± 14 (3 - 23)

2 (5)

9.5 ± / (2 - 17)

3 ± 7 (0 - 27)

Laboratory workup

Leukocytosis - no. (%)

Leukopenia - no. (%)

Increased PCR - no. (%)

Increased PCT - no. (%)

Bacterial coinfection - no. (%)

8 (18)

27 (66)

31(63)

6 (15)

9 (22)

Clinical outcome

Recovery without sequelae - no. (%)

Death - no. (%)

34 (89)

2 (4)

*Summary measures were calculated accounting for missing values.

**Expressed as median ± IQR (range)

Table 2 RDV administration, safety measures and other therapies

RDV administration

Dose of RDV

Duration of therapy (days) - median ± IQR (range)

≤ 5 days - no. (%)

> 5 days - no. (%)

Time from symptoms onset to administration (days) - median ± IQR (range)

Time from pneumonia to administration (days) - median ± IQR (range)

4 ± 1 (1 - 10)

32 (78)

9 (22)

6 ± 3 (0 - 15)

2 ± 2 (0 - 8)

Safety evaluation of RDV administration

AST (U/L, max value) - median ± IQR (range)

ALT (U/L, max value) - median ± IQR (range)

Creatinine (mg/dl, max value) - median ± IQR (range)

eGFR (ml/min, max value)* - median ± IQR (range)

Ipertransaminasemia - no. (%)

Bradicardia - no. (%)

Rash - no. (%)

Renal insufficiency (according to eGFR) - no. (%)

43 ± 47.3 (19 - 164)

54 ± 108 (6 - 350)

0.6 ± 0.4 (0.1 - 0.9)

120 ± 91 (79 - 236)

14 (44)

2 (4)

3 (6)

0 (0)

Antibiotic therapy

Macrolides - no. (%)

Azithromycin - no. (%)

Clarithromycin - no. (%)

Duration (days) - median ± IQR (range)

Other than macrolides** - no. (%)

Ceftriaxone or other cephalosporin - no. (%)

Piperacillin-tazobactam or tazobactam - no. (%)

Amoxicillin-clavulanate or other beta-lactam - no. (%)

Teicoplanin - no. (%)

Aminoglycosides - no. (%)

Fluoroquinolones - no. (%)

Linezolid - no. (%)

Meropenem - no. (%)

Metronidazole - no. (%)

Trimethoprim-sulfamethoxazole - no. (%)

Duration (days) - median ± IQR (range)

10 (24)

6 (15)

3 (7)

6.5 ± 5 (0 - 13)

13 (34)

12 (32)

7 (18)

4 (11)

3 (8)

1 (3)

9 ± 11 (4 - 28)

Corticosteroid therapy

Duration (days) - median ± IQR (range)

Desametasone - no. (%)

Methylprednisolone - no. (%)

Prednisone - no. (%)

9.5 ± 9 (3 - 36)

9 (27)

19 (58)

3 (9)

Other therapies

Heparin - no. (%)

Duration (days) - median ± IQR (range)

Monoclonal antibody - no. (%)

Duration (days) - median ± IQR (range)

Hyperimmune plasma - no. (%)

20 (63)

11 ± 20 (2 - 58)

3 (7)

2.5 ± / (1 - 4)

2 (8)

*The lowest value of the eGFR calculated by the MDRD, CDK-EPI or Cockroft-Gault formulas was reported for children aged 8 or more years

**Cefotaxime (n=1), ceftazidime (n=1); amoxicillin (n=1), ampicillin (n=1), ampicillin-sulbactam (n=1); amikacin (n=2), gentamicin (n=1); ciprofloxacin (n=2), levofloxacin (n=1).

Table 3 Comparison of patients based on days of RDV therapy.

RDV therapy

>5 days

RDV therapy

≤5 days

p-value

Total

9

32

-

Males - no. (%)

7 (78)

19 (59)

0.445

Weight (kg) - median ± IQR (range)

36.0 ± 42.5

(3.2 - 70.0)

67.5 ± 45.3

(4.0 - 130)

0.022

Age (years) - median ± IQR (range)

11.6 ± 13.1

(0.02 - 17.5)

12.8 ± 4.4

(0.2 - 17.1)

0.415

Hospitalization (days) - median ± IQR (range)

PICU admission - no. (%)

PICU admission (days)

20.5 ± 24

(10 - 42)

6 (67)

22 ± 7.3

(15 - 24)

10 ± 13

(2 - 63)

7 (22)

7 ± 9

(4 - 15)

0.034

0.018

0.010

Comorbidities - no. (%)

Obesity

Neurological disorder

Primary or secondary immunodeficiency

Pulmonary or thoracic condition

Congenital disorder

Other

6 (67)

0 (0)

2 (22)

0 (0)

27 (84)

9 (28)

5 (16)

2 (6)

4 (13)

3 (9)

0.342

0.167

0.637

1.000

0.559

1.000

Concomitant therapies - no. (%)

2 (25)

8 (30)

1.000

Reported contact with SARS-CoV-2 infected (%)

6 (67)

15 (47)

0.454

Symptoms - no. (%)

Fever

Temperature (°C, max value) - mean ± SD (range)

Cough

Dyspnea

Rhinorrhea

Sore throat

Chest pain

Diarrhea

Abdominal pain

Vomiting

Fatigue

Anorexia

Headache

Joint/muscle pain

Dysgeusia/anosmia

Hypotonia

Rash

Seizures

Conjunctivitis

8 (89)

39.1 ± 1.0

(38.0 - 40.8)

6 (67)

7 (78)

5 (56)

0 (0)

3 (38)

2 (22)

0 (0)

2 (20)

0 (0)

1 (11)

0 (0)

30 (94)

38.9 ± 0.5

(37.5 - 40.0)

25 (78)

22 (69)

4 (13)

8 (25)

5 (16)

4 (13)

3 (9)

5 (16)

2 (7)

3 (9)

2 (6)

1 (3)

0 (0)

0.535

0.317

0.662

0.702

0.014

0.164

0.563

0.128

0.299

0.568

0.213

1.000

0.395

1.000

-

Complications - no. (%)

Pneumoniae

Viral

Bacterial

Mixed

Acute respiratory failure

ARDS

MIS-C

7 (100)

9 (100)

3 (43)

0 (0)

4 (57)

7 (78)

5 (56)

2 (22)

20 (77)

31 (97)

18 (69)

1 (4)

6 (23)

16 (50)

2 (7)

1 (3)

0.301

1.000

0.337

1.000

0.161

0.254

0.003

0.116

Administration of O2 - no. (%)

Mask/nasal cannulae

High-flow nasal cannulae - HFNC

Non-invasive ventilation - NIV

Mechanical ventilation

Extra-Corporeal Membrane Oxygenation - ECMO

Total duration of O2 administration/ventilation (days)**

5 (56)

2 (29)

3 (38)

4 (44)

0 (0)

5 ± 15.5

(0 - 24)

21 (66)

9 (38)

7 (22)

1 (3)

0 (0)

2.5 ± 6

(0 - 19)

0.701

1.000

0.388

0.007

-

0.392

Clinical outcome

Recovery without sequelae - no. (%)

Death - no. (%)

5 (71)

0 (0)

26 (96)

1 (3)

0.101

1.000

Laboratory workup

Leukocytosis - no. (%)

Leukopenia - no. (%)

Increased PCR - no. (%)

Increased PCT - no. (%)

Bacterial coinfection - no. (%)

2 (22)

7 (78)

6 (67)

3 (33)

4 (67)

6 (17)

14 (61)

21 (68)

2 (7)

24 (86)

0.653

0.441

1.000

0.070

0.281

RDV administration

Time from onset to RDV administration (days)**

Time from pneumonia to RDV administration (days)**

8 ± 2

(5 - 11)

3 ± 2

(2 - 8)

5.5 ± 3

(0 - 15)

1 ± 2

(0 - 7)

0.069

0.010

Safety evaluation of RDV administration

AST (U/L, max value) - median ± IQR (range)

ALT (U/L, max value) - median ± IQR (range)

Creatinine (mg/dl, max value) - median ± IQR (range)

Ipertransaminasemia - no. (%)

Bradicardia - no. (%)

Rash - no. (%)

43 ± 26

(22 - 62)

25 ± 30

(21 - 58)

0.4 ± 0.4

(0.2 - 0.8)

0 (0)

43 ± 72

(19 - 164)

66 ± 123

(6 - 350)

0.6 ± 0.3

(0.1 - 0.9)

15 (65)

2 (6)

3 (9)

0.584

0.057

0.259

0.028

1.000

Antibiotic therapy

Macrolides - no. (%)

Duration (days) - median ± IQR (range)

Other than macrolides - no. (%)

Duration (days) - median ± IQR (range)

3 (33)

-

7 (78)

9 ± 16

(5 - 28)

6 (22)

6.5 ± 8

(0 - 9)

22 (69)

9.5 ± 9

(4 - 23)

0.660

0.480

0.702

0.836

Corticosteroid therapy - no. (%)

Duration (days) - median ± IQR (range)

7 (78)

11 ± 24

(4 - 36)

27 (84)

9 ± 7

(3 - 36)

0.637

0.784

Heparin - no. (%)

Duration (days) - median ± IQR (range)

3 (43)

24 ± 13

(8 - 28)

9 (38)

8.5 ± 11

(2 - 58)

1.000

0.940

*Summary measures were calculated accounting for missing values.

**Expressed as median ± IQR (range)

Table 4 Linear regression analysis (dependent variable: duration of RDV therapy in days)

Variable	Beta	C.I. 95%		p-value
		Lower bound	Upper bound
Sex (male)	1.313	-0.009	2.635	0.052
Duration of O2 administration (days)	0.122	0.021	0.224	0.020
Time from pneumonia to RDV administration (days)	0.336	-0.047	0.719	0.083
Comorbidity (yes)	1.793	0.219	3.367	0.027

No competing interests reported.

Use of Remdesivir in children with COVID-19: report of an Italian multicenter study

Status:

Version 1

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Methods

Statistical analysis

Results

Discussion

Declarations

References

Tables

Additional Declarations

Status:

Version 1