Use of Sotrovimab in 14 Children with COVID-19: A Single-center Experience

Abstract

Children affected by coronavirus disease 2019 (COVID-19) with preexisting comorbidities are at risk of complications. Monoclonal antibodies prevent severe COVID-19 courses in adults but data on children are scarce. Here we report on the use of Sotrovimab in 14 children at risk of severe disease treated at the University of Cologne Children’s Hospital. Tolerability was good and no infusion-related reactions were seen.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting coronavirus disease 2019 (COVID-19) have caused a global pandemic with more than 490 million infections and 6.1 million deaths worldwide. More than 23 million children with COVID-19 under the age of 15 years have been counted. Children often have mild or no symptoms, hospitalization is required in only about 10%.¹ However, COVID-19 is rarely severe among children, those children and adolescents with comorbidities are vulnerable to respiratory complications and have a higher risk of COVID-19-associated mortality.² COVID-19 vaccination is available for children ≥5 years of age in Germany since December 2021 but it is known for adult and adolescent patients with immunosuppressive therapy after solid organ transplantation (SOT) that the humoral response to COVID-19 vaccination is severely decreased compared with immunocompetent hosts.³ Apart from vaccines, anti-SARS-CoV-2 monoclonal antibodies (mAbs) are an option to prevent severe COVID-19 courses in patients at risk of progressing disease.² However, data on children are scarce and therapeutic options are limited. While safety and tolerability as well as clinical efficacy were evaluated in adults immediately, corresponding clinical trials with children meet significant challenges. Therefore, the subsequent approval of drugs for children by the local authorities needs careful consideration. Sotrovimab (Xevudy) is approved by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for children ≥12 years of age. In Germany, it is the only antibody effective in Omicron variants, which have been the predominating SARS-CoV-2 variants since November 2021. Experience with sotrovimab in children is barely existent, the drug’s approval is based on an original publication analyzing unvaccinated adult patients (≥18 years of age).⁴ Therefore, we evaluated all children treated with sotrovimab with proven COVID-19 disease at the Children’s Hospital of the University of Cologne, Germany.

PATIENTS AND METHODS

We report data from a retrospective single-center study of the Department of Pediatric Infectious Disease at the University Hospital of Cologne, a tertiary care hospital. We identified children and adolescents who received anti-SARS-CoV-2 mAb treatment with sotrovimab at the University of Cologne, Children’s Hospital, Germany. All patients had reverse-transcriptase–polymerase chain reaction (RT-PCR) confirmed COVID-19 disease and at least 1 risk factor for severe disease progression [obesity (BMI percentile >90), immunosuppressive therapy, another immunodeficiency, chronic kidney disease (estimated Glomerular Filtration Rate <90 ml/min/1.73m²), solid organ transplantation, congenital heart disease/congestive heart failure, chronic respiratory disease, neurodevelopmental disorder, dependence on gastrostomy/tracheostomy]. Data collection was performed via our hospital information system and patient records. We assessed patient characteristics, safety and tolerability as well as outcome in terms of hospitalization and patients’ baseline characteristics until May 31st, 2022.

RESULTS

From January to March 2022, 87 children and adolescents were hospitalized at our tertiary care children’s hospital with RT-PCR-confirmed COVID-19 infection. Of these, 14 were treated with sotrovimab. The indication for treatment with Sotrovimab was given by the attending physician after consulting a pediatric infectious disease specialist. All 14 patients presented with at least 1 risk factor for severe COVID-19 (Figure, Supplemental Digital Content 1 http://links.lww.com/INF/E877), and 11 patients had 3 or more risk factors. As illustrated in Table 1 median age was 12.9 years, and 1 patient was 20 years old. More than half of our patients had been vaccinated and had received either two (n = 4) or three (n = 5) doses of the mRNA vaccine. In 7 of the 9 vaccinated patients, seroconversion was monitored after vaccination, 3 patients had no seroconversion after ≥2 mRNA SARS-CoV-2 vaccinations and 2 more presented with <100 binding antibody units (BAU) per milliliter before infection. Detailed patient characteristics are found in Table 1 and Supplemental Digital Content 2 http://links.lww.com/INF/E878. Most common symptoms were cough (n = 11), malaise (n = 9), fever (n = 9), fatigue (n = 6) and diarrhea (n = 6). Clinical symptoms such as muscle ache/myalgia, headache, loss of taste/smell and joint pain were not assessable in 6 patients due to the child’s age or neurodevelopmental status and therefore not evaluable. Inpatient treatment was necessary in 10 children with 4 admissions to the intensive care unit (ICU), 1 additional patient received sotrovimab in an inpatient setting but was admitted only for the infusion. The median dose per kilogram was 12.5 mg if patients were <40 kg body weight, all patients ≥40 kg body weight received 500 mg of sotrovimab. Days from the onset of symptoms to mAb infusion was a median of 2 days, n = 12 received sotrovimab within 4 days. Only n = 2 had their mAb infusion after 11 and 16 days, respectively, whereas the first positive SARS-CoV-2 PCR was only 2 days before infusion in both. mAb infusion was tolerated very well, and no infusion-related reactions were reported. By May 31st, at the last follow-up, 12 children were discharged home with back-to-baseline characteristics. One child with chronic lung disease who needed Continuous Positive Airway Pressure ventilation during the night times before COVID-19, continued high-flow nasal cannula support was necessary after discharge, and 1 child had died due to progressive heart failure within primary heart disease.

TABLE 1.

Baseline Patient and Disease Characteristics of 14 Children with COVID-19 Treated with Sotrovimab

	n (total n = 14)
Median age	12.9 years
(IQR; min; max)	(7.5–13.8; 1.0; 20.0)
0–4 years	1
5–11 years	5
12–17 years	7
≥18 years	1
Sex
Male
Female
SARS-CoV-2 vaccination status
Not vaccinated	5
2 vaccines	4
3 vaccines	5
Risk factor for severe COVID-19
Obesity (BMI percentile >90)	3
Immunosuppressive therapy	9
Otherwise immunodeficient	1
Chronic kidney disease (estimated Glomerular Filtration Rate <90 ml/min/1.73m²)	9
Solid organ transplantation	8
Congenital heart disease/congestive heart failure	2
Chronic respiratory disease	3
Neurodevelopmental disorder	6
Dependence on gastrostomy, tracheostomy	5
No. of concurrent risk factors for severe COVID-19
1	1
2	2
≥3	11
Clinical symptoms
Fever	9
Cough	11
Shortness of breath	5
Muscle aches/myalgia (n = 8)	2
Headache (n = 8)	3
Fatigue	6
Malaise	9
Loss of taste/smell (n = 8)	0
Chills	0
Joint pain (n = 8)	1
Diarrhea	6
Nausea/vomiting	2
Type of patient care
Outpatient/inpatient only for mAb infusion	5
Inpatient	10
Inpatient intensive care unit	4
Median days from onset of symptoms—mAb infusion	2 days
(IQR; min; max)	(1.8–3.2; 0;16)
Median administered dose (mg/kg) in case of <40 kg body weight	12.5
(IQR; min; max)	(11.4–17.2; 11.4; 18.2)

COVID-19 indicates coronavirus disease 2019; mAbs, monoclonal antibodies; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

DISCUSSION

COVID-19 has affected a lot of children. Although the severe disease is rare the most vulnerable among them still have a high risk of respiratory complications and admission to the ICU.² Additionally, we observed that many families with immunocompromised children felt threatened by SARS-CoV-2 and isolated the children and themselves strictly leading to longer and more severe social isolation. Specific risk factors contributing to severe COVID-19 progression in adults are outlined by the FDA emergency use authorization: older age ≥65 years, obesity, pregnancy, immunosuppressive disease, chronic cardiac or pulmonary disease, neurodevelopmental disorders, technology dependence (eg, tracheostomy and gastrostomy), sickle cell disease, chronic kidney disease and diabetes. In children symptoms of lower respiratory tract infection at presentation and presence of any preexisting medical conditions were associated with ICU admission.⁵ Underlying comorbidities are obesity, chronic respiratory and cardiovascular disease, neurologic disorders, immune disorders, metabolic disease, hemato-oncologic disease and renal and gastrointestinal disease.^6,7 In our cohort, all patients had serious risk factors, which led to treatment with the mAb sotrovimab. Eleven patients presented with ≥3 risk factors, chronic kidney disease and immunosuppressive therapy were the most common ones. Whereas previously published reports on mAb therapy show a significant reduction of disease progression when administered early after diagnosis in adults,⁴ data on children treated with sotrovimab are limited. Sotrovimab is approved for children ≥12 years of age, adolescents, and adults who do not require oxygen supplementation. The EMA/FDA approval is based on a randomized controlled study with patients ≥18 years.⁴ The COVID-19 mAb Efficacy Trial–Intent to Care Early (COMET-ICE) which evaluated the efficacy and tolerability of sotrovimab also analyzed only nonhospitalized, nonvaccinated adults who did not require any form of oxygen supplementation.⁸ Currently, there are several ongoing trials including children (NCT05144178, NCT04790786, NCT04381936 and NCT05124210), and one active, but not recruiting phase 3 randomized trial (NCT04913675). One group from Italy recently published their experience on the safety of treatment with mAb infusion in children.⁹ Since their study was conducted before the overwhelming occurrence of omicron, only 4 of their 73 pediatric patients with COVID-19 received sotrovimab, all of them <12 years of age. Due to the small number of patients described here, a profound statement regarding risk reduction cannot be made. Of 10 inpatient-treated children, 4 were admitted to the ICU immediately after the presentation in the emergency department due to respiratory failure. At the time of mAb infusion in our cohort, data on sotrovimab therapy in hospitalized patients were not available. Two adult trials investigating bamlanivimab and casirivimab plus imdevimab in that setting described a potential therapeutic benefit in patients without endogenous antibody production.^10,11 The trial analyzing sotrovimab in that specific setting has just been published.¹² In our patients at risk for severe disease, a potential benefit of sotrovimab therapy outweighed the risk of rarely occurring adverse events.

At the last follow-up, 12 patients were at home with 1 of them in need of continuing high-flow ventilation support. All children with kidney disease and all kidney transplanted patients showed no change in kidney function after receiving sotrovimab infusion. Although most data point to a low risk of severe disease in this patient cohort, 1 recent article from Brazil showed a significantly higher mortality rate among children with kidney disease as compared with children without kidney disease.⁷

The tolerability of mAb infusion was excellent in our cohort. While in a previously published trial on adults, diarrhea was the most common reported adverse event (2%) and systemic infusion-related reactions (including hypersensitivity reactions) were seen in 1% in the sotrovimab-treated group as well as in the placebo group,⁸ no incidents were reported in our cohort and no infusion-related reactions occurred.

In terms of decreased neutralization activity of the Omicron variant BA.2¹³ a major limitation of this study is that viral sequencing was performed in our patients. While in January 2022, the Omicron sublineage BA.1 was present in >90% of the RT-PCR confirmed cases in Germany, the incidence of sublineage BA.2 increased rapidly until reaching a level of >88% by the end of March, 2022.¹⁴ However, clinical data from the UK in adults showed a potential effect in BA.2 despite tested resistance to sotrovimab in in-vitro experiments.¹⁵

In summary, experience with the application of sotrovimab in children and adolescents is limited. In our cohort, tolerability was excellent and the clinical course was favorable in all patients except 1. The major limitation of this report is the small number of patients, a conclusion in terms of efficacy cannot be drawn. While reasonable in Omicron BA.1, sotrovimab is of constrained use in Omicron BA.2. Nonetheless, sotrovimab could be offered as an option to children at high risk of severe COVID-19 progression with emerging new variants and again higher in-vitro neutralizing activity. Furthermore, collecting data is important until profound evidence from prospective, randomized controlled multicenter trials are available.

Supplementary Material

inf-42-e61-s001.docx ^{(38.4KB, docx)}

inf-42-e61-s002.docx ^{(19.1KB, docx)}