Tocilizumab for Treatment of Children and Young Adults With Severe Acute COVID-19: Experience at a Quaternary-care Children’s Hospital : The Pediatric Infectious Disease Journal

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Tocilizumab for Treatment of Children and Young Adults With Severe Acute COVID-19: Experience at a Quaternary-care Children’s Hospital

Teoh, Zheyi MD*; Danziger-Isakov, Lara MD, MPH*,†; Courter, Joshua D. PharmD; Frenck, Robert W. Jr MD*,†; Grimley, Michael S. MD†,§; Marsh, Rebecca A. MD†,§; Paulsen, Grant C. MD*,†; Phillips, Christine L. MD†,§; Spearman, Paul MD*,†; Chima, Ranjit S. MD†,¶; Schulert, Grant S. MD, PhD†,‖

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The Pediatric Infectious Disease Journal 42(2):p 119-121, February 2023. | DOI: 10.1097/INF.0000000000003763
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Abstract

The severe acute respiratory syndrome coronavirus 2 pandemic has led to approximately 1 million deaths, with approximately 1600 pediatric deaths in the United States as of July 2022.1 The rapidly evolving nature of the pandemic has led to the repurposing and study of different medications. Due to the similarities between cytokine release syndrome and the hyper-inflammatory state described in acute COVID-19, interest in the use of tocilizumab emerged early in the pandemic.

Tocilizumab, a monoclonal antibody that targets interleukin-6 (IL-6) receptors, is currently recommended by the Infectious Disease Society of America and the National Institutes of Health for hospitalized adults with severe COVID-19.2,3 While there have been several studies that evaluate the efficacy of tocilizumab in acute COVID-19, these are largely limited to adult participants.4–6 No specific recommendations exist for the use of tocilizumab in children with severe acute COVID-19 and the experience of using tocilizumab in such children has been rarely reported.7

In this single-center retrospective review, we describe the clinical characteristics and outcomes of patients with severe acute COVID-19 who were treated with tocilizumab at a quaternary children’s hospital.

METHODS

We performed a retrospective review from March 2020 to March 2022, identifying children, adolescents and young adults with severe acute COVID-19 who were treated with tocilizumab. Patients with acute COVID-19 were initially identified using International Classification of Diseases, 10th revision code U07.* and crossed-referenced with our institutional medication administration database, followed by chart review to assess inclusion eligibility. We included any patient over 2 years of age who was admitted to the pediatric intensive care unit (PICU) for primary management of acute COVID-19 and received tocilizumab for treatment of COVID-19. Tocilizumab was given as a single intravenous dose at 12 mg/kg for patients <30 kg or 8 mg/kg (with a maximum dose of 800 mg) for patients ≥30 kg. When there were intravenous dose shortages, tocilizumab was given subcutaneously at 162 mg given as 2 simultaneous doses. Patients who received tocilizumab for conditions besides acute COVID-19 such as cytokine release syndrome or multisystem inflammatory syndrome in children, and patients who received tocilizumab greater than 30 days after their primary COVID-19 disease were excluded. We collected demographic nonidentifiable data, clinical information and laboratory data from their hospital admission for COVID-19 disease. Our primary outcome of interest was discharge at 28 days following administration of tocilizumab. This study was approved by the Institutional Review Board at Cincinnati Children’s Hospital Medical Center (Identification: 2021-0826) and received a waiver for informed consent.

Descriptive statistics using t test or Wilcoxon rank-sum were used for comparison of parametric and nonparametric continuous variables and χ2 test for categorical variables. Statistical analyses were performed using STATA 17/BE (StataCorp, College Station, TX).

RESULTS

A total of 16 patients received tocilizumab (14 intravenous, 2 subcutaneous) for severe COVID-19. Half of the patients were female and the median age was 16 years with a range of 6–29 years of age. Most patients were at high risk of severe COVID-19 with 15 patients (94%) having at least 1 preexisting comorbidity, of which elevated body mass index ≥85th was most frequently identified in 12 patients (80%). None of the patients were documented or known to have received a severe acute respiratory syndrome coronavirus 2 vaccine. The majority of patients were additionally treated with a combination of dexamethasone (0.3 mg/kg daily with a maximum of 6 mg) (100%), antibiotics (94%) and remdesivir (5 mg/kg on day 1 followed by 2.5 mg/kg daily) (88%).

The median time from symptom onset to PICU admission was 7 days, and median time from symptom onset to tocilizumab administration was 8.5 days. Three patients (19%) were on high-flow nasal cannula, 7 patients (44%) were receiving noninvasive ventilation and 6 patients (37%) were invasively mechanically ventilated at the time of tocilizumab administration. In total, 9 patients (56%) ultimately required mechanical ventilation with 3 patients progressing to intubation after receiving tocilizumab.

Twelve patients (75%) were discharged by day 28, while 2 patients died 3 and 4 days after tocilizumab administration, and 2 patients were discharged 55 and 64 days after tocilizumab administration (Table 1). One patient suffered a cardiac arrest following emergent intubation, and another patient passed after redirection of care following prolonged mechanical intubation. Patients discharged at day 28 were more likely to be treated with tocilizumab earlier in their COVID-19 illness (median day of illness: 7 vs. 13.5 days; P = 0.034) and earlier in their PICU admission (median day of PICU admission: 0 vs. 4 days; P = 0.025).

TABLE 1. - Comparison of Baseline Characteristics, Severity of Illness, Time Course of COVID-19 Illness, and Laboratory Values With Primary Outcome (Discharge by Day 28 After Tocilizumab Administration)
Characteristics Discharged by Day 28 (n = 12) Died or Hospitalized at Day 28 (n = 4) P
Baseline characteristics and severity of illness
 Age, median (IQR) 16 (11.5–17) 22 (12–28) 0.279
 Female sex, n (%) 6 (50) 2 (50) 1.000
 Any comorbidity, n (%) 11 (92) 4 (100) 0.551
 Receiving BiPAP or mechanically intubated at PICU admission, n (%) 10 (83) 3 (75) 0.712
 PRISM III score at PICU admission, mean 3.5 3.3 0.671
Time course of COVID-19 illness
 Days since symptom onset at PICU admission, median (IQR) 7 (6–8.5) 7 (6–11) 0.819
 Days since symptom onset at steroid administration, median (IQR) 6 (5–7.5) 5 (3.5–9) 0.500
 Days since symptom onset at tocilizumab administration, median (IQR) 7 (6–10) 13.5 (10.5–15) 0.034
 Days since PICU admission at tocilizumab administration, median (IQR) 0 (0–1) 4 (1–7.5) 0.025
Laboratory values
 Baseline CRP (mg/dL), median (IQR) 9.4 (4.9–13.6) 8.1 (2.9–17.6) 0.770
 Repeat CRP (mg/dL) at 48–72 h, median (IQR)* 7.0 (6.8–16.1) 6.5 (<0.4–8) 0.464
 Baseline ferritin (ng/mL), median (IQR) 290.6 (212.8–496.7) 845.5 (513.2–2143.4) 0.058
 Repeat ferritin (ng/mL) at 48–72 h, median (IQR) 371.5 (192.6–741.4) 640.8 (160.4–2410.8) 0.630
 Baseline IL-6 (pg/mL), median (IQR) 18.0 (11–34) 64.5 (48–81) 0.218
*Only 5 and 3 patients in each group had a repeat CRP available.
Only 8 and 3 patients in each group had a repeat ferritin available.
Only 11 patients total had a baseline IL-6 and none had a repeat IL-6.
BiPAP indicates bilevel positive airway pressure; IQR, interquartile range; PRISM, Pediatric Risk of Mortality.

Patients discharged by day 28 had a trend towards lower baseline ferritin (median baseline ferritin: 290.6 vs. 845.5 ng/mL; P = 0.058) and lower baseline IL-6 (median baseline IL-6: 18.0 vs. 64.5 pg/mL; P = 0.218) although IL-6 was not routinely performed in all patients at our institution. Both groups had similar median baseline C-reactive protein (CRP) (9.4 vs. 8.1 mg/dL; P = 0.770) and both groups had similar illness duration, noninvasive and invasive mechanical ventilation support, timing of steroid administration and Pediatric Risk of Mortality III score at time of PICU admission. Finally, we also compared baseline characteristics of patients who were administrated tocilizumab early (≤7 days after symptom onset) compared with later (>7 days after symptom onset) and found no significant differences in baseline characteristics (age, sex, proportion of comorbidity) or clinical severity (World Health Organization severity or Pediatric Risk of Mortality score) with timing of tocilizumab administration.

DISCUSSION

In this review of children and young adults with severe COVID-19 and treated with tocilizumab at a quaternary children’s hospital, we found that discharge at day 28 was more likely seen in those treated with tocilizumab earlier in their illness and PICU admission. This appeared independent of baseline characteristics, clinical disease severity, timing of steroid treatment and other clinical characteristics at the time of PICU admission. Adult studies have similarly reported that early administration of tocilizumab was associated with improved outcomes in adults with COVID-19 disease.5,8,9 In these studies, factors related to severity of illness including mechanical ventilation at time of tocilizumab administration and treatment later during hospitalization were associated with poorer outcomes. These findings support the National Institutes of Health’s recommendation for using tocilizumab with steroids within 24 hours of admission to the intensive care unit.3

We also found that patients who were successfully discharged at day 28 had lower baseline ferritin and IL-6 levels at time of tocilizumab administration. Lower baseline inflammatory markers, including CRP, procalcitonin and IL-6 levels, at tocilizumab administration have been associated with improved prognosis, which may reflect an earlier stage of a COVID-19 triggered cytokine response, or more broadly a lower disease severity in this patient subset.9 Interestingly, we found that baseline CRP was similar in both outcome groups; other studies have also suggested that CRP may be a poor prognostic tool for predicting outcomes in patients treated with tocilizumab.10

There are several limitations of our study to consider. Our study is retrospective in nature and limited by the quality of documentation and may not account for undocumented confounding factors. Despite a 2-year inclusion period that included cases from the latest Omicron surge, our sample size was overall small and likely reflects the lower risk of severity COVID-19 seen in children and adolescents. Finally, we lack a comparator group of children admitted to the PICU with severe COVID-19 who did not receive tocilizumab. However, to date, there are few published studies (prospective or retrospective) that describe the use of tocilizumab in children and adolescents with COVID-19.

CONCLUSIONS

Delayed administration of tocilizumab after PICU admission for COVID-19, irrespective of clinical severity, may be an important predictor of poor outcomes in children and young adults. Inflammatory markers besides CRP, such as ferritin and IL-6, should be further studied as they could provide prognostic clues on the successful use of tocilizumab in severe COVID-19. Given the limitations of our retrospective study design, further comparative effectiveness studies are needed to evaluate the optimal use of tocilizumab and other immune modulators, especially in children and adolescents with severe COVID-19.

REFERENCES

1. Centers for Disease Control and Prevention. Coronavirus disease (COVID-19) Data Tracker. 2022. Available at: https://covid.cdc.gov/covid-data-tracker. Accessed July 25, 2022.
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3. National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. 2022. Available at: https://www.covid19treatmentguidelines.nih.gov/. Accessed July 25, 2022.
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Keywords:

child; COVID-19; critical care; intensive care units; pediatrics; tocilizumab

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