During the beginning of the coronavirus disease 2019 (COVID-19) pandemic, most children experienced minimal respiratory symptoms. However, an increasing number of pediatric patients are hospitalized with severe respiratory compromise and multiorgan involvement as the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has evolved into new variants. Although the treatment guidelines for SARS-COV-2 infection continue to be updated with new clinical trials for adults, recommendations for children remain uncertain and are largely based on adult studies. In addition to corticosteroids, antiviral agents, such as remdesivir, and immunomodulatory agents, such as tocilizumab, can be considered for critically ill patients. Remdesivir is now approved in the pediatric population, and tocilizumab remains available under Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA). We report the cases of 2 premature twins with severe coronavirus disease 2019 (COVID-19) pneumonia who received remdesivir and 1 of which received adjunctive therapy with tocilizumab. Both infants were subsequently discharged from the hospital on room air. Neither infant experienced significant bone marrow suppression, hepatic or renal dysfunction, or any other major adverse events.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019 and has since spread rapidly with 500 million cases and 6.1 million deaths noted worldwide as of April 2022.1 Although children generally have a lower risk of infection and milder symptoms, there have been reports of severe presentations including pneumonia, septic shock, multisystem inflammatory syndrome in children, and deaths.2 Systematic clinical trials of treatment options of COVID-19 in children are limited and, therefore, treatment guidelines are largely based on adult studies. Dexamethasone, remdesivir, and tocilizumab have been shown to have some success in reducing time to recovery in adults with severe infections.3–5 Remdesivir was approved for use in patients as young as 28 days by the FDA on April 25, 2022, and tocilizumab is available to pediatric populations under FDA EUA. We describe 2 premature twins with severe COVID-19 pneumonia who were treated with remdesivir and 1 of which was also treated with tocilizumab, both of whom were discharged from the hospital without experiencing significant adverse events. The mother provided informed consent to publish the case histories of her twin infants.
Case 1
A 6-week-old former 30 weeks’ gestation dichorionic-diamniotic twin male infant with history of a 5-week NICU hospitalization presented with apnea and was subsequently intubated. He had been in a healthy state at home in the 4 days before admission, feeding by mouth and needing no respiratory support. His birth history and initial hospitalization were uncomplicated. He required positive-pressure ventilation only in the delivery room and then nasal cannula oxygen for a total of 8 days.
His vitals on NICU readmission were notable for hypotension, hypothermia to 32.3°C, and poor tone. His lungs were clear to auscultation, he required 30% fraction of inspired oxygen (FiO2), and he exhibited good compliance on synchronized intermittent mandatory ventilation; however, he showed minimal spontaneous breaths. Nasopharyngeal swab was positive for SARS-CoV-2 by reverse transcriptase polymerase chain reaction, and viral sequencing reflected infection with the Omicron B.1.1.529 variant.
Blood and cerebrospinal fluid cultures were negative, but his urine culture grew 30 000 to 49 000 colony-forming units of Klebsiella aerogenes, and he was treated with a 7-day course of ceftazidime. The initial treatment was mainly supportive, and he required minimal ventilatory and oxygen support for the first 4 hospital days (HD). On HD 5, when his respiratory support was unable to be weaned and chest radiograph began to show worsening pulmonary disease (Fig 1), dexamethasone 0.15 mg/kg/day was initiated. On HD 6, he required significantly increased oxygen needs from 23% to 40% FiO2, so remdesivir (2.5 mg/kg loading dose then 1.25 mg/kg/day maintenance dose) was started for treatment of hypoxic respiratory failure from COVID-19 pneumonia. Recommendations on the dosing for remdesivir were extrapolated on the basis of the most recent National Institutes of Health (NIH) guidelines at that time for children weighing 3.5 to 30 kg.6 On HD 9, he had a fever to 38.3°C and tachycardia, prompting repeat cultures. Later that day he was found to have a right-sided pneumothorax, requiring stabilization with chest tube decompression and transition to high-frequency oscillatory ventilation.
Series of chest radiographs showing progression of pulmonary disease in case 1. A, HD 1. Streaky, perihilar infiltrates with prominent bronchovascular markings. B, HD 6. Multifocal pneumonia with interstitial airspace opacities in the upper lobes. C, HD 13. Extensive infiltrates, especially in the upper lobes and the right lower lobe. D, HD 26. Postextubation, improvement in bilateral airspace opacities.
Series of chest radiographs showing progression of pulmonary disease in case 1. A, HD 1. Streaky, perihilar infiltrates with prominent bronchovascular markings. B, HD 6. Multifocal pneumonia with interstitial airspace opacities in the upper lobes. C, HD 13. Extensive infiltrates, especially in the upper lobes and the right lower lobe. D, HD 26. Postextubation, improvement in bilateral airspace opacities.
His repeat urine culture on HD 9 grew 30 000 to 49 000 colony-forming units of Enterococcus faecalis, and he was treated with ampicillin for another 7-day course of antibiotics. The patient continued to require significant respiratory support (75% to 85% FiO2 and 12 to 15 cmH2O mean airway pressure on high-frequency oscillatory ventilation) and remained in hypoxic respiratory failure despite substantial improvement of the pneumothorax. At this time, his pulmonary presentation was attributed mostly to COVID-19 pneumonia given his worsening interstitial opacities, rather than complications from the resolving pneumothorax. On HD 14, he was treated with 1 single dose (12 mg/kg) of tocilizumab given his severe and persistent COVID-19 pneumonia. The dosing for tocilizumab was based on the typical dose of tocilizumab used to treat systemic juvenile idiopathic arthritis, which is also the same dosing recommendation from the NIH guidelines.6,7
He subsequently showed gradual improvement. He completed a 10-day course of dexamethasone from HD 5 to 14 before transitioning to an additional 8-day taper and completed a 10-day course of remdesivir from HD 6 to 15. He was extubated on HD 23 and ultimately weaned to room air on HD 34 (Fig 2). His complete blood count, transaminases, and creatinine were monitored throughout and after treatment with remdesivir and tocilizumab. There were no significant deviations from baseline (Supplemental Table 1). He was discharged from the hospital on HD 42 on room air and feeding by mouth.
Timeline of the clinical course for case 1. Medications are listed above timeline and respiratory support changes are listed below timeline. Legend indicates fraction of inspired oxygen. HFOV, high-frequency oscillatory ventilation; SIMV, synchronized intermittent mandatory ventilation; NC-IMV, nasal cannula intermittent mandatory ventilation.
Timeline of the clinical course for case 1. Medications are listed above timeline and respiratory support changes are listed below timeline. Legend indicates fraction of inspired oxygen. HFOV, high-frequency oscillatory ventilation; SIMV, synchronized intermittent mandatory ventilation; NC-IMV, nasal cannula intermittent mandatory ventilation.
Case 2
Case 1’s twin sister, who was also a 6-week-old former 30 weeks’ gestation infant, had presented to the emergency department 2 days before case 1’s admission after a period of lethargy, perioral cyanosis, and multiple apneic episodes witnessed at home. On admission, she was noted to be hypothermic to 35°C and hypoxic with 86% oxygen saturation. She was intubated in the NICU for apnea. She had received oxygen via nasal cannula initially during her birth hospitalization but had been on room air for 4 weeks before discharge home.
Her blood, urine, cerebrospinal fluid cultures were negative. Her nasopharyngeal swab was positive by reverse transcriptase polymerase chain reaction for SARS-CoV-2. Her initial treatment was also supportive given minimal evidence of pulmonary disease. She initially had no supplemental oxygen requirement; however, on HD 4 to 8, she required increasing FiO2 to 25% to 35% and imaging showed evidence of progressive lung involvement (Fig 3). On HD 6, she was started on dexamethasone given evidence of worsening lung parenchymal disease clinically and on imaging. On HD 7, treatment with remdesivir was started. The dosing of both were the same as in Case 1. This patient completed a 10-day course of dexamethasone and a 5-day course of remdesivir. She was weaned and extubated to intermittent mechanical ventilation via nasal cannula on HD 11 and weaned to room air on HD 19 (Fig 4). She was discharged from the hospital on room air and was taking formula by mouth on HD 21. She did not exhibit any signs of hepatic or renal dysfunction (Supplemental Table 2).
Series of chest radiographs showing progression of pulmonary disease in case 2. A, HD 0. Adequate aeration with mild interstitial prominence, bilaterally. Right upper lobe atelectasis. B, HD 4. Extensive interstitial opacities throughout the lungs with increased bibasilar opacities. C, HD 7. Persistent bilateral pulmonary opacities, decreased from prior. D, HD 12. Markedly improved interstitial lung disease.
Series of chest radiographs showing progression of pulmonary disease in case 2. A, HD 0. Adequate aeration with mild interstitial prominence, bilaterally. Right upper lobe atelectasis. B, HD 4. Extensive interstitial opacities throughout the lungs with increased bibasilar opacities. C, HD 7. Persistent bilateral pulmonary opacities, decreased from prior. D, HD 12. Markedly improved interstitial lung disease.
Discussion
The COVID-19 pandemic has struck the world with significant morbidity and mortality. Although children represent a minor proportion of COVID-19-associated hospitalizations in the overall population, the rate of hospitalization and severity of illness have significantly increased in infants and children during the Omicron-predominant period.8,9 There are no randomized controlled trials conducted in children on the treatment of COVID-19 infection. Treatment recommendations from the NIH have been proposed on the basis of adult studies.6 Antiviral agents such as remdesivir and immunomodulator agents such as tocilizumab have shown some success in reducing time to recovery and length of stay in adults.4,5
Until recently, remdesivir was only available under EUA for pediatric populations weighing 3.5 kg to <40 kg or those <12 years of age weighing at least 3.5 kg with positive SARS-CoV-2 who are either hospitalized or nonhospitalized at high risk for progression to severe COVID-19.10,11 A large case series of pediatric use of remdesivir including 12 patients <1 year old showed promising recovery with minimal adverse events.12 The most common side effects were elevated transaminases and creatinine level.13 There also have been reported cases of sinus bradycardia noted in children who received remdesivir, but generally it has been tolerated well with a low incidence of serious adverse events in children.14 As of April 25, 2022, the FDA approved remdesivir for use in pediatric patients who are at least 28 days of age and 3 kg, based in part on interim safety and efficacy data from an ongoing Phase 2 and 3 single-arm, open-label pediatric trial of remdesivir.15
Tocilizumab is an anti-interleukin-6 receptor monoclonal antibody used to treat systemic rheumatic diseases in children, such as systemic juvenile idiopathic arthritis and cytokine storms, by alleviating hyperinflammation. Tocilizumab has an EUA approval for hospitalized adults and children at least 2 years of age with severe COVID-19.16 Several randomized controlled trials in adults have shown modest but inconsistent clinical improvement with tocilizumab.17–19 Unfortunately, there are no dedicated trials in pediatric patients. Therefore, there is insufficient evidence to recommend for or against tocilizumab use in children with COVID-19 according to the NIH guidelines.6 However, the safety profile of tocilizumab in children, including children <2 years old, has been shown to be consistent with adults in previous studies, which included rare side effects of neutropenia, thrombocytopenia, hepatotoxicity, increased risk of serious infection, and intestinal perforation.7,20 On the basis of tocilizumab’s immunomodulatory property and safety observed in pediatric rheumatology patients, tocilizumab has been clinically used to treat children with severe COVID-19 and related multisystem inflammatory syndrome in children.21,22
Our 2 cases had apnea as the presenting symptom for their SARS-CoV-2 infection and subsequently developed severe COVID-19 pneumonia 5 to 7 days after initial presentation. Given their worsening illness, we treated both cases with dexamethasone and remdesivir and observed significant improvement in case 2. For case 1, his persistent and severe hypoxic respiratory failure prompted us to provide escalation of therapy with tocilizumab. At that time, we assessed his mortality risk from hypoxic respiratory failure to exceed the potential risks of treatment with tocilizumab. The risk of the FDA black box warning of serious infections from the immunomodulatory properties of tocilizumab were believed to be relatively low. We conducted a careful review of benefits and risks with pediatric infectious disease and rheumatology specialists and obtained informed consent from parents before administering tocilizumab. Although it is not possible to ascertain a causal relationship from this report, he did show gradual improvement after receiving tocilizumab. Rosas et al reported on adult patients who were treated with tocilizumab for severe COVID-19 and 22% of the patients did receive a second dose of tocilizumab. Interestingly, the patients who received a second dose had poorer clinical outcomes, likely because of selection bias as those who were sicker were more likely to receive an additional dose.18 There is insufficient data for NIH guidelines to recommend for or against a second dose of tocilizumab, but we would have considered a second dose for case 1 if the patient showed evidence of clinical worsening (sustained fevers, increasing inflammatory markers, or worsening respiratory status) had the putative immunomodulatory effects of the medication waned.6
Blood counts and hepatic and renal functions were monitored closely. Both cases had mild transient elevation of aspartate aminotransferase on day 2 to 3 of remdesivir treatment (<100 IU/L), which resolved within 1 to 2 days. There was no evidence of bone marrow suppression observed with either remdesivir or tocilizumab. No secondary infections were observed in our case 1 patient after receiving tocilizumab.
Although additional data and clinical trials are needed to fully establish the safety and efficacy of remdesivir and tocilizumab in infants, we believe the absence of significant adverse events and the improvement in disease that we observed in these 2 cases have important implications for their potential expanded use in younger children and infants. We encourage a thorough risk-benefit analysis for each specific case in considering use of remdesivir and tocilizumab with severe COVID-19.
Drs Bihm and Huang contributed to the conception and design of the report, reviewed the case data, drafted the initial manuscript, and revised the manuscript, figures, and citations during the writing process; Drs Yi, Posch, Brown, and Lai contributed to the conception and design of the report, critically reviewed, and revised the manuscript for important intellectual content throughout the writing process; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLOSURES: The authors have no conflicts of interest relevant to this article to disclose.
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