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Instructive Cases

Neonates With SARS-CoV-2 Infection and Pulmonary Disease Safely Treated With Remdesivir

Saikia, Bedangshu FRCPCH*; Tang, Julian FRCPath; Robinson, Simon FRCPCH*; Nichani, Sanjiv FRCPCH*; Lawman, Kelly-Beth MRCPCH*; Katre, Mahesh MRCPCH*; Bandi, Srini FRCPCH*

Author Information
The Pediatric Infectious Disease Journal: May 2021 - Volume 40 - Issue 5 - p e194-e196
doi: 10.1097/INF.0000000000003081

Abstract

The British Paediatric Surveillance Unit recently published their data on Neonatal SARS-CoV-2 infection in the United Kingdom and noted that while it is not uncommon, severe disease is rare.1 This is unlike the lower respiratory tract infection (LRTI) caused by the seasonal winter viruses.2 In the United Kingdom, respiratory syncytial virus (RSV) is the most common winter virus and is responsible for 75%–80% of all LRTI in young children. RSV LRTIm is usually mild but may cause severe disease in vulnerable infants; premature infants are at highest risk of serious RSV disease.2

Two premature neonates presented to pediatric intensive care unit at Leicester Children’s Hospital, United Kingdom, and both required intubation and mechanical ventilation for persistent apneas. Both tested positive for SARS-CoV-2 RNA and met the criteria for RDV treatment under the Emergency Use Authorization.3,4

Pulmonary disease due to COVID-19 may be more severe in premature neonates and, therefore, early treatment with RDV may be beneficial.

CASE 1

First case was born at 31/40 (corrected 37/40 weeks), weighed 2.7 kg and had been home for 1 week before admission. No other comorbidities were present. He presented to the emergency department with 1-day history of reduced feeds, bluish discoloration of extremities and apneas. A trial of CPAP delivered noninvasively was unsuccessful, and he required intubation within 1 hour of admission to pediatric intensive care unit.

A full sepsis screen was performed, including CSF testing. He was started empirically on intravenous (IV) triple antibiotics (cefotaxime, amoxicillin, and gentamicin) and acyclovir. The admission nasopharyngeal aspirate (NPA) was positive for SARS-CoV-2 RNA, while the extended respiratory viral PCR screen was negative. A bronchoalveolar lavage (BAL) confirmed the same results. The antibiotics were stopped after 3 days following negative cultures from all sources.

CSF viral PCR screen was only positive for Human herpesvirus 6—although it was not considered to be clinically significant, decision was taken to switch to ganciclovir from acyclovir while waiting for blood viral load.

His admission chest radiograph (CXR) was normal and mechanical ventilatory support was minimal without the need for supplemental oxygen. He was extubated on day 4. However, within 2 hours of extubation, he was reintubated for repeated apneas. MRI brain performed on day 5 did not show any evidence of neuroCOVID disease.5

His NPA remained positive for SARS-CoV-2 RNA. From day 6 onwards, his respiratory support requirement escalated with increasing oxygen demand. His serial CXRs were suggestive of progressive bilateral consolidation. His maximum ventilator settings were peak inspiratory pressure 24, positive end-expiratory pressure 8, and fraction of inspired oxygen (FiO2m) 0.5. He was commenced on hydrocortisone (0.5 mg/kg/d) on day 7 and completed a 10-day course. An ECHO conducted on day 8 revealed mild pericardial effusion, a follow-up ECHO after a week was normal.

Following multidisciplinary team discussions, RDV was considered on compassionate grounds and commenced on day 11 and completed a 5-day course (2.5 mg/kg loading on day 1 followed by 1.25 mg/kg once daily on days 2–5). We observed a dramatic improvement with reduction in the ventilatory and oxygen requirements after 2 days of RDV treatment. By the end of day 13, he was successfully extubated and breathing remained stable.

His SARS-CoV-2 RNA PCR became negative only after completion of treatment with RDV.

Family members were also screened for SARS-CoV-2 infection and his father was found to be positive from a combined nasal and throat swab.

CASE 2

The second case describes an ex 33/40, corrected to 35+2-week neonate at admission. He was born small for gestational age (birth weight 1.5 kg) and was at home for 1 week before admission. He presented to the emergency department with 1-day history of reduced feeds and lethargy; he was found to be hypothermic with repeated apneic episodes.

A full sepsis screen was sent including CSF analysis, and he was commenced on empiric triple antibiotics and acyclovir. He was intubated shortly after admission. The admission NPA was positive for SARS-CoV-2 RNA PCR. An extended respiratory viral PCR screen was negative for other viruses; the BAL confirmed similar results. His ventilator settings were minimal throughout, apart from a need for oxygen to maintain saturations >92%—maximal settings were peak inspiratory pressure 12, positive end-expiratory pressure 5, and maximum FiO2 of 0.4. His CXR performed following intubation was grossly normal.

The consensus from a multidisciplinary team meeting was that this patient would benefit from early treatment with RDV, and he was started on this from day 4—a similar dosing schedule to case 1 was used. He was also started on dexamethasone 150 µg/kg once daily on the same day.

The patient was extubated later the same day to high-flow nasal cannula therapy, 2 L/kg and with an FiO2 of 0.25. The high-flow therapy was weaned to low-flow nasal cannula oxygen support, 1 L/min—he came off oxygen by the next morning. An ECHO performed on day 3 was normal.

His SARS-CoV-2 RNA PCR became negative 2 days after treatment with RDV (day 6). He was given RDV for a total of 4 days and steroids for a total of 7 days. He was discharged home on day 9.

Both parents were found to be positive for SARS-CoV-2 RNA PCR from nasal and throat swabs.

Table 1 shows maximum values of blood parameters for both patients. Table 2 shows serial measurements of renal and liver function tests pre- and post-RDV treatment for both patients.

TABLE 1. - Maximum Values of Blood Parameters for Both Patients During the Course of the Hospital Admission
Blood Parameters (Normal Range) Case 1 Case 2
White cell count (6–17.5 × 10*9/L) 17.5 11.4
Neutrophil (1–8.5 × 10*9/L) 11.38 2.61
Lymphocyte (4–13.5 × 10*9/L) 4.2 7.58
C reactive protein (0–10 mg/L) 50 23
Lactate dehydrogenase (180–430 IU/L) 1271 347
Serum ferritin (23–540 μg/L) 1369 486
D-dimer (<0.5 μg/mL FEU) 1.35 1.04
Troponin I (ng/L) 31 116.2
Procalcitonin (ng/mL) <0.5 <0.5
NT-Pro BNP (<400 ng/L) 7097 NT
Interleukin 6 (pg/mL) 42.3 NT
BNP indicates B-type natriuretic peptide; FEU, fibrinogen equivalent units; NT, not tested.

TABLE 2. - Serial Renal and Liver Function Tests Pre- and Post-RDV Initiation for Case 1 and Case 2
Parameters
(Normal Range)
Patient Pre-RDV RDV
Day 1
RDV
Day 2
RDV
Day 4
RDV
Day 5
Urea
(0.8–5.5 mmol/L)
Case 1 3.1 2.6 3.2 4.5 2.9
Case 2 3.2 2.8 1.9 2.7 3.3
Creatinine
(15–21 μmol/L)
Case 1 20 20 21 21 20
Case 2 28 29 27 21 20
ALT
(5–100 IU/L)
Case 1 43 51 46 35 34
Case 2 20 23 25 40 45
AST
(2–53 IU/L)
Case 1 86 NT NT 27 41
Case 2 43 130 158 162 NT
ALP
(163–427 IU/L)
Case 1 316 NT NT 307 327
Case 2 151 NT 130 158 162
Total bilirubin
(0–21 μmol/L)
Case 1 3 3 2 2 2
Case 2 52 36 30 33 31
ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; NT indicates not tested; RDV, remdesivir

Timeline of significant events for case 1 (see Figure, Supplemental Digital 1A, http://links.lww.com/INF/E308) and worst CXR for case 1 before the treatment with RDV (see Figure, Supplemental Digital 1B, http://links.lww.com/INF/E309).

DISCUSSION

Apnea is a common presentation in infants with bronchiolitis. Close to 25% of infants with RSV bronchiolitis present with apneas; however, non-RSV bronchiolitis presents with apneas in about 5% of infants.6 Prematurity, younger corrected age (<2 weeks) and low birth weight (<2.3 kg) have been shown to be associated with a greater incidence of apneas.6 They detail that apneas can be the first presentation before further deterioration or resolve spontaneously.6,7 The exact mechanism by which apnea is produced in bronchiolitis is not clear, but it is likely that an increase in mucous secretions and inflammation of the airways leads to obstructive apneas in young infants.8 Facilitated release of GABA and its relationship to central apneas is described following infection, along with stimulation of laryngeal chemoreceptors.8

We believe SARS-CoV-2 infection is the likely reason for the persistent apneas in both our neonates requiring intubation and mechanical ventilation. Pulmonary disease progression in case 1 matches with the described pathophysiology of SARS-CoV-2 disease in adults.9 Following the commencement of RDV, there was with a significant reduction in the required respiratory support.

Frauenfelder et al,9 from the United Kingdom, recently reported about their experience with an expremature infant with SARS-CoV-2 infection and severe pulmonary disease. With report of a similar case9 and our own experience from case 1, we as a multidisciplinary team agreed that case 2 would benefit from RDV therapy to be started early in the course to prevent progression to potentially severe pulmonary disease. This patient was also born small for gestational age, which we considered as an additional risk factor.5,6 Case 2 was extubated on day 1 of RDV treatment and the NPA became negative for SARS-CoV-2 PCR by day 3 of RDV treatment.

In both our patients, we did not observe any RDV-related adverse drug reactions (derangement in renal or liver function) or infusion-related reactions (tachy-bradycardia, hypo-hypertension, hypoxia, fever, wheeze, angioedema, rash, nausea, and shivering) as detailed in the literature.3 After initiating RDV therapy, respiratory secretions were sent on day 1, 3, and 5 to monitor treatment response, i.e., the clearance of SARS-CoV-2 from the respiratory tract, using endotracheal aspirates while intubated and NPAs postextubation. It is difficult to say whether steroid use provided any benefit in this unique population and may possibly have enhanced viral replication.

Based on this experience, to expedite the overall process of treatment with RDV, our team has developed guidance on use of RDV across all pediatric age groups (<12 years of age)—this includes indication, dosage, compassionate procurement process together with monitoring instructions while on and after completion of therapy.

In conclusion, premature infants are a high-risk and vulnerable patient group, and SARS-CoV-2 infection needs are excluded if they become unwell and present to hospital. Early RDV therapy may be beneficial and should be considered if SARS-CoV-2-infected, along with other standard supportive measures.

REFERENCES

1. Gale C, Quigley MA, Placzek A, et al. Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance [published online ahead of print November 9, 2020]. Lancet Child Adolesc Health. doi: 10.1016/S2352-4642(20)30342-4.
2. Palivizumab passive immunisation against respiratory syncytial virus (RSV) in at-risk pre-term infants. 2020. Available from: https://www.england.nhs.uk/wp-content/uploads/2020/10/C0803_i_Rapid-policy-statement-re-Palivizumab-RSV_Oct-2020.pdf. Accessed December 01, 2020.
3. Fact sheet for healthcare providers emergency use authorization (EUA) of veklury® (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg. 2020. Available from: https://www.fda.gov/media/137566/download. Accessed November 15, 2020.
4. U.S. Food & Drug Administration. Coronavirus (COVID-19) update: FDA authorizes drug combination for treatment of COVID-19. 2020. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19. Accessed November 15, 2020.
5. Anzalone N, Castellano A, Scotti R, et al. Multifocal laminar cortical brain lesions: a consistent MRI finding in neuro-COVID-19 patients. J Neurol. 2020; ;267:2806–2809.
6. Mahant S, Parkin PC. Apnea in bronchiolitis: challenges of studying an uncommon complication of a common condition. J Pediatr. 2016; 177:11–12.
7. Bush A, Thomson AH. Acute bronchiolitis. BMJ. 2007; 335:1037–1041.
8. Ramos-Fernandez JM, Moreno-Perez D, Gutierrez Bedmar M, et al. Apnoea in infants with bronchiolitis: incidence and risk factors for a prediction model. An Pediatr (Barc). 2018; 88:160–166.
9. Frauenfelder C, Brierley J, Whittaker E, et al. Infant with SARS-CoV-2 infection causing severe lung disease treated with remdesivir. Pediatrics. 2020; 146:e20201701.
Keywords:

prematurity; neonates; COVID-19; SARS-CoV-2; remdesivir

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