Infant With SARS-CoV-2 InfectionCausing Severe Lung Disease TreatedWith RemdesivirClaire Frauenfelder, MBBS, MSurg,a,b Joe Brierley, MBChB, FRCPCH, FFICM,a Elizabeth Whittaker, MRCPCH, DTM&H, PhD,c

Giulia Perucca, MD,a Alasdair Bamford, MRCPCH, DTM&H, PhDa,d

abstractWe describe an ex-premature infant presenting with severe acute respiratorysyndrome coronavirus 2 infection in the fifth week of life. In current reports,researchers indicate that acute symptomatic severe acute respiratorysyndrome coronavirus 2 infection is relatively rare and much less severe thanin adults. This case highlights that infection can be associated with life-threatening pulmonary disease in young infants and that infection can followa similar disease course to that described in adults. We provide first data onthe use of the novel antiviral remdesivir in a young child and an innovativeapproach to expedited approval from a multidisciplinary clinical team andbioethics committee for compassionate access to the drug.

During the coronavirus disease2019 (COVID-19) pandemic, fewchildren have been infected, and thoseaffected have had a typically mildercourse than adults.1–8 We describe anex-premature infant who presentedwith severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2)infection in the fifth week of life. Hisclinical course differs from otherreported pediatric cases showing onlymild respiratory systeminvolvement.5,8 Severe respiratorydistress developed in a short timeframe, following severe airwaycompromise due to significant glotticswelling. Although his conditioninitially improved, severe acuterespiratory distress syndrome (ARDS)developed at the time prophylacticsteroids were given to prepare forextubation. High-frequency oscillatoryventilation, nitric oxide, andintermittent prone positioning werethen required, and after the use of theantiviral agent remdesivir, he madea full recovery before being dischargedfrom the hospital.

CASE REPORT

The patient is a twin born at 32 16 weeks for maternal preeclampsiawith a small atrial septal defect (,4mm) and cleft palate. He was intubatedat birth before weaning off respiratorysupport within a week. At 37 1 3weeks’ corrected gestational age, hedeveloped respiratory distress at homeand presented to the hospital. Of note,he had been in recent contact with bothfamily members and asymptomatichealth care workers, who subsequentlydeveloped symptoms and wereconfirmed to have SARS-CoV-2infection.

In the emergency department,progressive hypoxia led to severalfailed attempts at intubation.Nasopharyngeal aspirate SARS-CoV-2RNA polymerase chain reaction (PCR)result was positive (cycle threshold 20).Oxygenation and ventilation weremaintained via laryngeal mask duringtransfer to a quaternary center forotolaryngological input. He wassuccessfully intubated in theater via

aGreat Ormond Street Hospital for Children National HealthService Foundation Trust, London, United Kingdom; bDivisionof Surgery, Adelaide Medical School, The University ofAdelaide, Adelaide, South Australia; cDepartment ofPaediatric Infectious Diseases, Imperial College HealthcareNational Health Service Trust, London, United Kingdom; anddUniversity College London Great Ormond Street Institute ofChild Health, London, United Kingdom

Drs Frauenfelder, Brierley, and Bamfordconceptualized and designed the study, collated thepatient data, drafted the initial manuscript, andreviewed and revised the manuscript; Drs Peruccaand Whittaker collected data, revised radiologic andinfectious disease aspects of the data presented,respectively, and critically reviewed and revised themanuscript; and all authors approved the finalmanuscript as submitted and agree to beaccountable for all aspects of the work.

DOI: https://doi.org/10.1542/peds.2020-1701

Accepted for publication Jun 12, 2020

Address correspondence to Alasdair Bamford,MRCPCH, DTM&H, PhD, Department of PaediatricInfectious Diseases, Great Ormond Street Hospitalfor Children NHS Foundation Trust, Great Ormond St,London WC1N 3JH, United Kingdom.E-mail: a.bamford@ucl.ac.uk

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,1098-4275).

Copyright © 2020 by the American Academy ofPediatrics

FINANCIAL DISCLOSURE: The authors have indicatedthey have no financial relationships relevant to thisarticle to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors haveindicated they have no potential conflicts of interestto disclose.

To cite: Frauenfelder C, Brierley J, Whittaker E,et al. Infant With SARS-CoV-2 Infection CausingSevere Lung Disease Treated With Remdesivir.Pediatrics. 2020;146(3):e20201701

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microlaryngobronchoscopy by usingappropriate personal protectiveequipment for all personnel.9

Significant glottic swelling andcopious airway secretions were noted(Fig 1).

Initial moderate ventilatory pressuresand fraction of inspired oxygen of 0.6were weaned over 3 days. An initialchest radiograph revealed mildbilateral ground-glass opacities(Fig 2). C-reactive protein was42 mg/L, and the patient waslymphopenic (1.45 3 109/L) with anotherwise normal blood picture(Fig 3). Serial tracheal aspirates,urine, and stool cultures excludedbacterial or fungal coinfection. A line-associated femoral arterial thrombuswas treated with therapeuticanticoagulation.

After several days of laryngeal rest,ventilation parameters had improvedand he was suitable for a trial ofextubation. The multidisciplinaryteam decided to use usualprophylactic steroids to optimizelaryngeal conditions for extubation,particularly considering the difficultintubation. Two prophylacticdexamethasone doses were given.

Before extubation, the patientdeteriorated, developing fulminantARDS with corresponding worseningof chest radiograph findings (Fig 2).

He could no longer be managed withconventional ventilation and requiredhigh-frequency oscillatory ventilation,nitric oxide, prone ventilation, andinotropic support to maintainoxygenation and ventilation.Extracorporeal membraneoxygenation was considered but notrequired. Possible secondarybacterial infection was treated withbroad-spectrum antibiotics andexcluded by bronchoalveolar lavageby using strict personal protectiveequipment precautions.

Given the life-threateningdeterioration, an urgentmultidisciplinary meeting was held,followed by an innovative therapyreview with the bioethics team andparents via video link.10 Becausethere was limited evidence forhyperinflammation (interleukin6 ,50 pg/mL; ferritin 411 mg/L),antiviral therapy was preferred toimmunomodulation. A compassionateaccess application for remdesivir wasagreed on and was granted.11,12

An intravenous loading dose of5 mg/kg remdesivir was given,followed by 1.25 mg/kg maintenancedose for 10 days. Interleukin 10 wasraised (110 pg/mL) but normalizedby day 5 of treatment. C-reactiveprotein peaked at 63 mg/L on day 6,ferritin 789 mg/L on day 9, andD-dimer 1143 mg/L on day 10.

Initially positive SARS-CoV-2 RNAPCR tracheal aspirates becamenegative after 5 days of treatmentwith remdesivir, excluding an isolatedpositive result on day 10 ofremdesivir. No drug toxicity wasobserved.

The highest troponin was 138 ng/L.There were no clinical orechocardiographic signs ofmyocarditis. An echocardiogram onday 7 of illness revealed only a smallpatent foramen ovale with left-to-right shunt, mild dilation left sidestructures, and mild mitralregurgitation.

Ventilatory and inotropic supportwere weaned, and extubation wassuccessful on day 18 of illness (Fig 4).He has been discharged from thehospital.

DISCUSSION

We describe the clinical course of aninfant with SARS-CoV-2 infectioncausing severe airway inflammationand ARDS who improved aftertreatment with the novel antiviralremdesivir.

SARS-CoV-2 Infection in Infants andNeonates

No clear explanation has been foundas to the different severities of SARS-CoV-2 infection in children andadults.13 A low proportion of thoseinfected have been children, and evenfewer have been younginfants.1,7,8,14–17 In a large Chineseseries of 2143 pediatric patients,researchers found ,6% of SARS-CoV-2 infected children developedhypoxia, and ,1% progressed toARDS.4 A Spanish group reportedonly 4 of 41 SARS-CoV-2 infectedchildren (9.7%) required supportbeyond nasal prongs, and onlya single patient was intubated.6 In anearly study reporting infectionepidemiology in New York,researchers reported fewer than 1%of admissions were children, andnone required intensive care.18

FIGURE 1Operative photographs of airway swelling. A, Glottis with grossly swollen vocal folds. B, Trachea withmoderate inflammation and copious distal airway secretions.

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Airway Manifestation in This Infant

Cellular composition of airwayepithelium is similar betweenchildren and adults, and new researchindicates little difference in thetranscription of genes associated withSARS-CoV-2 infection in airwayepithelium between children andadults.19 In a large systematic reviewof upper airway symptoms observedduring the COVID-19 pandemic,researchers did not report stridor andairway compromise as features ofSARS-CoV-2 infection.20

Previous studies comparing ARDS inadults and children indicate different

phenotypical disease courses.21 Thischild was on the transition ofneonatal22 to pediatric ARDS23 at2.2 kg and 37 weeks’ correctedgestational age; however, aftersecondary lung deterioration, all age-specific ARDS definitions werefulfilled. His treatment responseinterestingly mapped adult ARDS byimproving with prone ventilation butonly moderately with nitric oxide.

Use of Corticosteroids

Large-scale systematic reviews haverevealed benefit in reducingpostextubation stridor and somereduction in reintubation rates

especially in those with high-riskairways or airway abnormalties.24–27

In early literature, researchersrecommend against the use ofcorticosteroids for treatment of SARS-CoV-2 infection unless for otherindications because of concerns aboutblunting the inflammatory responseto viral infection and previous studiesof similar viral infections suggestingimpaired viral clearance andincreased mortality.28,29 Because ofthe severity of glottic swelling seen atpresentation and the extremedifficulty intubating the child, thehighest risk was felt to be fromairway swelling, so corticosteroids

FIGURE 2Chest radiographs performed. A, Performed on day 2. B, Performed on day 5. C, Performed on day 6. Initially, only mild bilateral ground-glass opacitieswere present. Subsequent radiologic worsening is noted with progressive airspace opacification (day 5) and bilateral consolidation with predominantperipheral distribution, lung overinflation, and right basal pneumothorax (day 6).

FIGURE 3Patient results. Shown are the laboratory values including SARS-CoV-2 RNA PCR results throughout admission. Remdesivir treatment was prescribed fromday 7 to 17. Alb, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; Bili, bilirubin; CRP, C-reactive protein; Eos, eosinophils; Hb, hemoglobin;IFN-g, interferon-g; IL, interleukin; Lymph, lymphocytes; TNF-a, tumor necrosis factor a; WBC, white blood cell; -, no test performed.

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were administered in preparation forextubation.

Given the adult phenotype severepneumonitis with initialimprovement and then deteriorationin SARS-CoV-2 infection, it is unclearif this patient followed the adultpattern of delayed severe diseasetransition described by Gattinoniet al30 or if administration of steroidsaltered his disease course.

Radiologic Findings

Ground-glass opacification witha bilateral peripheral distribution isthe most common finding in COVID-19 and is mainly based on computedtomography experience in adults.31

Other findings, such as septalthickening and bronchiectasis mayappear later on with diseaseprogression, although pneumothoraxis uncommon, but is described inlater stages.31 Similar but milderchanges are described in children,31

but computed tomographic scanningis reserved for specific indications(eg, immunocompromised patients,atypical presentations).32 Chestradiographs may be completelyunremarkable in less severe cases.The parenchymal findings seen in ourpatient’s radiographs are particularlyprominent considering the age of thechild but are consistent with thecommon description in the literatureof ground-glass opacification andconsolidation.

Cardiac Involvement

In adults, a history of cardiovasculardisease has been associated withhigher morbidity and mortality fromSARS-CoV-2 infection, particularly inelderly patients.33 In total, 20% to30% of patients with severe infectiondeveloped infection-relatedmyocarditis and acute ischemicmyocardial injury during ARDS,characterized by elevated troponin.34

This patient’s troponin was mildlyelevated throughout the illness,peaking at 138 ng/L on day 10;however, no clinical signs ofmyocarditis or cardiac failure wereapparent. Echocardiography duringthis admission revealed no residualatrial septal defect. Although therewas some left-to-right shunting viaa patent foramen ovale, it was felt hiscardiac anatomy did not play a role inthe severity of his illness or hissusceptibility to infection.

Remdesivir

Remdesivir (GS-5734) is a nucleotideanalogue with broad-spectrumantiviral activity against several RNAviruses developed after theemergence of Ebola by GileadSciences, Inc. It is a 19-cyano-substituted adenosine nucleotideanalogue prodrug. In animal models,remdesivir has demonstrated in vitroand in vivo activity against othercoronavirus strains (severe acuterespiratory syndrome coronavirus 1and Middle East respiratory

syndrome coronavirus) by inhibitingreplication.35 Before the COVID-19pandemic, it has been used in thetreatment of Ebola.28,36 There isa report of a neonate infected withEbola-infected being treated withremdesivir and surviving.37 In vitrostudies of remdesivir havedemonstrated effective SARS-CoV-2inhibition.11 Early use in humans withSARS-CoV-2 has been promising.38

Currently, there are 2 phase 3 trialsbeing conducted to investigate theefficacy and safety of remdesivir inmoderate COVID-19 in adults andchildren .12 years, weighing .40 kg(www.clinicaltrials.gov; identifierNCT04292730) and severe COVID-19infection in adults (www.clinicaltrials.gov; identifier NCT04257656). Todate, there are no published reportsof children with COVID-19 treatedwith remdesivir. It is not possible ina single case report to determine thecontribution of remdesivir to clinicalrecovery; however, it is noteworthythat it was well tolerated.

Compassionate Access

In view of this patient’s diseaseseverity, off-label remdesivir use wasproposed. Our institution developedand published39 a bespoke decision-making bioethics framework for suchsituations, involving children andtheir families.40 The case wasdiscussed at an urgentmultidisciplinary team includingintensive care, infectious diseases,

FIGURE 4Events and treatments during patient admission. This figure depicts respiratory support requirements, treatment with antiviral and antibacterial agents,and other significant medications. LMA, laryngeal mask airway; PC, pressure control; PS, pressure support; PSV, pressure support ventilation; SIMV,synchronized intermittent mandatory ventilation.

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virology, pharmacy, the bioethicsteam, and the parents. This processincludes a mandatory second opinionfrom another institution. A successfulcompassionate access application wasmade for remdesivir.41

CONCLUSIONS

This case highlights a positiveoutcome for a critically unwell infantwith SARS-CoV-2 infection. Thepatient’s illness was atypically severeand presentation with severe airwayobstruction was unusual comparedwith other adult or pediatric cases.We describe the intensive caremanagement and decision-makingprocess to treat with remdesivir viacompassionate access bioethicspathway. The infant toleratedremdesivir treatment withoutcomplication and was dischargedfrom the hospital. This informationprovides urgent first data to informthe treatment of children presentingwith SARS-CoV-2 disease as thepandemic affects children acrossthe globe.

ACKNOWLEDGMENTS

We thank the following colleagues fortheir input with the case study: GarthDixon, Caroline Dalton, KimberlyGilmore, Mark Gilchrist, Joe Standing,Louis Granjean, Delane Shingadia,Nele Alders, Karyn Moshal, JudithBreuer, members of the GreatOrmond Street Hospital ethicscommittee, and Gilead Sciences, Inc,for access to medication to treatthe child.

ABBREVIATIONS

ARDS: acute respiratory distresssyndrome

COVID-19: coronavirus disease2019

PCR: polymerase chain reactionSARS-CoV-2: severe acute respira-

tory syndromecoronavirus 2

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