Bernardi Stefania

Campana Andrea

Chiurchiu Sara

Ciofi Degli Atti Marta Luisa

D'Argenio Patrizia

Lombardi Mary Haywood

Romani Lorenza

Santilli Veronica

Scarselli Alessia

Villani A

English

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/APA.15465 This article is protected by copyright. All rights reservedDR. LORENZA  ROMANI (Orcid ID : 0000-0003-4195-6626)Article type      : Brief Report1 COVID-19 in Italian pediatric patients: the experience of a tertiary children’s hospital2 Lorenza Romani1*, Sara Chiurchiù1*, Veronica Santilli2, Stefania Bernardi2, Mary Haywood 3 Lombardi3, Alessia Scarselli3, Alberto Villani1, Marta Luisa Ciofi Degli Atti4, Andrea Campana3, 4 Patrizia D’Argenio25 * Contributed equally as co-first authors6 1 Pediatric and Infectious Diseases Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy7 2 Research Unit in Congenital and Perinatal Infections, Academic Department of Pediatrics 8 (DPUO), Division of Immunology and Infectious Diseases, Bambino Gesù Children's Hospital, 9 IRCCS, Rome, Italy10 3 Pediatrics, University Department of Pediatrics, Bambino Gesù Children’s Hospital, IRCCS, 11 Rome, Italy12 4 Unit of Clinical Epidemiology, Bambino Gesù Children’s Hospital, IRCCS Rome, Italy13 Short title14 SARS-CoV-2 infection in 43 Italian children15 Keyword16 Pediatrics, Sars - CoV - 2 infection, COVID-19, SARS-CoV-2 pneumonia17 Corresponding Author18 Lorenza Romani, MD19 Pediatric and Infectious Diseases Unit, Bambino Gesù Children Hospital, IRCCS20 Piazza Sant’Onofrio 4, 00165 Rome, Italy. 21 Phone +3906859308022 E-mail: lorenza.romani@opbg.netAccepted ArticleThis article is protected by copyright. All rights reserved23 Coronavirus disease (COVID-19) caused by the novel SARS-CoV-2 has spread worldwide since 24 its onset in Wuhan in December 2019. In Italy COVID-19 rapidly increased in February 2020 and 25 by 12 May 2020, 2.0 % of the confirmed cases were under 18 years and 3.7% of those had been 26 hospitalized (1). This case series report reviews the demographic characteristics, clinical course, 27 laboratory findings, radiologic features and treatment of children admitted with COVID-19 to a 28 tertiary care hospital in Italy. 2930 The study included the children with COVID-19 admitted between the March 15- May 6 2020 at 31 the Bambino Gesù Children’s Hospital. Diagnosis of SARS-CoV-2 infection was defined by the 32 detection of virus RNA through real-time polymerase chain reaction on naso-pharyngeal swab. 33 Family cluster was defined as the presence of a family member (mother, father, household) with 34 certain or suspected diagnosis of SARS—CoV-2 infection at the time of the admission in the 35 hospital. 36 The institutional ethics board approved the study and written, informed consent was provided by 37 the parents.   3839 In total 43 patients were identified with a median age of 7 years. Patients’ characteristics are 40 presented  in Table 1. Thirty-eight on forty-three children belonged to a family cluster. In 14/38 41 (37%) of cases the family member was a health care worker.  42 The symptoms at the admission are reported in Table 1.43  On 43 patients, 5 children (12%) developed new symptoms during hospitalization including: 44 respiratory symptoms requiring supplemental oxygen for three days in a 7 years-old-boy, mild 45 diarrhoea with spontaneous resolution of ileal thickening detected on ultrasound in a 12-years-old 46 girl, conjunctival hyperemia without SARS-CoV-2 detected on ocular surface in a 6 years-old-boy 47 and the hyperinflammatory syndrome in 15-and-14 years old boys. These two patients were 48 admitted with fever and cough at the onset of the disease; after two days and three weeks from the 49 admission respectively, they developed abdominal pain, diarrhoea, high fever associated to 50 lymphopenia, high levels of inflammatory indexes (C - reactive protein, ferritin, D-dimer) and a 51 progressive mild heart failure. The transfer to the PICU was necessary. The clinical course and 52 treatment of these two patients will not be discussed in this brief report.53 Patients laboratory findings at the admission are presented in Table 1.Accepted ArticleThis article is protected by copyright. All rights reserved54 During the hospitalization lymphopenia and neutropenia were observed in 16/43 (37%) and 11/43 55 (26%) of patients, respectively. The C-protein remained negative in 32/43 (74%) children.  56 Transient and self-limited thrombocytopenia (112 x 109/L) was detected in the child who 57 presented the respiratory deterioration, as described above. 58 The imaging was performed in 15/43 (35%) cases with suspected lower respiratory tract infections 59 (Table 1). Chest X ray was performed in 14/43 (33%) patients while only 5/43 (12%) children 60 were subjected to chest CT scan. In 2/43 (5%) children over the age of 12 years the CT scan 61 showed more extensive lung involvement than the X-ray, with ground glass opacities: one 62 monolateral and one bilateral. Brain magnetic resonance imaging identified pneumonia in a patient 63 without respiratory symptoms after afebrile seizures extended to the chest. 64 In our cohort ten patients were treated with different combination of medications (table 1). 65 Because of the co-administration of drugs that potentially could prolong QT, routine ECGs were 66 performed every 48-72 hours. In all these patients the QT interval remained in the normal range.67 A 15-years-old girl, affected by a connective tissue disorder in therapy with Hydroxychloroquine 68 (HCQ) and Mycophenolate, was treated with a combination of HCQ and lopinavir-ritonavir. We 69 observed bradycardia (HR 50-60 bpm) likely related to drug-drug interaction between the two 70 drugs (HCQ and lopinavir-ritonavir). The heart rate returned to the normal rate after 71 discontinuation of lopinavir-ritonavir. 7273 In general, our data suggest that SARS-CoV-2 infection in children may be mild or atypical 74 compared to adult patients, strengthening the hypothesis that pediatric cases may be 75 underdiagnosed and misdiagnosed. Multiple hypothesis have been proposed to justify the different 76 clinical presentation of COVID-19 between adults and children; still today there is no a univocal 77 explanation. Noteworthy, although a small percentage is reported, pediatric patients may develop a 78 hyperinflammatory syndrome that needs to be carefully evaluated for a prompt treatment. Notably, 79 adults have a much higher prevalence of increased C-reactive protein, suggesting a much milder 80 immunological response and less immune-mediated tissue damage in children (3).  In our study, 81 we did not find a correlation between the lymphocyte count and the course of the disease. One 82 asymptomatic child with COVID-19 had pneumonia, which suggests specific paediatric imaging 83 criteria so that lower respiratory tract infections are detected. The treatment strategy for children 84 with COVID-19 is based on adult experience. The combination therapy with azithromycin and 85 hydroxychloroquine is supported by the evidence, albeit of small size, that hydroxychloroquine Accepted ArticleThis article is protected by copyright. All rights reserved86 treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients 87 and that its effect is reinforced by azithromycin (4). Antiviral treatment has been used in only one 88 immunocompromised patient but data on its efficacy in children with COVID-19 are missing (2). 89 Pending on a pediatric clinical trial we included lopinavir-ritonavir in our guidelines.9091 In our experience, and according with the literature (5) although children are just as susceptible to 92 COVID-19 as adults, they appear to have a milder clinical course. We observed that the major 93 pattern of viral transmission was intra-family therefore the risk of family cluster transmission from 94 children harboring virus and the impact to community-based epidemic prevention should be taken 95 into consideration in policy making for epidemic control. 9697Accepted ArticleThis article is protected by copyright. All rights reserved98 FUNDING99 There is no funding source100101 CONFLICTS OF INTEREST102 We have no conflicts of interest 103104  105 References 106 1) Epicentro, Epidemiology for public health, Istituto Superiore di Sanità (ISS). Sorveglianza 107 Integrata COVID-19 in Italia. Update at 12th of May 2020- Available at:  108 https://www.epicentro.iss.it/coronavirus/109 2)  Ludvigsson JF (2020) Systematic review of COVID-19 in children shows milder cases and a 110 better prognosis than adults. Acta Paediatr. doi: 10.1111/apa.15270. 111 3) Qiu H, Wu J, Hong, L et al (2020) Clinical and epidemiological features of 36 children with 112 coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study.  Lancet 113 Infect Dis. doi: 10.1016/S1473-3099(20)30198-5114 4) Gautret P, Lagier JC, Parola P (2020) Hydroxychloroquine and azithromycin as a treatment of 115 COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. doi: 116 10.1016/j.ijantimicag.2020.105949117 5) Zhang C, Gu J, Chen Q, et al. Clinical and epidemiological characteristics of pediatric SARS-118 CoV-2 infections in China: A multicenter case series. PLoS Med. 2020 Jun; 17(6): e1003130. 119 Published online 2020 Jun 16. doi: 10.1371/journal.pmed.1003130Accepted Article This article is protected by copyright. All rights reserved Table 1 Demographic, Epidemiological and Clinical features on admission Characteristics Value n (%) Median age 7 years Range 8 days to 17 years < 1 month 4/43 (9) 1 month – 6 years 13/43 (30) 6-12 years 15/43 (35) ≥ 12 years 11/43 (26) Boys 24/43 (56) Epidemiological history  Contact with a confirmed/suspected case of COVID-19 38/43 (88) Related to a family cluster  38/43 (88) Family healthcare worker 14/38 (37) Underlying diseases  Previously healthy 33/43 (77) Neurological disorder 4/43 (9) Cardiovascular disease 1/43 (2) Other * 5/43 (12) Clinical symptoms n (%) Fever 27/43 (63) Cough 18/43 (42) Diarrhoea/vomiting 10/43 (23) Headache 7/43 (16) Accepted Article This article is protected by copyright. All rights reserved Dyspnoea 5/43 (12) Nasal congestion 5/43 (12) Arthralgia 4/43 (9) Myalgia 3/43 (7) Febrile seizure 2/43 (5) Sore throat 2/43 (5) Anosmia  2/43 (5) Abdominal pain 1/43 (2) Seizure  1/43 (2) Laboratory values Value Mediana (IQR) White blood cells (109/L) 6.56 (5.30-9.98) Lymphocytes (109/L) 2.66 (1.79-4.34) C- reactive protein (mg/dl) 0.08 (0.04-0.46) Radiological findings N (%) Chest X ray 14/43 (33) Interstizial abnormalities 11 Local patchy opacities 2 Bilateral patchy opacities 1 Chest Computer Tomografy  5/43 (12) Interstizial abnormalities, Local patchy opacities, Bilateral patchy opacities, Tree in bud 1 Ground glass opacity 2 Chest MRI  2/43 (5) Accepted Article This article is protected by copyright. All rights reserved Local patchy opacities, Ground glass opacity 1 Medication ** n (%) Hydroxychloroquine + Azithromycin  7/41 (17)  Hydroxychloroquine 2/41 (5) Hydroxychloroquine + lopinavir-ritonavir 1/41 (2) *(prematurity, neonatal respiratory distress, urogenital tract malformation)** the treatment of the two patients with the hyperinflammatory syndrome is not included Accepted Article

COVID-19 in Italian pediatric patients: the experience of a tertiary children's hospital

https://art.torvergata.it/bitstream/2108/317123/1/COVID-19%20in%20Italian%20pediatric%20patients%20the%20experience%20of%20a%20tertiary%20children%27s%20hospital.pdf

COVID-19 in Italian pediatric patients: the experience of a tertiary children's hospital

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