Clinical presentation of paediatric patients with COVID-19 admitted to a single paediatric intensive care unit (PICU) in Iran

Objectives To describe the clinical characteristics of paediatric patients admitted to a single paediatric intensive care unit (PICU) in Iran with COVID-19. Methods A cross-sectional study of paediatric patients who were admitted to a COVID-19-dedicated PICU from 16 March 2020 to 21 April 2020 with COVID-19. Results Six children had confirmed COVID-19 and four had suspected COVID-19. Six had pre-existing chronic medical conditions. Nine had respiratory failure and needed ventilation. Five children, of whom four had chronic medical conditions, died. Four had cardiac arrhythmias. Clinical presentation included fever and cough. Conclusion COVID-19 can be fatal in paediatric patients, especially in those with a chronic medical condition.


INTRODUCTION
The coronavirus pandemic originated in Wuhan, China 1 2 . The current outbreak of infections with SARS-CoV-2 was termed COVID-19 by the WHO. 3 The disease rapidly spread from Wuhan to other areas of the world, so that the WHO announced that the outbreak was a pandemic in March 2020. 4 The first paediatric case was a 10-year-old Chinese boy, whose family had visited Wuhan City. 4 A retrospective study on 366 children hospitalised for respiratory infections in January 2020 confirmed COVID-19 infection in 6 (1.6%) of them. This study suggests that COVID-19 infections in children occurred early in the epidemic. 5 Children were rarely tested for the virus in the earlier phase of the outbreak, so there are limited data on the prevalence of COVID-19 in children. 6 The virus can produce a Kawasaki-like illness in children. WHO developed a preliminary case definition for this condition which was later named 'multisystem inflammatory disorder' in COVID-19 (MIS-C). 7 In Iran, the first COVID-19 cases were detected in February 2020 in Qom city. There are a few reports from critically ill paediatric patients in the country. In this article, we describe the characteristics of paediatric patients with COVID-19 admitted in paediatric intensive care unit (PICU) of Namazi Hospital in Shiraz, Iran.

METHODS
Namazi Hospital, in Shiraz, is the largest and the main tertiary referral centre in the south of Iran with more than 1000 beds. The medical PICU of this hospital has 18 beds with two separate sections, one of which was devoted to COVID-19 cases from the beginning of the outbreak and those with suspected or confirmed COVID-19 were admitted in this ward. All children aged 1 month to 18 years admitted to the COVID-19 PICU between 16 March and 21 April were included.
A confirmed case of COVID-19 was defined by a positive result on a reverse transcriptase PCR (RT-PCR) assay of a specimen collected on an oropharyngeal swab, nasopharyngeal swab or What is known about the subject? ► COVID-19 infection is less frequent and severe in paediatric patients than adult patients. ► The main symptom is fever and few paediatric patients need mechanical ventilation or inotrope support.

What this study adds?
► COVID-19 infection may be fatal in paediatric patients, especially in those with chronic medical conditions. ► The main respiratory problems in severe cases are oxygenation failure and a hypotensive state necessitating inotropes. ► The main causes of mortality in our study were cardiac arrhythmia and refractory hypoxemia.

From 16
March 2020 to 21 April 2020, six patients were admitted with confirmed COVID-19 and four had suspected COVID-19 (tables 2 and 3). Only one of them was transferred from the emergency department with suspected COVID-19. Nine were transferred from other wards with other suspected diagnoses. The median age was 7.9 years. Eight patients were men, six patients had chronic medical conditions (table 2). The other four were previously healthy.
Five patients had a positive history of contact to confirmed or suspected cases (three patients had contact to positive RT-PCR cases) or possible cases with fever and cough. The main symptoms were fever, cough, abdominal pain, lethargy and encephalopathy. The median time from the presentation of symptoms to PICU admission was 4.7 days (range 3-8 days).
All the children had tachypnoea and tachycardia on admission to the PICU. All patients had Pa02/Fio2 (the ratio of arterial oxygen partial pressure to fractionalinspired oxygen) less than 300 and nine patients needed intubation and mechanical ventilation (all were intubated due to respiratory failure outside the PICU). One patient responded to oxygen supplementation via nonrebreathing mask despite decreased o2 saturation and PaO2 of 47 mm Hg.
In other intubated patients, the main problem was severe hypoxia. Although they needed a low peak inspiratory pressure for acceptable tidal volume, their oxygen saturation could not reach 85%, so peak expiratory pressure was increased even up to 18 and prone positioning was ordered to increase the oxygen saturation (cases number 4 and 6). Extracorporeal membrane oxygenation (ECMO) was not available in our centre.
Unfortunately, five patients died. Four of the five had chronic medical conditions. Cardiac arrhythmias occurred in three of the children who died.
Nine children had hypotension. Six children received high dose of norepinephrine (more than 0.3 µ/kg/ min) in addition to other inotropes. Enoxaparin was started with the aim of antithrombotic prophylaxis in all the patients. In all patients broad spectrum antibiotics (meropenem and vancomycin) were started in addition to hydroxychloroquine (ECG was taken first and all had normal Corrected QT interval (QTc) in electrocardiogram; equal to or less than 0.40 s) and kaletra (lopinavir/     Open access ritonavir), and intravenous immune globulin was given to eight patients due to severe septic shock (except for cases number 5 and 10). In hypotensive patients, hydrocortisone, ascorbic acid and thiamine were started. In all of the patients, blood culture, tracheal aspirate, urine culture and PCR for influenza A and B were negative (tables 2 and 3).
Patient number 3 presented with fever, abdominal pain and tachypnoea. He was transferred by his parents to our centre with the diagnosis of acute liver failure (Namazi Hospital is the referral centre for liver transplant in Iran). On arrival, he was intubated due to decreased o2 saturation and decreased level of consciousness. He had hypotension, fever and patchy ground glass infiltrations in the chest CT scan. Surprisingly, the serum bilirubin level was very high (total bilirubin was 35); the other lab data in addition to alkaline phosphatase: 387 and gamma-glutamyl transferase: 45 are shown in table 3.The patient tests for hepatitis A, B, C, Epstein-Barrvirus (EBV), herpessimplex virus(HSV), cytomegalovirus(CMV) were negative and serum ceruloplasmin level and anti-liverkidney microsomal antibody were in normal range; he had a negative history of taking medications or substance abuse. His parents had fever and cough and their nasopharyngeal RT-PCR for COVID-19 turned positive in both.

DISCUSSION
There are few studies regarding paediatric patients admitted in PICU. Paediatric data from Madrid, Spain, reported no mortality, but described one child who needed mechanical ventilation and two who needed non-invasive ventilation. 11 In a Chinese study, there was only one case who needed mechanical ventilation. 12 In a cohort study in children hospital in Wuhan, three paediatric patients were admitted in the PICU, all with comorbidities and one case died. 13 In another study from Wuhan, one patient without comorbidity was admitted in PICU and survived. 5 In our study, all patients were febrile and 70% had cough, but in some studies, non-critical paediatric fever was present in less than 50%. 5 12 13 In a study on 48 paediatric patients with COVID-19 admitted in 46 North American PICUs, 83% had significant pre-existing comorbidities, 73% presented with respiratory symptoms, 38% required invasive ventilation and 23% had failure of two or more organ systems. The mortality rate was 4% in their study (up to the time of the report). Three patients were intubated, one patient was taking ECMO and only 25% needed vasoactive support. 14 In the beginning of the pandemic, it was assumed that the main organ involvement in COVID-19 was respiratory, but several studies have reported Kawasaki-like syndrome MIS-C later. 15 DeBiasi et al 16 described a 177 paediatric patients series in the Washington, DC metropolitan region; among them, 9 cases required critical care, 8 needed respiratory support and 1 had Kawasaki-like shock syndrome.
In our study, some of our severely infected patients had elevated troponin level and fulfilling the criteria for MIS-C on arrival to PICU. Also hypotension and organ hypoperfusion can explain the aetiology of high level of troponin.
It has been shown that coronavirus infection (SARS, Middle EastRespiratory Syndrome and even; COVID-19) could damage the liver, and mild to moderate elevation of alanine aminotransferase (ALT); decreased albumin and increased serum bilirubin levels occur frequently, [17][18][19][20] but extremely high ALT and bilirubin levels in patient number 3 was noteworthy with some probable explanation like acute liver failure caused by COVID-19 or a rare complication of the disease. 21 Through reporting the characteristics of our patients, we aim to share our experience regarding COVID-19 patients.
There is a general conception that paediatric patients infected by COVID-19 have less severe symptoms and better outcomes, but severe and fatal cases occur as well.