key: cord-0884386-k1tuda5o authors: Mustafa, Naira M; A Selim, Laila title: Characterisation of COVID-19 Pandemic in Paediatric Age Group: A Systematic Review date: 2020-05-08 journal: J Clin Virol DOI: 10.1016/j.jcv.2020.104395 sha: c9c54797438170c579941953b13aa0678ab7238a doc_id: 884386 cord_uid: k1tuda5o Abstract Background Coronavirus disease 2019 (COVID-19) is a pandemic first originated in Wuhan the capital of Hubei province, China in December 2019 and then spread globally. It is caused by SARS-CoV-2. Until 1 April 2020, the number of cases worldwide was recorded to be 823,626 with 40,598 deaths. Most of the reported cases were adults with few cases described in children and neonates. Objectives We performed a systematic review to analyse the disease characterisation in paediatric age group including the possibility of vertical transmission to the neonates. Methods Articles published up to the 2nd April 2020 in PubMed and google Scholar were considered for this study. Findings The most frequently reported symptoms were cough 49% (95% CI: 42 – 55%) and fever 47% (95% CI: 41- 53%). Lymphopenia and increased Procalcitonin were recorded in (21%, 95% CI:12 – 30%) and (28%, 95% CI:18 – 37%) respectively. No sex difference for COVID-19 in paediatric age group (p = 0.7). Case fatality rate was 0%. Four out of 58 neonates (6.8%) born to COVID-19 confirmed mothers tested positive for the disease. Conclusion The disease trajectory in Paediatric patients has good prognosis compared to adults. Intensive care unit and death are rare. Vertical transmission and virus shedding in breast milk are yet to be established. Coronavirus disease 2019 (COVID-19) is a pandemic that originated in Wuhan, China in December 2019 and then spread globally. Although the consequences of COVID-19 infection are devastating, it can be described as a primarily disease of adulthood rather than childhood as inferred by the reported number of cases worldwide [1] . On the 3 rd of January 2020, the Chinese Center for Disease Control and Prevention confirmed that the disease is caused by a novel member of enveloped RNA coronavirus which [2] [3] [4] . The International Committee on Taxonomy of Viruses officially announced the name of this new corona virus to be "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). The World Health Organization (WHO) announced that the official name of the disease caused by SARS-CoV-2 is Corona Virus Disease-19 (COVID-19) [5] . Herein, we reviewed the characterisation of COVID-19 infections in the Paediatric age group. The initial infections were linked to Huanan Seafood market in China, mostly due to animal contact. However, COVID-19 is not considered as direct zoonosis as its transmission now is primarily human to human [6] . The mode of transmission of the virus between humans is via respiratory droplets [7] . However, aerosol spread could be a potential route of transmission as illustrated by a study investigating the aerosol and surface stability of SARS-CoV-2 [8], where the authors studied the viability of the virion particles on different surfaces including stainlesssteel, plastic, cardboard, and copper as well as in aerosol particles (< 5 µm). It was found that the virus remains viable in aerosol particles for up to 3 hours with a median half-life of 1. Vertical transmission is still a matter of debate and yet to be established. In two studies performed on pregnant women with confirmed COVID-19 infection who delivered by either normal vaginal delivery or caesarean section, all neonates tested negative for COVID-19 [10, 11] . Other study has found that 3 out of 33 neonates born to COVID-19 positive mothers had positive nasopharyngeal and rectal swabs for COVID-19 [12] . Fecal-oral transmission could be an alternative route of transmission as several studies have reported positive stool samples, even after nasopharyngeal/throat swabs were COVID-19 negative [13, 14] . SARS-CoV-2 is a primarily a lung pathogen. Its entry to the lung is facilitated by the binding of S protein to angiotensin-converting enzyme 2 (ACE2) receptors [15] , which may be the same as SARS-CoV which also enter cells via ACE2 receptors [16, 17] . Moreover, it uses the host Transmembrane protease serine 2 (TMPRSS2) for S protein priming and fusion of viral and host cell membranes [6] . ACE2 receptor binding can be shown by two lines of evidence: (1) sequence analysis of the receptor binding motif, which is the part of receptor binding domain that comes into direct contact with ACE2 receptor, which has revealed extensive similarities between SARS-CoV and SARS-CoV-2, and (2) the blockade of SARS-2-S driven cell entry by using human ACE2 antisera. The gold standard test for SARS-CoV-2 is the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test. It is believed to be highly specific, and its sensitivity was reported to J o u r n a l P r e -p r o o f be 91% [95% CI: 83-97%] for initial RT-PCR [18] . Other study reported RT-PCR sensitivity as high as 95-97% [19] . Although less sensitive than chest computed tomography (CT), chest radiography is the firstline imaging modality used to scan patients with suspected COVID-19. Its abnormalities mirror those of the CT and include consolidation or ground-glass opacity (GGO), which in most cases are bilateral and peripheral, and have lower zone predominance. Lung ultrasound may be also useful in the evaluation of critically ill COVID-19 patients [21, 22] . The utilisation of CT radiological findings to diagnose/screen for COVID-19 is controversy. An American-Singaporean panel published that CT findings were not part of the diagnostic criteria for COVID-19 [19] . However, CT findings have been used as a surrogate diagnostic test by others [23, 24] . We searched PubMed and Google Scholar from inception through 2 April 2020 using the words "COVID", "COVID-19", "COVID" AND "children", "COVID" AND "neonates", "SARS-CoV-2", "SARS-CoV-2" AND "children", "Wuhan" AND "children" AND "COVID", "COVID" AND "vertical transmission", "COVID" AND "ACE2", "COVID" AND "ICU", "COVID" AND "epidemiology", "COVID-19" AND radiology", "COVID-19" AND "CT". For further relevant studies, the references of selected articles were also identified through manual search. The literature search process is presented in (Figure 1 ). We included all studies that have reported the clinical picture, laboratory diagnosis, modes of transmission of COVID-19 in Paediatric age group. The excluded articles were published in J o u r n a l P r e -p r o o f languages other than English, adult only studies, abstract only, and studies with insufficient data to be analysed. Data were collated in Microsoft Excel 2019 MSO 64-bit then analysed using RStudio version 3.6.1 (R. RStudio, Inc., Boston, MA), packages "Hmisc". Categorical variables were expressed as number (%). Numerical variables were expressed as median and range or mean and standard deviation as appropriate. p values of less than 0.05 were assigned significance. Six studies [10,11, [25] [26] [27] [28] were reviewed and analysed to determine whether SARS-CoV-2 could be transported from an infected mother to her neonate via vertical transmission ( Table 1 ). The mean age of the pregnant females was 30.9± 2 years (95% CI, [29] [30] [31] [32] [33] . They gave birth by normal vaginal delivery 21% (12 cases, 95% CI: 10 -32%) or Caesarean section (CS) 79% (45 cases, 95% CI: 68 -90%) and all were COVID-19 positive. Seven females (12%) (95% CI: 4 -29%) experienced premature rupture of membranes. The average gestational age (GA) was 37 + 4 days ±2 (95% CI, 34 -41). Neonatal outcome was as follows: the average birth weight was 3,031 kg (95% CI, 2,579 -34,83). Prematurity was estimated to be 28 %. (16 cases, 95% CI:16 -40%). Apgar scores were 8-9 in 1 minute, and 9 -10 in 5 minutes. The neonates clinical picture varied from intrauterine fetal distress 17% (10 cases, 95% CI:7 -27%), shortness of breath (SOB) 19 % (11 cases, 95% CI: 9 29%), gastrointestinal symptoms 14% (8 cases, 95% CI:5 -23%), and fever 8% (5 cases, 95% CI: 1 -15%). One neonate died from multiorgan failure and DIC. Four neonates tested positive for COVID19 (6.8%) (95% CI: 0 -9%). The affected neonates were all males and delivered by caesarean section. J o u r n a l P r e -p r o o f Eleven studies were reviewed and analysed to investigate the incidence, clinical picture and laboratory finding of children and neonates with COVID 19 disease (Table 2) . (4, 5, 13, 14, 20, (29) (30) (31) (32) (33) (34) (35) . The median age was 6.5 years (0-12 years). Among those patients, males were 59% (147 cases, 95% CI 53-65%) and females were 41% (104 cases, 95% CI 35 -47%). There was no statistically significant difference between males and females (p = 0.7). Most of patients presented with either a cough 49% (122 cases, 95% CI: 42 -55%) or fever 47% (118 cases, 95% CI: 41-53%). Some children presented with sore throat 36% (90 patients, 95% CI: 30 -42%); gastrointestinal (GIT) symptoms in the form of vomiting or diarrhoea were present in 17% (42 cases, 95% CI:12 -21%). Other symptoms include a rhinorrhoea 9% (22 cases, 95% CI: 5 -12%) and a few cases that presented with sneezing and fatigue. Pneumonia was recorded in 60% (151 cases, 95% CI: 54 -66%). However, many studies have recorded that most of the children present with mild pneumonia which could be unilateral or bilateral [13, 14] . The majority of the cases had mild disease, with only 4% (9 cases -95% CI: 1 -6%) were admitted to the ICU. The case fatality rate was 0%. According to laboratory findings, full blood count showed the following: Leucopenia and leucocytosis were present in 19% (15 cases, 95% CI:10 -27%) and 11% (9 cases, 95% CI: 4 -18%) respectively. Lymphopenia and lymphocytosis were present in 21% (17 cases, 95% CI:12 -30%) and 5% (4 cases, 95% CI: 0 -10%) respectively; thrombocytopenia was found in only 4% (3 cases, 95% CI: 0 -8%). Raised C-reactive protein concentrations were present in 28% (22 cases, 95% CI:18 -37%). Procalcitonin (PCT) concentrations were raised in 28% (22 cases, 95% CI: 18 -37%). Raised transaminase and lactate dehydrogenase activities were demonstrated in 13% (10 cases, 95% CI: 5 -20%) and 5% (4 cases, 95% CI: 0 -10%) respectively. Su et al. and Sun et al. [5, 34] analysed circulating cytokine concentrations, as well as those of lymphocyte surface markers. CD4 + was raised in 6 out of 15 patients (95% CI: 15 -65%). Concentrations of the pro-inflammatory cytokines IL-6 and IFN-γ were increased in two patients (13%) and concentrations of the anti-inflammatory IL-10 were raised in 33% (5 patients, 95% CI: 9 -57%). A large case series was published by The Chinese Center for Disease Control and Prevention; this study included 72,314 cases which were classified as either confirmed, suspected, clinically diagnosed cases, or asymptomatic cases. Amongst the confirmed cases group, there were 416 (0.93%) less than 10 years old and 549 (1.2%) aged between 10 and 19 years old; the case fatality rate in children younger than 9 years old was 0% [1] . However, on the 31 st of March 2020, a child aged 13 years old was the first UK death from COVID-19 at this age, the child died at London Hospital trust but no details are available (BBC news,2020). On the same day, 13-Year-Old-Belgian girl died with COVID-19 (Euro news, 2020). A study in China reviewed all affected infants under one-year-old in the period between 6 December 2019 and 8 February 2020 [29] . They found that only nine infants were affected. This figure reflects the rarity of COVID-19 in infants. Additionally, all cases were mild enough so that none of them required intensive care admission, mechanical ventilation nor developed complications. There are many factors that could explain why SARS-Cov-2 is not primarily a disease with large consequences for paediatric populations. [6] . This finding infers that foetal lung ACE2 receptors have different characteristics than mature lung tissue (e.g. lower binding capacity). Secondly, the children are exposed to other respiratory viruses such as respiratory syncytial virus, Influenza A and Influenza B viruses, which enhance their serum antibody levels and could provide cross protection [4] . Children's immune system is not fully mature and they respond to infections in a manner different from adult's response. Finally, it is worth mentioning that the actual number of COVID-19 in children may be higher than the published figures. Nonetheless, due to the mild symptoms or even asymptomatic cases, it may be underdiagnosed. Widening the screening scale may pick up larger number of childhood cases. The incubation period for the SARS-CoV-2 ranges between 2 -14 days [7]. Nonetheless, this incubation period varies according to disease severity [36] . No age is immune against COVID-19 infection; nevertheless, elderly people, pregnant females and those with impaired immunity are liable to more sever disease sequelae than the paediatric age group [37] . Childhood COVID-19 disease usually runs a mild course. The children can be a symptomatic or present with cough, fever and fatigue. Some studies have reported low grade fever or even no fever at all [14] [35] . This is usually accompanied by upper respiratory tract symptoms like nasal congestion and headache [7] . The affected children can also present with gastrointestinal manifestations such as diarrhoea, vomiting or abdominal distension [35] . The disease has good prognosis in children with most of the cases are recovered after a mild disease course and it is very uncommon to progress to severs lower respiratory disease [38] . Data from adult patients showed that they can develop difficulty breathing one week after the initial symptoms which can progress to severe acute respiratory distress syndrome, respiratory failure, septic shock, J o u r n a l P r e -p r o o f metabolic acidosis and coagulopathy [7] . However, this trajectory is extremely rare in children [38] . Sun et al. [34] described eight critically/severely ill patients who were admitted to the ICU. One patient had underlying immuno-suppression from acute lymphoblastic leukaemia which made him more susceptible to critical COVID19 disease. In this study four patients developed complications in the form of septic shock, multi organ system failure, kidney stones, hydronephrosis, coagulopathy, DIC, intussusception, status epilepticus, and hypoglobulinemia. A ten-month old female developed encephalopathy and her circulating cytokines were high as a complication of COVID-19 infection [34] . Additionally, One study reported a case of Acute necrotizing encephalopathy (ANE) in an adult female patient with COVID-19 [39] . ANE is a rare complication of influenza and other viral respiratory infections and has been related to intracranial cytokine storms, which result in blood-brain-barrier breakdown [40] . SARS-CoV-2 seems to behave like these respiratory viruses as reported in the adult and infant cases. were critically ill and most of them (7 -0.3%) were infants (53.8%). This study elucidated that childhood illness is generally not severe and that children less than one-year-old are the most vulnerable group to critical illness and ICU admission [4] . Moreover, this study pooled the data of disease severity amongst suspected and confirmed cases, this means that the 0.6% who showed critical illness could have a respiratory disease other than COVID-19 e.g.: RSV, influenza virus type A or B. Studies done so far revealed that vertical transmission of COVID19 is yet to be established One study reported a neonate with positive COVID-19 born to a mother with confirmed COVID-19. However, considering this as a vertical transmission is controversial. First, the J o u r n a l P r e -p r o o f sample was taken 36 hours after delivery, so the child could be infected by direct contact [27] . Secondly, both cord blood and placenta samples were tested negative for SARS-CoV-2. On the other hand, vertical transmission could not be ruled out completely as the negative screening in the cord blood and placenta can be attributed to low viral load at the time of delivery that was below the detection limit of the PCR. So, further studies are needed. Whether breast milk feeding is prohibited in COVID-19 confirmed lactating women is yet to be established. Nevertheless, two studies examined breast milk in COVID19 positive females and the milk was tested negative [10, 26] . This indicates that the virus is not transmitted to breast milk and that breast milk feeding may be safe in this situation, although further studies with larger sample sizes are needed to prove this. Paediatric age group are liable to infection by COVID-19. However, the disease usually has a mild course with fever and cough are the most frequently observed symptoms. Intensive care unit and death are extremely rare. Vertical transmission and virus shedding in breast milk are yet to be established. Naira Mustafa: Conceptualization, Methodology, Software, Data Curation, Revision and Visualisation. Laila Selim: : Conceptualization, Supervision, writing, Reviewing and Editing. Funding: This study did not require fund. The authors have indicated that they have no conflicts of interest to disclose. 1/9 (11%) 6/6 (100%) 1/9 (11%) Sneezing 2/10 (20%) 0/9 (0%) 0/6 (0%) 0/9 (0%) Stuffy nose 3/10 (30%) 0/9 (0%) 0/6 (0%) 0/9 (0%) Rhinorrhoea 2/10 (20%) 1/9 (11 %) 0/6 (0%) 0/9 (0%) Sore throat 4/10 (40%) 0/9 (0%) 0/6 (%0) 0/9 (0%) Dyspnoea 0/10 (0%) 0/9 (0%) 6/6 (100%) 0/9 (0%) Diarrhoea 0/10 (0%) 0/9 (0%) 0/6 (0%) 0/9 (0%) ICU admission 0/10 (0%) 0/9 (0%) 1/6 (16.6%) 0/9 (0%) Nausea/vomiting 0/10 (0%) 0/9 (0%) 0/6 (0%) 0/9 (0%) fatigue 0/10 (0%) 0/9 (0%) 0/6 (0%) 0/9 (0%) Pneumonia 4/10 (40%) 0/9 (0%) 4/6 (66.6%) 1/9 (11.1%) complications 0/10 (0%) 0/9 (0%) 0/6 (0%) 0/9 (0%) Laboratory leucopenia 1/10 (10%) NA 4/6 (33.3%) 2/9 (22.2%) lecocytosis 3/10 (30%) NA 0/6 (0%) 1/9 (11.1%) Neutrophilia 1/10 (10%) NA 0/6 (0%) 0/9 (0%) Neutropenia 3/10 (30%) NA 3/6 (50%) 1/9 (11.1%) Lymphopenia 0/10 (0%) NA 6/6 (100%) 0/9 (0%) lymphocytosis 1/10 (10%) NA 0/6 (0%) 1/9 (11.1%) Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention Supramolecular architecture of the coronavirus particle Inferring the number of COVID-19 cases from recently reported deaths Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China The different clinical characteristics of corona virus disease cases between children and their families in China-the character of children with COVID-19 SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2 Participation of both host and virus factors in induction of severe acute respiratory syndrome (SARS) in F344 rats infected with SARS coronavirus Structure of SARS coronavirus spike receptor-binding domain complexed with receptor Essentials for radiologists on COVID-19: an update-radiology scientific expert panel Radiology Department Preparedness for COVID-19: Radiology Scientific Expert Panel Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults First-line diagnosis of paediatric pneumonia in emergency: lung ultrasound (LUS) in addition to chest-X-ray (CXR) and its role in follow-up Findings of lung ultrasonography of novel corona virus pneumonia during the 2019 -2020 epidemic An update on COVID-19 for the radiologist-A British J o u r n a l P r e -p r o o f society of Thoracic Imaging statement Essentials for radiologists on COVID-19: an update-radiology scientific expert panel Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia Perinatal Transmission of COVID-19 Associated SARS-CoV-2: Should We Worry? 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ALT (18.5 -