key: cord-0797639-llf45k08
authors: Perikleous, Evanthia; Tsalkidis, Aggelos; Bush, Andrew; Paraskakis, Emmanouil
title: Coronavirus global pandemic: An overview of current findings among pediatric patients
date: 2020-10-07
journal: Pediatr Pulmonol
DOI: 10.1002/ppul.25087
sha: 05688ddf4a3fcacb025d735eb5d6fe57efe134de
doc_id: 797639
cord_uid: llf45k08

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) epidemic has been emerged as a cardinal public health problem. Children have their own specific clinical features; notably, they seem to be escaping the severe respiratory adverse effects. The international scientific community is rapidly carrying out studies, driving to the need to reassess knowledge of the disease and therapeutic strategies. AIM: To assess the characteristics of COVID‐19 infected children worldwide of all ages, from neonates to children and adolescents, and how they differ from their adult counterparts. SEARCH STRATEGY: An electronic search in PubMed was conducted, using combinations of the following keywords: coronavirus, SARS‐CoV‐2, COVID‐19, children. The search included all types of articles written in English between January 1, 2019 until August 15, 2020. RESULTS: The search identified 266 relevant articles. Children were mainly within family clusters of cases and have relatively milder clinical presentation compared with adults; children were reported to have better outcomes with a significantly lower mortality rate. Cough and fever were the most common symptoms while pneumonia was the cardinal respiratory manifestation of infected children. Laboratory results and thoracic imaging give varying results. CONCLUSIONS: Children were mainly family cluster cases and usually presented with a mild infection, although cases presented with the multisystem inflammatory syndrome are becoming more apparent. Studies determining why the manifestations of SARS‐CoV‐2 infection are so variable may help to gain a better understanding of the disease and accelerate the development of vaccines and therapies.

In early December 2019, a cluster of cases of atypical pneumonia of unknown origin appeared in Wuhan city, in the Hubei province of China. 1, 2 The majority of patients had been exposed to the Huanan seafood and animal wet market. 1, 2 These cases were the first signs of what was to become a pandemic which is currently causing a huge number of deaths and stressing health care systems globally to an unprecedented degree. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the underlying pathogen, belongs to the β-coronavirus genus 3, 4 ; and its genome sequence has considerable similarity to divers β-coronaviruses discovered in bats. 3, 5 Remarkably, the genome is more than 85% homologous to that of bat SARS like virus ZC45 (bat-SL-CoVZC45, MG772933.1). 6 Previously, four common communityacquired human coronaviruses, namely 229E, NL63, OC43, HKU1 had been described. Two other coronaviruses led to previous epidemics infecting more than 10,000 patients, namely severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle east respiratory distress syndrome coronavirus (MERS-CoV). 7, 8 Symptomatic patients infected with SARS-CoV-2 are the main sources of transmission, but asymptomatic carriers can also transmit the disease. Respiratory droplets and person-to-person contact are thought to be the principal routes of transmission, 9 but fecal transmission may also play a role. 6,10-17 A risk of indirect transmission through fomites is also plausible. SARS-CoV-2 has a half-life of 3.5 hours on cardboard, 5.6 h on stainless steel, and 6.8 h on plastic. 18 No age is exempt, but data on children are scarce compared with adults. Nonetheless, the fact that children often only have trivial symptoms which may mimic common childhood illnesses such as mild bronchiolitis or diarrhea means they may become an important source of infection transmission.

The aim of this study was to review the characteristics of SARS-CoV-2 infected children and discuss the differences between adult and pediatric patients with confirmed infection.

We performed an electronic search in PubMed, using combinations of the following keywords: coronavirus, SARS-CoV-2, COVID-19, children. Articles were screened by title, abstract, and full text to locate all manuscripts pertinent to children. The search included all types of articles written in English, between January 1, 2019 and August 15, 2020.

A total of 1995 articles were found, and 266 relevant scientific articles and letters were eventually included. Exclusion criteria were the following: not written in English (n = 81, 46 Chinese, 4 German, 14 French, 12 Spanish, and Russian, Hebrew, Swedish, Italian, Hungarian n = 1 each), not original research (n = 775), including letters to the editor (n = 335), reviews (n = 293), protocols/guidelines (n = 62) perspectives/expert consensus (n = 85), and data not relevant (n = 873), for example, other coronaviruses and other respiratory viruses, extraneous issues during the outbreak, such as psychological impacts, domestic violence, molecular aspects and pathophysiology of SARS-CoV-2 infection, pediatric surgery during the outbreak. The strategy and results are displayed in Figure 1 . Table S1 summarizes the current literature on the characteristics of children infected with SARS-CoV-2. Table 1 summarizes the clinical presentation and outcome of infection from the literature review. In Table 2 , we enumerate current knowledge of the differences between adults and children infected with SARS-CoV-2. Infected children are principally in family clusters, or have a history of close contact with an infected patient. 19, 20 Furthermore, children with COVID-19 had milder symptoms than adults. 19, 20 Characteristics of pediatric SARS-CoV-2 infected populations included:

Cough: Initial symptoms were fever and cough; even among neonates. 30 Cough was experienced by the majority of patients, [10] [11] [12] 14, 15, 19, it was mainly dry, but was sometimes followed by productive cough in moderately severe cases. 19 There may be upper airway symptoms, such as nasal congestion, rhinitis, and sore throat. 19 Wheezing may be a feature but is generally not prominent. Fever: One of the commonest early symptoms is fever, 11, 14, 15, [19] [20] [21] [22] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [61] [62] [63] [64] [65] 67, 68, occasionally low grade. In Zhejiang province, fever clinics that exclusively accept for admission patients suspected of being positive for SARS-CoV-2 were set up. 27 Pneumonia/CT findings: Many pediatric patients had COVID-19 pneumonia 10, 11, 16, [19] [20] [21] [22] [23] [24] 26, [28] [29] [30] [31] 34, 38, 40, [42] [43] [44] [47] [48] [49] [50] [51] [52] [53] [54] 56, 57, 60, 61, 64, 66, 68, [70] [71] [72] [74] [75] [76] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [90] [91] [92] 94, 95, 99, 100, 103, 155 and thoracic computerized tomography (CT) scan showed multifocal or nodular consolidation with ground glass F I G U R E 1 Flow chart of the search strategy. COVID-19, 2019 novel coronavirus disease; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2 opacities. 11, 15, 16, 19, 22, 23, [26] [27] [28] [29] [30] 33, 34, 39, [42] [43] [44] [47] [48] [49] [50] [52] [53] [54] 60, 61, 64, 66, 72, 74, [78] [79] [80] [81] [83] [84] [85] [86] 91, 95, 100, 103, 107, 164, 165 More adult patients had all five lobes affected 33, 166 ; the manifestations of the COVID-19 pneumonia are diverse and our understanding of the spectrum of disease is changing rapidly. Radiologists must therefore have a high index of suspicion. The role of follow up CT scans in children is currently unclear. Chest CT is a particularly sensitive diagnostic instrument to detect pneumonia; the sensitivity relevant to COVID-19 is estimated to be 97.5%. 149 Gastrointestinal symptoms: It is currently reported that SARS-CoV-2, despite being predominantly a respiratory virus, causes gastrointestinal symptoms in approximately 10% of infected children, 134,167 including abdominal pain, diarrhea, and vomiting. 11, 14, 15, 19, 20, 22, 26, 28, 31, 40, 41, 52, 53, 57, 59, 62, 65, 67, [70] [71] [72] [73] 77, 81, 83, 84, [86] [87] [88] [89] [90] [91] [92] [93] 100, 104, [106] [107] [108] 114, 116 Laboratory results: Complete blood counts may be normal, 11, [14] [15] [16] 19, 22, 26, 29, 32, 39, 40, 44, [48] [49] [50] 54, 61, 79, 93, 102, 165, 168 or show either decreased 14, 16, 19, 25, 26, 29, 31, 39, 40, 44, 49, 55, 61, 70, 93, 100, 108 or elevated white blood cell counts. 11, 14, 20, 22, 26, 44, 47, 50, 54, 60, 61, 93, 99 Lymphocyte counts may be increased, 15, 19, 24, 26, 29, 44, 60, 78, 79, 82, 84, 93, 96, 103, 169 or decreased. 14, 19, 22, 23, [25] [26] [27] [28] 31, 34, 39, 44, 49, 55, 70, 79, 82, 84, 88, 99, 100, 103, 113, 116 Increased C-reactive protein (CRP), 15, 19, 22, 25, 26, 28, 29, 31, 40, 41, 44, 47, 49, 50, 56, 73, 74, 77, 83, 84, 88, 93, 101, 103, 104 procalcitonin (PCT) 15, 22, 26, 31, 44, 49, 50, 56, 73, 77, 84, 88, 93, 99 and lactate dehydrogenase 14, 15, 22, 25, 47, 81, 83, 84, 93 have been reported. CRP is estimated to rise in 10%-20% of cases, in one study, the maximum value was 35 mg/L. 10 One group reported that leukocytopenia and CRP levels above 10 mg/L, were pointers to underlying pneumonia. 34 Serum ferritin was markedly higher in severe adult cases compared with moderately affected patients. 170 High serum levels of liver enzymes, muscle enzymes and myoglobin, and raised D-dimers are found in severely affected patients. 157 In addition, in critically ill cases; a cytokine storm is a feature, characterized by increased serum proinflammatory and antiinflammatory cytokines. 14, 22, 56, 73, 77, 84, 88, 93, 156, 171, 172 In a study of 157 children, moderate cases had higher interleukin 10 levels compared with mild cases. 81 Another original article reporting eight severe or critically ill children, ranged from 2 months to 15 years, reported elevated IL-6 (2/8), IL-10 (5/8), and IFN-γ (2/8). 22 IL-6 and IL-10 levels were significantly elevated in two critically ill children, of whom one was suffering from acute lymphocytic leukemia. These patients had a prolonged course of the disease duration (more than 20 days). A paper written in Chinese described a case of a severely ill infant with increased IL-6 levels. 171 Abnormal blood examinations may prompt pediatricians to screen for SARS-CoV-2. 26 Co-infections: Children not only vulnerable to SARS-CoV-2 infection, but can also be coinfected with numerous respiratory viral and bacterial pathogens. In a single-center study of 50 children with COVID-19 from Wuhan, there was documented co-infection in 14% of children, n = 6 (12%) Mycoplasma infection and one (2%) with respiratory syncytial virus (RSV). 103 In a multicenter Italian study of Fever [11, 14, 15, 19, 20, 22, [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [61] [62] [63] [64] [65] 67, 68, 5077 Gastrointestinal symptoms [11, 14, 15, 19, 20, 22, 26, 28, 31, 40, 41, 52, 53, 57, 59, 62, 65, 67, [70] [71] [72] [73] 77, 81, 83, 84, [86] [87] [88] [89] [90] [91] [92] [93] 100, 104, [106] [107] [108] 114, 116] 4227 Vomiting: 0-23 Diarrhea: 5-37.5

Disease severity [19, 38, 39, 55, 57, 81, 83, 103, 117] T A B L E 2 Summary of discrepancy aspects between adults and children COVID-19 patients specifically one had sinus tachycardia, two had a history of atrial septal defect surgery, one had an atrial arrhythmia, one had firstdegree atrioventricular block, one had an incomplete right bundlebranch block, and one had a previous history of epilepsy as a consequence of previous viral encephalitis. 26 COVID-19, only three children required intensive care support and invasive mechanical ventilation. All three children had an underlying medical condition; one had hydronephrosis, one had leukemia and was receiving maintenance chemotherapy, and one had intussusception. 34 This last baby died 4 weeks after admission from multiorgan failure. 34 In an Italian pediatric study from a hepatology and liver transplantation center, three of ten children became positive for SARS-CoV-2, did not develop pneumonia and survived. 189 were suffering from allergies, including allergic rhinitis (n = 28), drug allergy (n = 3), atopic dermatitis (n = 3), allergic rhinitis and drug allergy (n = 5), allergic rhinitis and atopic dermatitis (n = 1), allergic rhinitis and food allergy (n = 1), allergic rhinitis and food allergy and drug allergy (n = 1), asthma and urticaria and drug allergy (n = 1); there were no differences in COVID-19 clinical features and disease course between atopic and non-atopic children. 91 Data in cystic fibrosis are scarce and few patients, mainly adults, had confirmed COVID-19, without obvious impact on cystic fibrosis disease severity. [197] [198] [199] Interestingly, despite the frequency of these conditions, there are very few reports of SARS-CoV-2 in children with asthma, bronchopulmonary dysplasia, or chronic suppurative lung disease such as cystic fibrosis.

Risk factors for disease severity: Very little is known about this important subject. Radiologic involvement of more than three lung segments carried a higher risk of development of a severe form of the disease. 47 In addition, the elevation of IL-6, total bilirubin and D-dimer are associated with worse disease. 47 In a review of the Chinese experience, risk factors for severity were increased respiratory rate, clouding of consciousness, elevated levels of lactic acid, bilateral or multilobular lesions on imaging, pleural effusion, or rapid progression. 200 Other risk groups were patients below 3 months of age or those with co-existing conditions, such as congenital heart disease, bronchopulmonary dysplasia, severe malnutrition, and immunodeficiency. 200 The majority of infected children were within family clusters; so infection risk will probably be higher for those living in low-income families, in crowded housing, and with blue-collar parents. 201 Sadly, physical distancing is harder to implement in those with adverse social determinants and might further impact the risk of COVID-19. 202 In a study of 48 children admitted to the intensive care unit 83% had underlying conditions including obesity (n = 7). 125 Three adolescents with Covid-19 and septic shock were also all obese. 203 Among 50 children, 9 children with severe disease had significantly higher CRP and PCT on admission, elevated peak IL-6, ferritin, and D-dimer levels and obesity was again significantly related to the need for mechanical ventilation in patients 2 years or older. 88 Obesity is a known significant risk factor for severe disease in adults. 204 There is a compelling need to understand why the natural history of SARS-CoV-2 is milder in children. This may be related to alterations in the pediatric immune system leading to a qualitatively distinct response to the virus. 137 Developmental differences in the location, quantity, and activation status of the viral receptors are regularly revealed as potent causes of the age-associated variations in incidence. 230, 231 One hypothesis about the frequency of mild cases among children is linked to changes in the expression of angiotensin-converting enzyme II (ACE-2) receptor to which SARS-CoV-2 binds 137 ; there is lower nasal epithelial ACE-2 expression in children compared with adults. 231 Most patients described were adults who usually have pneumonia and abnormal CT chest imaging. 2, 149, 150 Elderly males with comorbidities do worse. 134,136 Those adults doing badly had a high prevalence of diabetes, obesity, hypertension, cardiovascular, and chronic airway disease. 9 Children suffering from other medical conditions, such as congenital heart, and chronic respiratory diseases may be vulnerable to COVID-19. 6 One pediatric study indicates an increased risk of hospitalization in children with a history of arrhythmia. 26 However it is noteworthy that children with pre-existing diseases do not seem to figure prominently in pediatric series.

A major limitation of the current study methodology is that for resource reasons we could not include any foreign language papers and unsurprisingly, many studies are published solely in Chinese, the pandemic having originated in China.

We need more data on how COVID-19 affects children with underlying medical conditions. As with so many diseases, there is a need for randomized controlled trials of treatment in children. The development of a safe and effective vaccine is of paramount importance. We need to be alert to novel manifestations of the disease in children, and understand the pathophysiology and how best to treat the emerging multi-system inflammatory complications discussed above.

SARS-CoV-2 infection affects all ages. In contrast to adults, children mostly have a mild form of the disease, as was the case in SARS, but nonetheless, they may transmit the disease. Identification of effective treatment strategies, and above all, a vaccine, is imperative. This literature review has highlighted the paucity of information about the interaction of the disease with underlying medical conditions in children and the lack of evidence with regard to investigation and treatment.

The authors declare that there are no conflict of interests.

http://orcid.org/0000-0002-9537-5133

Aggelos Tsalkidis https://orcid.org/0000-0001-5478-2149

Andrew Bush https://orcid.org/0000-0001-6756-9822

Emmanouil Paraskakis https://orcid.org/0000-0002-7115-757X

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Asymptomatic case of Covid-19 in an infant with cystic fibrosis

Epidemiological analysis of COVID-19 and practical experience from China

COVID-19 in children in the United States: intensive care admissions, estimated total infected, and projected numbers of severe pediatric cases in 2020

COVID-19 and the impact of social determinants of health

Septic shock presentation in adolescents with COVID-19

Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019-COVID-NET, 14 states

Hospitalization rates and characteristics of children aged < 18 years hospitalized with laboratory-confirmed COVID-19-COVID-NET, 14 states

Coronavirus infections in children including COVID-19: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children

The role of children in transmission of SARS-CoV-2: a rapid review

The role of chest imaging in patient management during the COVID-19 pandemic: a multinational consensus statement from the Fleischner society

An outbreak of severe kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study

Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic: a time-series analysis

Multisystem inflammatory syndrome in children during the coronavirus 2019 pandemic: a case series

SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study

Cardiac dysfunction and thrombocytopenia-associated multiple organ failure inflammation phenotype in a severe paediatric case of COVID-19

Pediatric inflammatory multisystem syndrome with central nervous system involvement and hypocomplementemia following SARS-COV-2 infection

Multisystem inflammatory syndrome in U.S. children and adolescents

Multisystem inflammatory syndrome in children in New York state

Multisystem inflammatory syndrome in children (MIS-C) related to COVID-19: a New York city experience

Pediatric case of severe COVID-19 with shock and multisystem inflammation

SARS-CoV-2-induced Kawasaki-like hyperinflammatory syndrome: a novel COVID phenotype in children

Toxic shock-like syndrome and COVID-19: a case report of multisystem inflammatory syndrome in children (MIS-C)

Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2

Multisystem inflammatory syndrome in children (MIS-C) associated with 2019 novel coronavirus (SARS-CoV-2) infection. Case Rep Pediatr

Severe SARS-CoV-2 infection in children with suspected acute abdomen: a case series from a tertiary hospital in Spain

Case report: systemic inflammatory response and fast recovery in a pediatric patient with COVID-19

Multi-system inflammatory syndrome in a child mimicking Kawasaki disease

Three cases of pediatric multisystem inflammatory syndrome associated with COVID-19 due to SARS-CoV-2

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort

SARS-COV-2 infection and Kawasaki disease: case report of a hitherto unrecognized association

Are children less susceptible to COVID-19?

Nasal gene expression of angiotensin-converting enzyme 2 in children and adults

Coronavirus global pandemic: An overview of current findings among pediatric patients