key: cord-293136-lfwqzf8m authors: Escosa‐García, Luis; Aguilera‐Alonso, David; Calvo, Cristina; Mellado, María José; Baquero‐Artigao, Fernando title: Ten key points about COVID‐19 in children: the shadows on the wall date: 2020-08-13 journal: Pediatr Pulmonol DOI: 10.1002/ppul.25025 sha: doc_id: 293136 cord_uid: lfwqzf8m The pandemic of the new coronavirus disease (COVID‐19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), initially described in China, is challenging the healthcare systems of all countries. Every emerging disease raises many questions with a scarcity of answers since all its characteristics are still being discovered. In the case of SARS‐CoV‐2, most of the literature comes from adult patients. Children seem to be less affected. Pediatric patients diagnosed with COVID‐19 disease usually suffer a mild illness, with low risk of complications or mortality. Defining the role of children in the transmission of SARS‐CoV‐2 is critical as some national infection control decisions involving children, such as school closures or social distancing, will probably impact the dynamics of the virus. To aid in the knowledge on COVID‐19 in children, this work presents an expert review of the literature published from January 1 to April 20, 2020, including peer‐reviewed and pre‐print non‐peer‐reviewed studies, along with some relevant articles afterwards, summarizing ten key points that characterize the disease in children. This article is protected by copyright. All rights reserved. The average age reported of COVID-19 confirmed cases in most countries is around 50 years old, with small differences depending on the demographic characteristics of each country (Figure 1 ). Most of the data from several countries place the prevalence of confirmed cases in children around 1-2% of all diagnosed cases 4 5 , which is strikingly low compared to infections caused by other respiratory viruses. The most recent official report on the epidemiology of COVID-19 in Spain (May 18, 2020), describes among the total notified cases only 0.3% cases in the groups under 10 years-old and 0.3% cases in the group 10-19 years-old 6 . Subsequent studies in a late stage of the epidemic in China have suggested a similar transmission in children 7 8 . The data from Iceland offer an accurate view of the age distribution, because the screening included the asymptomatic population 9 . This study describes a lower prevalence in population screening in children under 10 years of age compared to adolescents and adults (0/848 [0%] vs 100/12,232 [0.8%], respectively). Targeted diagnosis also showed a parallel trend: 6.7% vs 13.7% confirmed cases among children <10 years old and those 10 years of age or older, respectively. This has been similarly reported in a screening study carried out in Vo, a small population next to Padua (Italy) 10 . Seroprevalence studies are being performed in different countries and settings. A preprint study conducted in Geneva (Switzerland) showed an increasing seroprevalence throughout April, from 6.1% to 9.7% 11 . The seroprevalence in the 5-19 year old group (6.1%) did not differ (p=0.12) from that in the year old group (8.4%). However the first group did not include children under 5 years old, and it included a broad range of ages. A similar study conducted in Spain (ENE-COVID19 study) between Abril 27 to May 10, coordinated by the Spanish Ministry of Health, has shown a global seroprevalence of 5% 12 . One of This article is protected by copyright. All rights reserved. the most interesting aspects of this study is the low seroprevalence among children: the younger the age group, the lower the percentage of seroprevalence (1.1% in <1 years old; 2.2% in 1-4 years old; 3% in 5-9 years old; 3.9% in 10-14 years old and 3.8% in 15-19 years old). In several contact-tracing studies, children do not seem to be the usual source of infection in most cases 13 14 . Based on the data currently published, it seems that children have not been a major vector for transmission in the current pandemic, but further information is needed to draw clear conclusions. Whether this lower propensity to acquire and transmit the infection is due to biological resistance or due to less exposure is still a question to be answered. To evaluate the real impact of COVID-19 among children, screening strategies, including serological studies, are essential, since children usually have nonsevere symptoms or are even asymptomatic, which implies that they are underdiagnosed in studies following targeted diagnosis strategies. These data will be key to determining the role of children in the transmission of SARS-CoV-2 and, as a consequence, adopting decisions regarding non-pharmacologic preventive approaches. To summarize, the prevalence of COVID-19 disease in children is lower than in adults. Although initially children were supposed to have a relevant role in the transmission of the infection, several studies suggest that they do not have such an important position. Clinical features seem to be mild in comparison with adults 15 . At the time of writing, at least 3473 COVID-19 cases had been reported in children (Table 1) , but detailed data remain scarce. The best established features are presence or absence of fever and cough, but these have only been recorded in 31% of children in case reports. Fever is the most frequent symptom (58.3%), followed by cough (47.3%) and sore throat (18.3%). Rhinorrhea (15.9%) and gastrointestinal symptoms (12.7%) are also frequent. Some data in adults have established fever (71-83%) and cough (65-80%) as the most commonly reported symptoms 16 15 . Other symptoms in adults, such as headaches or myalgia, are not usually reported in children. Non-mild disease (defined as pneumonia or This article is protected by copyright. All rights reserved. need for hospitalization) or a more severe illness accounted for 33.3% and 9.1% of all the cases reported, respectively, in this review. Notably, some singular presentations that could be associated with SARS-CoV-2 infection have been described in children, such as infection-induced chilblains 17 in adolescents and young adults. By mid-April an increase in episodes similar to Kawasaki disease and/or toxic shock syndrome were reported in several countries (e.g., UK, US, France, Italy or Spain). It was initially named Pediatric multisystem inflammatory syndrome (PIMS) temporally associated with COVID-19 by the Royal College of Paediatrics and Child Health (RCPCH) 18 To date, some cases of neonatal SARS-CoV-2 infection have been reported 27 28 . Most were asymptomatic or had mild symptoms, but some cases progress to a severe infection 29 30 . The earliest diagnosed patient using molecular diagnosis from a nasopharyngeal specimen was a 36-hour-old newborn 31 . Breastfeeding has not been discouraged by most scientific societies (e.g., WHO, UNICEF, Spanish Society of Neonatology or Academy of Breastfeeding Medicine). To note, recently the detection of SARS-CoV-2 in human breast milk by RT-PCR has been published, which deserves further studies 32 . Some questions about vertical transmission have been raised after the publication of three newborns born to mothers with SARS-CoV-2 infection who presented positive IgM against SARS-CoV-2 at birth, but a negative SARS-CoV-2 PCR 33 34 , and the detection of SARS-CoV-2 RNA in the placenta of pregnancies with COVID-19 35 . However, these data should be interpreted with caution. In summary, pediatric patients with a SARS-CoV-2 infection usually develop a mild disease. However, the increasing number of patients with PIMS, who usually have a severe presentation, deserve a detailed analysis in order to establish the best definition and treatment. Regarding the vertical transmission, currently there is not enough information and further studies are needed. Typical COVID-19 laboratory markers in adults are not prevalent in children, but the vast majority (Table 1) do not document information about laboratory tests, so inaccurate extrapolation from adult literature is frequent. Leukocyte counts are often normal, but lymphocytosis is frequent (44%) in children with COVID-19. Lymphocytopenia has been reported as the most common sign in blood count for adults 36 37 , but it is only present in 17.5% of children. It has been related to poorer prognosis in adults, so perhaps the low prevalence in our review might be explained by a high frequency of mild cases (66.7% in this review). Procalcitonin levels seem to be greater (37.1%) than adults but reference ranges were not clearly defined. C-reactive protein is within normal range in about 74.8% of children, but in contrast it remained normal in only 37.5% (3/8 cases) of children requiring intensive care 38 . Liver enzymes are frequently normal in pediatric patients 39 40 41 , in contrast to adults. Remarkably, 50% of children in a case series of severe and critically ill patients presented abnormal liver function 38 . Other typical markers in adults such as high lactate dehydrogenase, ferritin, D-dimer or interleukin-6 are not evident in children but may be altered in severe and critical patients. In our experience, from 43 confirmed pediatric cases who underwent a blood test, 30% presented lymphocytes below 1200/mm3 and 70% a D-dimer above 700 mg/dL 42 . So, some analytical markers to take into account when evaluating a child with confirmed or suspected COVID-19, are lymphocyte count, D-dimer, C-reactive protein, procalcitonin and liver enzymes. However, their cut-off points in COVID-19 and the association with severe disease is not as well defined as in adults. Most data in children are provided by computed chest tomography (CCT) studies from China (Table 1) . From our perspective, it is surprising that CCT has become the COVID-19 gold standard in radiology diagnosis in children in some regions as radiation concerns might exist with doubtful medical benefit. In Spain, CCT is not recommended by pediatric guidelines in mild and moderate COVID-19 43 . Few data are available from chest radiographs in children with COVID-19. No abnormalities in radiographs are shown in 48.1% of cases. Unilateral or bilateral infiltrates in CCT are found in 60.9% of children. Bilateral ground glass opacities are the most prevalent findings. In addition, patchy shadows and consolidations are frequent. Accurate and reliable diagnosis of SARS-CoV-2 infections remains the cornerstone of the public health strategy for disease containment. The virus nucleic acid real time-polymerase chain reaction (RT-PCR) test has become the current standard diagnostic method, using specimens collected via nasopharyngeal swab 31 . Most patients have high viral loads in upper respiratory specimens soon after symptom onset which peak in the first few days before declining 32 . A study including 57 children showed that symptomatic infants had higher nasopharyngeal SARS-CoV-2 viral loads (measured as cycle threshold) than older children 33 . Recent data from a German study indicate that viral loads in the very young (age group 0-6 years) do not significantly differ from those of adults 44 To put it briefly, SARS-CoV-2 PCR of nasopharyngeal swab is considered the gold standard diagnostic test for acute COVID-19 disease. However, due to its suboptimal sensitivity, retest of the same specimen or even invasive specimens may be considered for non-confirmed cases. On the other hand, SARS-CoV-2 serology has a relevant diagnostic role in the late stages of the disease, including PIMS, or for seroprevalence studies. Mycoplasma (1/2) 48 . In contrast, other case series did not document coinfections with respiratory viruses such as influenza, parainfluenza or RSV 39 40 . The clinical relevance of co-infections is an issue that may have important implications. This article is protected by copyright. All rights reserved. At the time of writing this article, 12 studies have recorded information on underlying conditions, which is less than 26% of the total patients in this review. Among patients with reliable information, 26.4% had at least one comorbidity. The CDC in an April 6, 2020 report established that chronic lung disease (including asthma) is the most prevalent pre-existing condition (50%), followed by cardiovascular disease (31%) and immunosuppression (12.5%). Additionally, a study highlighted that 40/48 (83%) patients <21 years old admitted to PICU had significant preexisting comorbidities 49 . Of note, immunosuppressive therapy has not been linked to poorer prognosis in small pediatric case series. D'Antiga et al. In summary, comorbidities in children does not appear to be a relevant risk factor among children with COVID-19 in studies focused on cohorts of children with specific chronic conditions. However, as is shown below, a relevant percentage of children with COVID-19 admitted to PICU have some comorbidity. Anyway, due to the vulnerability of patients with chronic conditions, a special caution seems to be recommended when attending these children during SARS-CoV-2 epidemics. The vast majority of symptomatic children recover from COVID-19 within 1-2 weeks. In contrast to adults, severe COVID-19 infection in children is not frequent. Some of the proposed hypotheses as to why there is different severity among children compared to adults are 57 58 : 1) different angiotensinconverting enzyme 2 expression in cell membranes 59 ; 2) better control of viral replication through innate immunity; 3) different inflammatory signaling pathways; 4) pre-existing immunity to common coronaviruses 60 ; 5) differences in clotting function; and 6) lower comorbidities. However, none of these hypotheses has been validated. A study from China included 2143 children with microbiology-confirmed (34%) or clinically suspected COVID-19 (66%). Severe (defined as hypoxic) or critical cases were documented in 5.8% and 2.8% of the total SARS-CoV-2 confirmed patients, respectively. Children aged <1 year had the highest prevalence of severe and critical disease (10.6%), and 53% of children in pediatric intensive care units (PICU) were infants. However, as a limitation, this group had the highest proportion of clinically suspected disease, so other viruses may have led to severe disease. Of note, children aged 1-5 years might have a poorer prognosis (7.3% had severe and critical disease) compared to children >5 years and adolescents (3-4.2%). The CDC report included prognostic information, but hospitalization status was declared in only 29% of children 15 . Hospitalization was more frequent among children aged <1 year and 5.2% of infants required intensive care admission. In addition, 33% of children in intensive care units were aged <1 year. Patients This article is protected by copyright. All rights reserved. with underlying conditions also required more frequent hospitalization than healthy children. Out of hospitalized patients, 77% were children with chronic conditions which stands in contrast to 12% of non-hospitalized COVID-19 infected children. Information on children with COVID-19 requiring intensive care is scarce and incomplete. Deterioration starts typically after 7-10 days of clinical course. Currently, the main treatment for COVID-19 disease is supportive care, ensuring adequate oxygenation and nutritional support for the patient. The specific treatment has focused on two different strategies 64 (Table 3) 43 . Regarding the antiviral treatments proposed, they target different stages of the viral replication cycle 66 . Among antimicrobials 64 (e.g., lopinavir/ritonavir, chloroquine/hydroxychloroquine or ivermectin), only remdesivir has proved to This article is protected by copyright. All rights reserved. be of clinical benefit in a clinical trial including patients ≥18 years old 67 . In terms of anti-inflammatory drugs, some guidelines have included systemic steroids to be considered for COVID-19 disease 68 . Tocilizumab, an anti-IL-6 antibody, is being evaluated in several studies 69 Severe hypoxemia, severe distress or hemodynamic disfunction Signs of lung infection. Supportive care (1) Hospital admission. Consider compassionate use of remdesivir (2) . Consider systemic steroids and/or tocilizumab. 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Figure 1 . Age distribution of SARS-CoV-2 confirmed cases in different countries. Percentages are calculated from the total of confirmed cases in each country. In the case of the UK, the group aged 80-89 includes >89 years old. In the case of Iceland, the 0-9 group includes 0-12 years old; the 10-19 group includes [13] [14] [15] [16] [17] Chest X-ray Treatment Management Consider compassionate use of remdesivir (2) .