key: cord-0780635-5azti19e authors: Ludvigsson, Jonas F title: Children are unlikely to be the main drivers of the COVID‐19 pandemic – a systematic review date: 2020-05-19 journal: Acta Paediatr DOI: 10.1111/apa.15371 sha: 15b5d3ae2b05e1cddd33c2caa655f90873d60a2a doc_id: 780635 cord_uid: 5azti19e AIM: Many countries have closed schools and kindergartens to minimise COVID‐19, but the role that children play in disease transmission is unclear. METHODS: A systematic literature review of the MEDLINE and EMBASE databases and medRxiv/bioRxiv preprint servers to 11 May 2020 identified published and unpublished papers on COVID‐19 transmission by children. RESULTS: We identified 700 scientific papers and letters and 47 full texts were studied in detail. Children accounted for a small fraction of COVID‐19 cases and mostly had social contacts with peers or parents, rather than older people at risk of severe disease. Data on viral loads were scarce, but indicated that children may have lower levels than adults, partly because they often have fewer symptoms, and this should decrease the transmission risk. Household transmission studies showed that children were rarely the index case and case studies suggested that children with COVID‐19 seldom caused outbreaks. However, it is highly likely that children can transmit the SARS‐COV‐2 virus, which causes COVID‐19, and even asymptomatic children can have viral loads. CONCLUSION: Children are unlikely to be the main drivers of the pandemic. Opening up schools and kindergartens is unlikely to impact COVID‐19 mortality rates in older people. In late 2019, a new highly infectious virus, severe acute respiratory syndrome coronavirus (SARS-CoV-2) was discovered in Wuhan, China 1 . The SARS-CoV-2 virus causes coronavirus disease 2019 , which typically presents with severe acute respiratory symptoms 2 . However, other manifestations, such as gastrointestinal symptoms, 3 and severe outcomes, including stroke, coagulation disorders and possibly hyperinflammation 4 , have also been reported 5 Health Organization (WHO) has classified the COVID-19 outbreak as a pandemic. By 11 May 2020, there had been more than 4,000,000 confirmed cases and nearly 300,000 deaths worldwide due to COVID-19 6 . Children often have a milder disease than adults and deaths are extremely rare 7 , but children in many countries have been subjected to the same social confinement as adults. There is a growing interest in the role that children play in transmitting the virus that causes COVID-19 and this is referred to as COVID-19 transmission in this paper for the sake of simplicity. The issues around potential transmission by children has quickly become an issue, as countries need to know when to send children back to school as lock-down restrictions are eased. There have also been fears that opening up schools will lead to an increase in COVID-19 transmission 8 . However, the role of children in COVID-19 transmission is unclear. This paper reviews the current evidence on various aspects of COVID-19 transmission in children, following a systematic literature search of published papers in the MEDLINE and EMBASE databases. We also searched the medRxiv/bioRxiv preprint servers, which contain preprints, which are unpublished papers. This paper reviews the evidence for COVID-19 transmission from children and does not deal with adult-to-child transmission or intrauterine vertical transmission. This article is protected by copyright. All rights reserved Two experienced librarians at the Karolinska Institutet University Library, Stockholm, Sweden, performed a systematic literature review of the MEDLINE and EMBASE databases on 11 May 2020 to identify papers on COVID-19 transmission in children (Appendix S1). We used a broad range of search terms, such as transmission and transmit*, attack rate, infect*, incidence and prevalence, which were combined with childhood age keywords and words such as preschool, pupil and kindergarten. The search yielded 381 hits in MEDLINE and 381 hits in EMBASE. Although the numbers were identical for the two databases, they related to different publications. Removing the duplicates identified 508 scientific papers and letters. The titles and abstracts were screened and 40 publications were read in detail 7 9-47 . That search was complemented by a search of the medical preprint server medRxiv/bioRxiv on 12 May 2020, which yielded 192 unpublished preprints, including seven that were deemed relevant 48-54 (Appendix S2). In addition, we identified two more relevant unpublished preprints 55 56 when we reviewed the references lists of the publications that were identified by this second search. There was no pre-specified protocols prior to the review. An unpublished preprint from Charité -Universitätsmedizin, Berlin 55 , that used real-time polymerase chain reaction (PCR), reported the viral loads for 3,712 patients positive for COVID-19 This preprint has generally been interpreted as demonstrating an equal viral load in children above the age of one year and adults. However, translating the logarithmic viral load data into actual numbers yielded the following PCR counts for individuals positive for COVID-19: 43,000 for those aged 1-10 years, 63,000 for 11-20 years, 183,000 for 21-30 years and 164,000 for 31 -40 years. When the authors tested the PCR viral count differences using the Kruskal-Wallis test they found a p value of 0.008, which indicated a difference between the age groups. However, they did not formally point out which age groups had the lowest viral loads. The fact that their postdoc tests failed to attain statistical significance was probably due to the large number of pairwise comparisons they carried out, instead of comparing children versus adults. The percentage of cases that tested positive for COVID-19 in this German study was lower in children (3.0%) than in adults (5.5%) 55 . Lower viral loads were also found in in children with underlying diseases 55 . Importantly, the German study mainly tested symptomatic individuals 55 , which is of less relevance to school openings and closures. In a recent letter to Lancet Infectious Diseases, Liu et al 57 showed that patients with severe COVID-19 had an average viral load that was 60 times higher than mild cases. That study did not distinguish between children and adults. This article is protected by copyright. All rights reserved Our literature review did not identify any viral load studies that specifically looked at asymptomatic children attending kindergartens and schools. Infectious diseases can be transmitted in a number of ways. These include bloodborne diseases, such as human immunodeficiency viruses and Hepatitis B, which can also be vertically transmitted during pregnancy. They also include airborne transmission, as in measles, faecal transmission, as in rotavirus diseases, and the droplet transmission identified in diseases like COVID-19. Droplet transmission can occur through contact with surfaces touched by an infected individual, but it is more likely to occur because of sneezing, coughing and close contact. Children have less symptoms, such as coughing and sneezing, than adults 58 and this could suggest that the actual physical transmission of disease is lower in this age group. In an unpublished study from Guangzhou, China, Luo et al reviewed 4950 close contacts and examined them according to mode of contact and clinical characteristics, using logistic regression 56 . This study found a strong association between disease severity and COVID-19 transmission (p<0.0001). The symptoms linked to an increased risk of disease transmission were fever, but not a cough, fatigue or myalgia. Viral transmission can also occur when individual touch their eyes, nose and throat, if the hand contains viral particles. Schools and kindergartens all over the world are currently implementing hygienic hand washing to counteract that risk. We did not find any studies that examined if these measures decreased COVID-19 transmissions in children. In addition, we did not find any studies that examined whether children could infect other people with COVID-19 through faecal transmission. Many children are socially active and when they are playing this often involves physical contact 59 . Earlier research on respiratory disease transmission suggest that school children primarily This article is protected by copyright. All rights reserved interact with individuals of the same age, 59 rather than older people. More time spent in kindergartens and schools may, therefore, decrease their exposure to older people, such as grandparents, who are more likely to die from COVID-19. Our literature search failed to identify any data on attack rates from children, namely the proportion of exposed individuals that go on to develop COVID-19. Other literature has stated that two studies examined attack rates from children to adults, but that does not seem to be the case 12 52 . In a Chinese study of 391 COVID-19 cases, children were as likely to be infected as adults from a household contact with COVID-19 12 . However, this paper did not present data on the attack rate when the index case was a child (personal communication with co-author Lessler, 13 May 2020). The second study, by Mizumoto et al, only reported that children were less likely to become infected 52 , not that they had a lower or higher attack rate. There is now extensive literature on household transmission involving children 31 54 28 37 and these reported that children were less susceptible to COVID-19 than adults at home 31 . When a paper by Choi et al, published online on 6 April 2020, summarised the literature, they found no cases of child to child or child to adult transmission 16 . However, a few reports have described family clusters where a child was identified with COVID-19 first, followed by other family members who tested positive 45 13 . Zhang et al reported a three-month-old child who was diagnosed prior to her parents 45 , although it has been argued that this may have been due to a shorter incubation period in the child rather than the child being the index case in this family 15 . A study by Cai et al, cited in a paper by Cao et al 13 , described a seven-year-old boy who is believed to have infected his mother with COVID-19 after a visit to Wuhan. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved This review showed that children constituted a small fraction of individuals with COVID-19 7 and that most had social contacts with peers or parents, rather than with older people who face a risk of severe disease. Data on viral loads were scarce, but those that were available indicated that children may have had lower levels than adults. Children tended to have milder or no respiratory symptoms and this probably decreased the risk of viral transmission. Household transmission studies showed that children were rarely the index case and case studies suggested that children with COVID-19 seldom caused outbreaks. Despite this, it also seems clear that asymptomatic children can have viral loads. It is also highly likely that children can transmit the disease. Milder disease and potentially lower viral loads in children may prime adults who are infected, so that they develop a response to COVID-19 and are not overwhelmed by the infection. In the future, it would be interesting to explore if adults who have received the disease from a child are less likely to progress to severe disease than those adults who were infected by other adults. It is notable that the German study by Jones et al found lower viral loads in children with underlying diseases 55 . Since underlying diseases do not protect against viral infections, one explanation could be that the clinical threshold for testing these children was lower than for children without pre-existing comorbidities, but it is also possible that these children were tested at a later stage, when viral levels had begun to declne 55 . There are now a number of reports that also suggest that children with comorbidities that test positive for COVID-19 have a good prognosis 36 . Sick children should not attend school, and, as long as schools and kindergartens only contain healthy children, they should not become nodes of disease transmission. A small number of children may attend schools just before symptoms appear, because they do not realise that they are just about to become sick, but this should only account for a few cases. That said, more This article is protected by copyright. All rights reserved studies are needed on viral loads in asymptomatic children, since data suggest that viral loads can be high in asymptomatic individuals, at least in elderly people 61 . The rationale for school closures is to limit the transmission of COVID-19 in society, but, as several authors have pointed out, the arguments put forward have not been compelling 10 . Although school closures may decrease the transmission of influenza, as children play a major role in the household transmission of influenza 62 , this does not mean that school closures would limit COVID-19 transmission in society more than marginally. The adverse effects of school closures can include lack of education and disproportionally affect vulnerable and disadvantaged children. In addition, in some countries school nurses cater for the health needs of children, schools often offer subsidised free meals and they look after children for much of the day when parents work. Armitage et al have, therefore, suggested other measures than closing schools to decrease COVID-19 transmission, such as promoting hygiene and physical distancing in schools 10 . School closures also tend to increase child care obligations, especially of healthcare workers, as this group often have small children. Bayham and Fenichel have estimated that if mortality rates for COVID-19 increased by more than 17% -from 2.00% to 2.35% in their model -as a result of healthcare worker shortages, school closures would result in more deaths than the lives gained due to slower COVID-19 spread because of the school closures 11 . By now, it is clear that risk groups mainly consist of individuals aged 70 plus years and adults with certain underlying disorders, including cardiovascular disease, obesity and type 2 diabetes 2 . Opening up schools and kindergartens is unlikely to increase the transmission of COVID-19 to older people who need protection. Because children tend to have mild forms of the disease, if they infect other children this should not have an impact on the bigger picture of COVID-19 mortality. This review also found evidence that children primarily interact with peers of a similar age or with parents. The main strength of this review was the systematic search of the MEDLINE and EMBASE databases, which identified more than 500 published scientific papers and letters, but also our This article is protected by copyright. All rights reserved use of the medRxiv/bioRxiv preprint servers to identify unpublished preprints, which reflect the latest knowledge. However, unpublished preprints need to be interpreted with caution, because they have not yet undergone peer review. Given that the pandemic originated in China, a large proportion of the relevant papers concerned COVID-19 in that country and more data are needed from other countries. It was beyond the scope of this review to examine factors that might protect people, including children, against COVID-19 transmission, such as wearing masks 63 and hand washing. In addition, the current paper did not explore the circumstances that predict such behaviour in children, as opposed to adults. Some data have indicated that the parents' socioeconomic background had an impact on wearing masks and hand washing 64 . Also, we did not include papers dealing exclusively with mathematical modelling 32 65 66 . The conclusion of this systematic review is that children are unlikely to be the main drivers of the pandemic. Opening up schools and kindergartens is unlikely to impact COVID-19 mortality rates in older people. 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