key: cord-0979923-8s0f253t authors: Soraya, Gita Vita; Ulhaq, Zulvikar Syambani title: Interleukin-6 levels in children developing SARS-CoV-2 infection date: 2020-05-04 journal: Pediatr Neonatol DOI: 10.1016/j.pedneo.2020.04.007 sha: 3a32042e78fa3dc60f629d85e3249739b0afcfc2 doc_id: 979923 cord_uid: 8s0f253t nan Since the declaration of the coronavirus disease 2019 (COVID-19) pandemic status, the total number of cases developing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has reached 1,696,588 worldwide, with a mortality rate of 6.24%. 1 Interestingly, reports have shown that, compared to adults, the pediatric populations have lower infection rates, less severe clinical presentation with lower likelihood of progression, and more favorable prognosis. 2 However, the mechanism behind this phenomenon remains elusive. Recently, we demonstrated that COVID-19 severity in adult patients was strongly associated with higher interleukin-6 (IL-6) levels. 3 Thus, in this article, we aimed to evaluate the current evidence regarding IL-6 levels in pediatric COVID-19 cases. Records, dated up to April 5th, 2020, were identified through electronic databases with search terms such as "COVID-19," "SARS-CoV-2," "IL-6," "pediatrics," "neonates," "infants," "children," and "adolescents." No language restrictions were applied. We synthesized the data from seven studies with a total sample size of n Z 127 pediatric patients, with ages ranging from newborn to adolescence. 4e10 Subsequently, one study was excluded 10 due to samples testing negative for SARS-CoV-2 The final sample yielded a size of n Z 117, with slightly higher infection rates among males (59.8%), which is consistent with previous reports. 5 In contrast to our previous result in adults, 3 we observed that pediatric COVID-19 cases had IL-6 levels within normal range (mean: 86.3%; range from 67 to 100%) ( Table 1) and that all of the current studies observed patients having mild * Corresponding author. E-mail address: zulhaq@kedokteran.uin-malang.ac.id (Z.S. Ulhaq). 1 These authors share first co-authorship to this manuscript. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 symptoms. To illustrate, a study with a representative population range of three days to 16 years of age 5 found an overall mild clinical presentation among cases and increased IL-6 levels were only observed in 17.14% of the total population. In line with this finding, the tendency of mild clinical presentation in children has likewise been recognized in a large epidemiologic study of 2163 children in China 11 , among which only 0.6% progressed into severe disease. This finding reinforces previous notions that the cytokine storm, indicated by excessive circulating IL-6, is a possible mechanism of COVID-19 progression 3 and that this aggressive inflammatory cascade is less likely to occur in children. The findings also emphasize that IL-6 better reflects the severity of COVID-19 clinical presentation and is relatively more consistent compared to other inflammatory markers such as C-reactive protein (CRP). 12 Several factors may contribute to the milder presentation observed in children in regard to the immunopathogenic response. The less mature immune system of children may result in the lower capability to elicit cytokine release against viral infection, relative to the more mature and vigorous immune responses observed in adults. Other possible explanations include healthier respiratory tracts and less pre-existing damage in children compared to adults. There are several limitations identified in this current analysis. Only a few studies reported the IL-6 level in COVID-19-infected pediatric patient, with some variations on the IL-6 reference ranges between studies. Thus, further studies with larger sample size and homogenous or standardized measurement are needed to confirm these findings. Additionally, more studies need to focus on the neonate age group, as data regarding clinical presentation of COVID-19 in this highly susceptible age group remains scant. In summary, these findings confirm that IL-6 reflect presence of marked inflammation and severe COVID-19. Based on current evidence, IL-6 levels of children with SARS-CoV-2 infection tend to be within normal range, which reflects the mild nature of clinical presentation in the pediatric population. None to declare. 4 Yu et al. 5 Du et al. 6 Sun et al. 7 Su et al. 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 WHO. Coronavirus disease 2019 (COVID-19) situation report Clinical characteristics of novel coronavirus disease 2019 (COVID-19) in newborns, infants and children Interleukin-6 as a potential biomarker of COVID-19 progression Detectable SARS-CoV-2 viral RNA in feces of three children during recovery period of COVID-19 pneumonia The clinical and epidemiological features and hints of 82 confirmed COVID-19 pediatric cases aged 0-16 in Wuhan Clinical characteristics of COVID-19 in children compared with adults outside of hubei province in China Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study The different clinical characteristics of corona virus disease cases between children and their families in China -the character of children with COVID-19 First case of neonate infected with novel coronavirus pneumonia in China Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia Epidemiology of COVID-19 among children in China Laboratory abnormalities in children with novel coronavirus disease 2019