The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the disease termed coronavirus disease 2019 (COVID-19), emerged in China in early December 2019.1 The outbreak was declared a public health emergency of international concern by the World Health Organization on January 30, 2020.2 The virus has rapidly spread causing a global pandemic with a major burden on the health care system and economy.
During the early stages of the outbreak, it was thought that children were rarely affected by SARS-CoV-2 which could have been as a result of their lower nosocomial exposure and less frequent contact with animals.3 However, a number of reports suggest that children are just as likely as adults to become infected with SARS-CoV-2 but have fewer symptoms and less severe disease, as well as a much lower case-fatality rate.4,5 Many of the initial studies in China were done in adults hospitals, so it is not surprising that the numbers of children reported were small.3,6 Furthermore, as many children with mild disease might not be tested, the true rate of infection and viral carriage is likely underestimated.
In this review, we summarize the epidemiologic characteristics and clinical features of children infected with SARS-CoV-2 reported in pediatric case series to date. We also summarize perinatal outcomes of infants born to women infected with SARS-CoV-2 during pregnancy. Understanding the clinical presentation of this virus in this age group is important for early identification of children with SARS-CoV-2 to provide optimal medical care and to help control the pandemic.
PEDIATRIC CASE SERIES
We found 11 case series, including a total of 333 children (range 6–171 children) with confirmed SARS-CoV-2 infections (Tables 1–4).7–17 All of the series are from China. One case series included only infants13 and one only children who were admitted to an intensive care unit.16 In 2 of the studies, there were patients that overlapped7,16 and further duplicate reporting of patient could not be excluded in 2 other studies.7,11 We did not include single case reports,18–23 publications which did not give enough clinical details17,24–26 or studies which were retracted.27 The age of the children ranged from 1 day to 16 years, 55% (183) were male. The majority of diagnoses were made by real-time polymerase chain reaction on nasopharyngeal or other respiratory samples. Overall, 83% (275, range 52%–100%) of children had a positive contact history, mostly with family members. Three studies reported incubation periods which varied between 2 and 25 days (mean 7 days, median 6 and 11 days, respectively).9,15,16 Several studies reported that the nasopharyngeal or throat swabs can be positive before the onset of symptoms.7,11,14 However, false-negative swabs have also been described.11 There were 4 studies which did consecutive sampling: real-time polymerase chain reaction on respiratory samples remained positive between 1 and 22 days and in stool between 5 and over 30 days.8,9,14,17 Viral shedding from the gastrointestinal tract might last longer and also be greater than that from the respiratory tract.14
Three studies investigated for co-infections (Table 1).11,16 One study only for influenza A and B, which was found in 1 of 8 children16 and the other 2 studies for a broader range of pathogens, which were found in 45% and 79% of children.11,15 Mycoplasma (20%, 26%) and influenza A and B (15%, 35%) were the most common co-infections, followed by respiratory syncytial virus (5%, 6%) and Epstein-Barr virus (6%). Cytomegalovirus, parainfluenza and adenovirus were also isolated.11,15
Depending on the study design, up to 35% of children were asymptomatic (Table 2). The most common symptoms were cough in 48% (160, 19%–100%), fever in 42% (140, 11%–100%, mean duration 3–6 days, range 1–16 days) and pharyngitis in 30% (99, 11%–100%). Further symptoms were tachypnoea (0%–100%), nasal congestions (0%–30%), rhinorrhea (0%–20%), wheezing (33%), diarrhea (8%–23%), vomiting (8%–50%), headache (8%–13%) and fatigue (8%–13%).
Typical laboratory findings were minor changes in white blood cell counts (reports of both increased and decreased lymphocyte and, less commonly, neutrophil counts), as well as mildly elevated inflammatory markers (erythrocyte sedimentation rate, C-reactive protein or procalcitonin), liver enzymes, creatine kinase, lactate dehydrogenase or D-dimers (Table 3).
Radiologic findings were unspecific and milder compared with those in adults.28 They included unilateral or bilateral infiltrates on chest radiograph or computer tomography and, sometimes, additional ground-glass opacities or consolidations with a surrounding halo sign in the latter (Table 3).
Twenty (6%) children were reported to require oxygen (Table 4). Other treatments used were oseltamivir, ribavirin (±lopinavir), interferon, glucocorticoids, immunoglobulin, antibiotics and traditional Chinese medicine.8,10,12,15–17 The hospital stays ranged from 5 to more than 28 days with means of 13–14 days.8,10–12,16
Nine children (3%) needed admission to an intensive care unit7,12,16 (there was an overlap of the reporting of 3 patients between 2 studies).7,16 Of these 9 children, only 2 were described to have a preexisting condition (leukemia and hydronephrosis, respectively). A 10-month-old girl admitted to an intensive care unit developed intussusception, encephalopathy, septic shock and multiple organ dysfunction, and died.7 A further death due to COVID-19 of a 14-year-old boy has been reported in an epidemiologic study from China29 and further deaths have now been reported in Europe and the USA.
SARS-CoV-2 INFECTION DURING PREGNANCY, VERTICAL TRANSMISSION AND PERINATAL OUTCOMES
There are 9 small case series (all from China) and 2 case reports including a total of 65 pregnant women (67 neonates) who were infected with SARS-CoV-2 during pregnancy (Table 5).30–39 The number of women in each case series varied between 2 and 16 (median 7). Two women were infected at 25 and 27 weeks of pregnancy, the remaining during the third trimester. Three women were discharged, the remaining delivered between 30 and 40 weeks of pregnancy, mostly by Cesarean section 88% (56). Fetal distress was reported in 31% (20). A total of 38% (724) women delivered preterm. Maternal complications included premature rupture of membranes 12% (8), pre-eclampsia 3% (2), gestational hypertension 6% (4), gestational diabetes 5% (3), hypothyroidism 3% (2), tachycardia 2% (1) and abnormal umbilical cord 3% (2). Two women (3%) were admitted to intensive care unit for mechanical ventilation, one of whom developed multi-organ failure and was still on extracorporeal membrane oxygenation at the time of the publication.35,36 Neonatal complications included respiratory distress or pneumonia 18% (12), low birth weight 13% (9), rash 3% (2), disseminated intravascular coagulation 3% (2), asphyxia 2% (1) and perinatal death 3% (2).34,36 SARS-CoV-2 could not be isolated from amniotic fluid, placenta tissue, vaginal swabs, cord blood or breast milk, or from neonatal nasopharyngeal and throat swabs in 27 mother-infant pairs.30–36,38,39 However, 1 healthy neonate and 3 neonates who developed pneumonia tested positive on throat, nasopharyngeal and anal swabs on days 2 and 4 of life.37 This was despite strict infection control and prevention procedures during delivery and separation of mother and neonates. Additionally, three neonates whose mother presented with COVID-19 infection 23 days before delivery were found to have immunoglobulin M and G against SARS-CoV-2 at birth.39,40 Therefore, vertical transmission could not be excluded.
This review confirms that, compared with adults, children with SARS-CoV-2 infection have milder clinical symptoms and fewer laboratory and radiologic abnormalities. The same findings have previously been reported for SARS- and Middle East respiratory syndrome (MERS)-CoV.41–46
There are several hypotheses for why children infected with SARS-CoV-2 have less severe symptoms (Table 6). One potential explanation is differences in the immune system between children and adults, especially elderly adults.47 Mice models of infections with SARS-CoV show that both CD4 and CD8 T cells, as well as antibodies, play an important role in virus clearance.48–50 Children have a stronger innate immune response, higher proportion of total lymphocytes and absolute numbers of T and B cells, as well as natural killer cells, which might help to fight the virus.51 However, children are often described to have an ‘immature’ immune system and, for infections with other respiratory tract viruses, for example, respiratory syncytial virus or influenza, infants and children are at higher risk for serious disease and hospital admission.52 This suggests that protective immunity against SARS-CoV-2 differs to that against other common respiratory viruses.
Furthermore, children have a less proinflammatory cytokine response and are less prone to develop acute respiratory distress syndrome.51,53 It is therefore possible that the cytokine storm which plays an important role in the pathogenesis of severe COVID-19 in adults, is attenuated in this age group.54
The second factor that may contribute to the reduced severity of COVID-19 is the lower prevalence in children of the co-morbidities that have been associated with severe disease, such as diabetes, chronic lung, heart and kidney problems or arterial hypertension.55
The third potential explanation for the milder symptoms of SARS-CoV-2 infections in children is that common circulating coronaviruses are frequent in this age group, responsible for approximately 8% of acute respiratory tract infections.56–58 Preexisting immunity and cross-reacting antibodies to SARS-CoV-2 may play a protective role. Despite the fact that most individuals develop antibodies to common circulation coronaviruses during childhood,59–62 reinfections later in life occur,56,63,64 suggesting waning immunity against coronaviruses and increased susceptibility in adults.
The fourth potential explanation is the higher mucosal colonization by viruses and bacteria, which could limit colonization and growth of SARS-CoV-2 through microbial interactions and competition.65,66
A fifth hypothesis for the less severe symptoms in children is that children are usually infected by an adult, which means that they are infected by a second or third generation of the virus. For SARS- and MERS-CoV, these following generations have been described to have decreased pathogenicity.67,68
The sixth potential explanation related to angiotensin-converting enzyme 2 (ACE2) receptors that are one of the main receptors for the entry of SARS- and SARS-CoV-2 into human cells.69,70 It has been suggested that adults who are taking ACE inhibitors or angiotensin receptor blockers for arterial hypertension might have a higher number of ACE2 receptors, potential making them more susceptible to SARS-CoV-2.71,72 However, this theory remains controversial.73 It has been postulated that children have less ACE2 receptors with lower affinity compared with adults and therefore might be less affected by SARS-CoV-2.74 ACE2 is important in regulating the immune response, especially in the lungs. In animal studies, it has been shown to protect against SARS-CoV- and influenza-associated lung injury.75–77 For Pseudomonal lung infections, it has been shown that a dynamic variation of pulmonary ACE2 is required for protection against lung injury.78 The interaction between ACE2 concentration and the number and affinity of ACE2 receptor is likely complex and might also be influenced by genetics.79,80
The majority of children included in this review had a reported adult or family contact infected with SARS-CoV-2. It is still uncertain whether asymptomatic children transmit the virus and therefore the role of children as a reservoir for SARS-CoV-2 and for transmission of the virus remains unclear. However, it has been reported that even asymptomatic children can have high viral loads of SARS-CoV-220 and can excrete the virus in stool for a prolonged period.9,14,17
Unpublished data suggests that the clinical features of COVID-19 in children varies in different countries. While in Asian countries and Europe children have been reported to have milder disease, recent data from the US reports that, by March 27, 2020, at least 35 children needed mechanical ventilation and one infant died. It has been suggested that this could be due to differences in Bacillus-Calmette-Guérin vaccination policies, as this vaccine’s off-target immunomodulatory effects might alter the immune response to SARS-CoV-2.81–83
The influence of SARS-CoV-2 infection on pregnancy and neonatal outcomes is also unclear. SARS- and MERS-CoV cause more severe disease in pregnant women compared with non-pregnant women.84,85 To date, this has not been reported for SARS-CoV-2.25,86 Nevertheless, 3% of pregnant women infected were admitted to intensive care unit.35,36 There is no evidence that SARS-CoV or MERS-CoV can be vertically transmitted to the fetus, however, maternal infections have been associated with intrauterine growth retardation, preterm delivery, stillbirths and perinatal deaths.85,87–91 Similarly, low birth weight, preterm delivery and 2 perinatal deaths have been reported in association with SARS-CoV-2.30,31,33–37 It is unclear if some of the reported maternal and neonatal complications are due to the virus or were iatrogenic (eg, decision for a Cesarean leading to preterm delivery and neonatal respiratory problems). Nevertheless, 1 case-control study reported that the number of pre-term deliveries were higher in SARS-CoV-2-infected women compared with non-infected women.31 Furthermore, fetal distress and preterm ruptures of membranes have been reported in SARS-CoV-2 infected women.30,31,34,37
The one healthy neonate and 3 neonates who developed pneumonia and tested positive for SARS-CoV-2 on day 2 of life and the three neonates who had immunoglobulin M against SARS-CoV-2 at birth, despite strict infection control and prevention procedures during delivery and separation of mother and infants, suggests the possibility of vertical transmission of SARS-CoV-2.37–40
There is no evidence for the presence of SARS-CoV-2 in genital fluids.33 However, the virus can be isolated from feces, meaning it is possible that vaginal delivery poses a greater risk for infection of the infant. Most of the women delivered by Cesarean section as recommended in Chinese guidelines. It is still unclear whether the virus can be transmitted through breast milk. However, close contact during breast-feeding, might risk droplet or contact transmission from the mother to the neonate.
1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–733.
2. WHO. Coronavirus disease 2019 (COVID-19) Situation Report - 11. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200131-sitrep-11-ncov.pdf?sfvrsn=de7c0f7_4
. Published 31 January 2020. Accessed March 23, 2020.
3. Wu Z, McGoogan JM. 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. JAMA. 2020.
4. Bi Q, Wu Y, Mei S, et al. Epidemiology and transmission of COVID-19 in Shenzhen China: analysis of 391 cases and 1,286 of their close contacts. medRxiv. 2020. https://doi.org/10.1101/2020.03.03.20028423
5. Zimmermann P, Curtis N. Coronavirus infections in children including COVID-19: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children. The Pediatric Infectious Disease Journal. 2020.
6. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020.
7. Lu X, Zhang L, Du H, et al. SARS-CoV-2 infection in children. N Engl J Med. 2020.
8. Qiu H, Wu J, Hong L, et al. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. The Lancet Infectious Diseases.
9. Cai J, Xu J, Lin D, et al. A case series of children with 2019 novel coronavirus infection: clinical and epidemiological features. Clin Infect Dis. 2020; pii:ciaa198.
10. Tang A, Xu W, shen m, et al. A retrospective study of the clinical characteristics of COVID-19 infection in 26 children. medRxiv. 2020. https://doi.org/10.1101/2020.03.08.20029710
11. Xia W, Shao J, Guo Y, et al. Clinical and CT features in pediatric patients with COVID-19 infection: different points from adults. Pediatr Pulmonol. 2020.
12. Liu W, Zhang Q, Chen J, et al. Detection of covid-19 in children in early january 2020 in Wuhan, China. N Engl J Med. 2020.
13. Wei M, Yuan J, Liu Y, et al. Novel coronavirus infection in hospitalized infants under 1 year of age in China. JAMA. 2020.
14. Xu Y, Li X, Zhu B, et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nature Medicine. 2020.
15. Zhang C, Gu J, Chen Q, et al. Clinical characteristics of 34 children with coronavirus disease-2019 in the West of China: a multiple-center case series. medRxiv. 2020. https://doi.org/10.1101/2020.03.12.20034686
16. Sun D, Li H, Lu XX, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center’s observational study. World J Pediatr. 2020.
17. Xing Y, Ni W, Wu Q, et al. Prolonged presence of SARS-CoV-2 in feces of pediatric patients during the convalescent phase. medRxiv. 2020. https://doi.org/10.1101/2020.03.11.20033159
18. Cui Y, Tian M, Huang D, et al. A 55-Day-Old Female Infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage. J Infect Dis. 2020 pii:jiaa113
19. Ji LN, Chao S, Wang YJ, et al. Clinical features of pediatric patients with COVID-19: a report of two family cluster cases. World J Pediatr. 2020.
20. Kam KQ, Yung CF, Cui L, et al. A well infant with coronavirus disease 2019 (COVID-19) with high viral load. Clin Infect Dis. 2020;pii:ciaa201.
21. Chan JF, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020.
22. Zhang YH, Lin DJ, Xiao MF, et al. [2019 novel coronavirus infection in a three-month-old baby]. Zhonghua Er Ke Za Zhi. 2020;58:182–184.
23. Cai JH, Wang XS, Ge YL, et al. [First case of 2019 novel coronavirus infection in children in Shanghai]. Zhonghua Er Ke Za Zhi. 2020;58:E002.
24. Lou XX, Shi CX, Zhou CC, et al. Three children who recovered from novel coronavirus 2019 pneumonia. J Paediatr Child Health. 2020.
25. Liu H, Liu F, Li J, et al. Clinical and CT imaging features of the COVID-19 pneumonia: focus on pregnant women and children. J Infect. 2020;pii:S01634453(20)301183.
26. Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020;368:m606.
27. Wang XF, Yuan J, Zheng YJ, et al. [Retracted: clinical and epidemiological characteristics of 34 children with 2019 novel coronavirus infection in Shenzhen]. Zhonghua Er Ke Za Zhi. 2020;58:E008.
28. Feng K, Yun YX, Wang XF, et al. [Analysis of CT features of 15 Children with 2019 novel coronavirus infection]. Zhonghua Er Ke Za Zhi. 2020;58:E007.
29. Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020.
30. Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. The Lancet.
31. Li N, Han L, Peng M, et al. Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study. medRxiv. 2020. https://doi.org/10.1101/2020.03.10.20033605
32. Chen Y, Peng H, Wang L, et al. Infants Born to Mothers With a New Coronavirus (COVID-19). Frontiers in pediatrics. 2020;8:104.
33. Fan C, Lei D, Fang C, et al. Perinatal transmission of COVID-19 associated SARS-CoV-2: should we worry? Clin Infect Dis. 2020.
34. Zhu H, Wang L, Fang C, et al. Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia. Transl Pediatr. 2020;9:51–60.
35. Liu Y, Chen H, Tang K, et al. Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy. J Infect. 2020.
36. Wang X, Zhou Z, Zhang J, et al. A case of 2019 Novel Coronavirus in a pregnant woman with preterm delivery. Clin Infect Dis. 2020.
37. Zeng L, Xia S, Yuan W, et al. Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China. JAMA pediatrics. 2020.
38. Yu N, Li W, Kang Q, et al. Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study. The Lancet Infectious Diseases. 2020; pii:S14733099(20)301766
39. Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020.
40. Zeng H, Xu C, Fan J, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA. 2020.
41. Hon KL, Leung CW, Cheng WT, et al. Clinical presentations and outcome of severe acute respiratory syndrome in children. Lancet. 2003;361:1701–1703.
42. Chiu WK, Cheung PC, Ng KL, et al. Severe acute respiratory syndrome in children: experience in a regional hospital in Hong Kong. Pediatr Crit Care Med. 2003;4:279–283.
43. Bitnun A, Allen U, Heurter H, et al. Other Members of the Hospital for Sick Children SARS Investigation Team. Children hospitalized with severe acute respiratory syndrome-related illness in Toronto. Pediatrics. 2003;112:e261.
44. Leung CW, Kwan YW, Ko PW, et al. Severe acute respiratory syndrome among children. Pediatrics. 2004;113:e535–e543.
45. Al-Tawfiq JA, Kattan RF, Memish ZA. Middle East respiratory syndrome coronavirus disease is rare in children: an update from Saudi Arabia. World J Clin Pediatr. 2016;5:391–396.
46. Alfaraj SH, Al-Tawfiq JA, Altuwaijri TA, et al. Middle East respiratory syndrome coronavirus in pediatrics: a report of seven cases from Saudi Arabia. Front Med. 2019;13:126–130.
47. Simon AK, Hollander GA, McMichael A. Evolution of the immune system in humans from infancy to old age. Proc Biol Sci. 2015;282:20143085.
48. Zhao J, Zhao J, Perlman S. T cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice. J Virol. 2010;84:9318–9325.
49. Chen J, Lau YF, Lamirande EW, et al. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J Virol. 2010;84:1289–1301.
50. Zeng LP, Ge XY, Peng C, et al. Cross-neutralization of SARS coronavirus-specific antibodies against bat SARS-like coronaviruses. Sci China Life Sci. 2017;60:1399–1402.
51. Valiathan R, Ashman M, Asthana D. Effects of ageing on the immune system: infants to elderly. Scand J Immunol. 2016;83:255–266.
52. Tregoning JS, Schwarze J. Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology. Clin Microbiol Rev. 2010;23:74–98.
53. Nye S, Whitley RJ, Kong M. Viral infection in the development and progression of pediatric acute respiratory distress syndrome. Front Pediatr. 2016;4:128.
54. Mehta P, McAuley DF, Brown M, et al. HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–1034.
55. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020.
56. Uddin SMI, Englund JA, Kuypers JY, et al. Burden and risk factors for coronavirus infections in infants in rural Nepal. Clin Infect Dis. 2018;67:1507–1514.
57. Taylor S, Lopez P, Weckx L, et al. Respiratory viruses and influenza-like illness: Epidemiology and outcomes in children aged 6 months to 10 years in a multi-country population sample. J Infect. 2017;74:29–41.
58. Gaunt ER, Hardie A, Claas EC, et al. Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method. J Clin Microbiol. 2010;48:2940–2947.
59. Dijkman R, Jebbink MF, El Idrissi NB, et al. Human coronavirus NL63 and 229E seroconversion in children. J Clin Microbiol. 2008;46:2368–2373.
60. Hasony HJ, Macnaughton MR. Prevalence of human coronavirus antibody in the population of southern Iraq. J Med Virol. 1982;9:209–216.
61. Kaye HS, Marsh HB, Dowdle WR. Seroepidemiologic survey of coronavirus (strain OC 43) related infections in a children’s population. Am J Epidemiol. 1971;94:43–49.
62. Leung TF, Li CY, Lam WY, et al. Epidemiology and clinical presentations of human coronavirus NL63 infections in hong kong children. J Clin Microbiol. 2009;47:3486–3492.
63. Isaacs D, Flowers D, Clarke JR, et al. Epidemiology of coronavirus respiratory infections. Arch Dis Child. 1983;58:500–503.
64. Monto AS, Lim SK. The Tecumseh study of respiratory illness. VI. Frequency of and relationship between outbreaks of coronavirus infection. J Infect Dis. 1974;129:271–276.
65. Gonzalez AJ, Ijezie EC, Balemba OB, et al. Attenuation of influenza a virus disease severity by viral coinfection in a mouse model. J Virol. 2018;92.
66. Nickbakhsh S, Mair C, Matthews L, et al. Virus-virus interactions impact the population dynamics of influenza and the common cold. Proceedings of the National Academy of Sciences of the United States of America. 2019.
67. Chowell G, Abdirizak F, Lee S, et al. Transmission characteristics of MERS and SARS in the healthcare setting: a comparative study. BMC Med. 2015;13:210.
68. Breban R, Riou J, Fontanet A. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk. Lancet. 2013;382:694–699.
69. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273.
70. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020;5:562–569.
71. Perico L, Benigni A, Remuzzi G. Should COVID-19 concern nephrologists? Why and to What Extent? The emerging impasse of angiotensin blockade. Nephron. 2020:1–9.
72. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The Lancet Respiratory medicine. 2020.
73. Tignanelli CJ, Ingraham NE, Sparks MA, et al. Antihypertensive drugs and risk of COVID-19? The Lancet Respiratory Medicine. 2020.
74. Fang F, Luo XP. [Facing the pandemic of 2019 novel coronavirus infections: the pediatric perspectives]. Zhonghua Er Ke Za Zhi. 2020;58:81–85.
75. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–116.
76. Zou Z, Yan Y, Shu Y, et al. Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun. 2014;5:3594.
77. Wang J, Zhao S, Liu M, et al. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism. medRxiv. 2020. https://doi.org/10.1101/2020.02.05.20020545
78. Sodhi CP, Nguyen J, Yamaguchi Y, et al. A dynamic variation of pulmonary ACE2 is required to modulate neutrophilic inflammation in response to pseudomonas aeruginosa lung infection in mice. J Immunol. 2019;203:3000–3012.
79. Luo Y, Liu C, Guan T, et al. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang. Hypertens Res. 2019;42:681–689.
80. Liu D, Chen Y, Zhang P, et al. Association between circulating levels of ACE2-Ang-(1-7)-MAS axis and ACE2 gene polymorphisms in hypertensive patients. Medicine (Baltimore). 2016;95:e3876.
81. Miller A, Reandelar MJ, Fasciglione K, et al. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. medRxiv. 2020. https://doi.org/10.1101/2020.03.24.20042937
82. Moorlag SJCFM, Arts RJW, van Crevel R, et al. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect. 2019;25:1473–1478.
83. Messina NL, Zimmermann P, Curtis N. The impact of vaccines on heterologous adaptive immunity. Clin Microbiol Infect. 2019;25:1484–1493.
84. Lam CM, Wong SF, Leung TN, et al. A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome. BJOG. 2004;111:771–774.
85. Assiri A, Abedi GR, Al Masri M, et al. Middle east respiratory syndrome coronavirus infection during pregnancy: a report of 5 Cases From Saudi Arabia. Clin Infect Dis. 2016;63:951–953.
86. Liu D, Li L, Wu X, et al. Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: a preliminary analysis. AJR Am J Roentgenol. 2020:1–6.
87. Wong SF, Chow KM, Leung TN, et al. Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome. Am J Obstet Gynecol. 2004;191:292–297.
88. Shek CC, Ng PC, Fung GP, et al. Infants born to mothers with severe acute respiratory syndrome. Pediatrics. 2003;112:e254.
89. Payne DC, Iblan I, Alqasrawi S, et al. Jordan MERS-CoV Investigation Team. Stillbirth during infection with Middle East respiratory syndrome coronavirus. J Infect Dis. 2014;209:1870–1872.
90. Alserehi H, Wali G, Alshukairi A, et al. Impact of Middle East Respiratory Syndrome coronavirus (MERS-CoV) on pregnancy and perinatal outcome. BMC Infect Dis. 2016;16:105.
91. Malik A, El Masry KM, Ravi M, et al. Middle east respiratory syndrome coronavirus during pregnancy, Abu Dhabi, United Arab Emirates, 2013. Emerg Infect Dis. 2016;22:515–517.