Coronavirus infections in children: from SARS and MERS to COVID-19, a narrative review of epidemiological and clinical features

Main Article Content

Rosanna Iannarella
Claudia Lattanzi
Giulia Cannata
Alberto Argentiero
Cosimo Neglia
Valentina Fainardi
Giovanna Pisi
Susanna Esposito

Keywords

Coronavirus, Middle-East respiratory syndrome (MERS), Severe Acute respiratory syndrome (SARS), COVID-19, children, clinical manifestations.

Abstract

Emerging and re-emerging viruses represent an important challenge for global public health. In the 1960s, coronaviruses (CoVs) were recognized as disease agents in humans. In only two decades, three strains of CoVs have crossed species barriers rapidly emerging as human pathogens resulting in life-threatening disease with a pandemic potential: severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, Middle-East respiratory syndrome coronavirus (MERS-CoV) in 2012 and the recently emerged SARS-CoV-2. This narrative review aims to provide a comprehensive overview of epidemiological, pathogenic and clinical features, along with diagnosis and treatment, of the ongoing epidemic of new coronavirus disease 2019 (COVID-19) in the pediatric population in comparison to the first two previous deadly coronavirus outbreaks, SARS and MERS. Literature analysis showed that SARS-CoV, MERS-CoV and SARS-CoV-2 infections seem to affect children less commonly and less severely as compared with adults. Since children are usually asymptomatic, they are often not tested, leading to an underestimate of the true numbers infected. Most of the documented infections belong to family clusters, so the importance of children in transmitting the virus remains uncertain. Like in SARS and MERS infection, there is the possibility that children are not an important reservoir for novel CoVs and this may have important implications for school attendance. While waiting for an effective against SARS-CoV-2, further prevalence studies in paediatric age are needed, in order to clarify the role of children in different age groups in the spread of the infection.

a

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...
Abstract 2 | PDF Downloads 1

References

1. Lai MM. Coronavirus: organization, replication and expression of genome. Annu Rev Microbiol. 1990;44:303‐333. doi:10.1146/annurev.mi.44.100190.001511
2. Masters PS, Perlman S. Coronaviridae. In: Fields Virology, 6th ed, Knipe DM, Howley PM, Cohen JI, et al (Eds), Lippincott Williams & Wilkins, a Wolters Kluwer business, Philadelphia 2013. Vol 2, p.825
3. Woo PC, Huang Y, Lau SK, Yuen KY. Coronavirus genomics and bioinformatics analysis. Viruses. 2010;2(8):1804‐1820. doi:10.3390/v2081803
4. N. James Maclachlan Edward J Dubovi. In: Fenner's Veterinary Virology, 5th ed (2017), Chapter 24, p. 435
5. Su S, Wong G, Shi W, et al. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends Microbiol. 2016;24(6):490‐502. doi:10.1016/j.tim.2016.03.003
6. World Health Organization. Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003. Available at http://www.who.int/csr/sars/country/table20030923/en/print.html; last accessed March 30 2020
7. World Health Organisation. Severe Acute Respiratory Syndrome Surveillance Team. Personal Communication
8. Chan WM, Kwan YW, Wan HS, Leung CW, Chiu MC. Epidemiologic linkage and public health implication of a cluster of severe acute respiratory syndrome in an extended family. Pediatr Infect Dis J. 2004;23(12):1156‐1159.
9. Hui DS, Sung JJ. Severe acute respiratory syndrome. Chest. 2003;124(1):12‐15. doi:10.1378/chest.124.1.12
10. Chan CW, Chiu WK, Chan CC, Chow EY, Cheung HM, Ip PL. Osteonecrosis in children with severe acute respiratory syndrome. Pediatr Infect Dis J. 2004;23(9):888‐890. doi:10.1097/01.inf.0000137570.37856.ea
11. 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(3):279‐283. doi:10.1097/01.PCC.0000077079.42302.81
12. Leung CW, Kwan YW, Ko PW, et al. Severe acute respiratory syndrome among children. Pediatrics. 2004;113(6):e535‐e543. doi:10.1542/peds.113.6.e535
13. Ng PC, Lam CW, Li AM, et al. Inflammatory cytokine profile in children with severe acute respiratory syndrome. Pediatrics. 2004;113(1 Pt 1):e7‐e14. doi:10.1542/peds.113.1.e7
14. Leung CW, Chiu WK. Clinical picture, diagnosis, treatment and outcome of severe acute respiratory syndrome (SARS) in children. Paediatr Respir Rev. 2004;5(4):275‐288. doi:10.1016/j.prrv.2004.07.010
15. Bitnun A, Allen U, Heurter H, et al. Children hospitalized with severe acute respiratory syndrome-related illness in Toronto. Pediatrics. 2003;112(4):e261. doi:10.1542/peds.112.4.e261
16. Li G, Chen X, Xu A. Profile of specific antibodies to the SARS-associated coronavirus. N Engl J Med. 2003;349(5):508‐509. doi:10.1056/NEJM200307313490520
17. Tsou IY, Loh LE, Kaw GJ, Chan I, Chee TS. Severe acute respiratory syndrome (SARS) in a paediatric cluster in Singapore. Pediatr Radiol. 2004;34(1):43‐46. doi:10.1007/s00247-003-1042-2
18. Leung CW, Li CK. PMH/PWH interim guideline on the management of children with SARS. HK J Paediatr 2003;8:168-9
19. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia [published correction appears in N Engl J Med. 2013 Jul 25;369(4):394]. N Engl J Med. 2012;367(19):1814‐1820. doi:10.1056/NEJMoa1211721
20. World Health Organisation. Middle East respiratory syndrome coronavirus (MERS-CoV) – The Kingdom of Saudi Arabia. Available at: https://www.who.int/csr/don/24-february-2020-mers-saudi-arabia/en/; last accessed March 4 2020
21. Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. Lancet. 2015;386(9997):995‐1007. doi:10.1016/S0140-6736(15)60454-8
22. Bartenfeld M, Griese S, Uyeki T, Gerber SI, Peacock G. Middle East Respiratory Syndrome Coronavirus and Children. Clin Pediatr (Phila). 2017;56(2):187‐189. doi:10.1177/0009922816678820
23. Memish ZA, Al-Tawfiq JA, Makhdoom HQ, et al. Screening for Middle East respiratory syndrome coronavirus infection in hospital patients and their healthcare worker and family contacts: a prospective descriptive study. Clin Microbiol Infect. 2014;20(5):469‐474. doi:10.1111/1469-0691.12562
24. Khuri-Bulos N, Payne DC, Lu X, et al. Middle East respiratory syndrome coronavirus not detected in children hospitalized with acute respiratory illness in Amman, Jordan, March 2010 to September 2012. Clin Microbiol Infect. 2014;20(7):678‐682. doi:10.1111/1469-0691.12438
25. Memish ZA, Al-Tawfiq JA, Assiri A, et al. Middle East respiratory syndrome coronavirus disease in children. Pediatr Infect Dis J. 2014;33(9):904‐906. doi:10.1097/INF.0000000000000325
26. Thabet F, Chehab M, Bafaqih H, Al Mohaimeed S. Middle East respiratory syndrome coronavirus in children. Saudi Med J. 2015;36(4):484‐486. doi:10.15537/smj.2015.4.10243
27. Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, et al. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis. 2013;13(9):752‐761. doi:10.1016/S1473-3099(13)70204-4
28. World Health Organisation. Middle East respiratory syndrome coronavirus: case definition for reporting to WHO. Available at: https://www.who.int/csr/disease/coronavirus_infections/case_definition/en/; last accessed March 4 2020
29. World Health Organisation. WHO Statement Regarding Cluster of Pneumonia Cases in wuhan, China. Available at: https://www.who.int/china/news/detail/09-01-2020-who-statement; last accessed March 4 2020
30. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727‐733. doi:10.1056/NEJMoa2001017
31. World Health Organization. Coronavirus disease (COVID-19) outbreak. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019; last accessed March 4 2020
32. World Health Organisation. WHO Virtual press conference on COVID-19. March 11, 2020. Available at: https://www.who.int/docs/defaultsource/coronaviruse/transcripts/who-audio-emergencies-coronavirus-press-conference-full-and-final11mar2020.pdf?sfvrsn=cb432bb3_2; last accessed March 16 2020
33. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270‐273. doi:10.1038/s41586-020-2012-7
34. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565‐574. doi:10.1016/S0140-6736(20)30251-8
35. Ren LL, Wang YM, Wu ZQ, et al. Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study. Chin Med J (Engl). 2020;133(9):1015‐1024. doi:10.1097/CM9.0000000000000722
36. Guo Q, Li M, Wang C, Wang P, Fang Z, Tan J, Wu S, Xiao Y, Zhu H. Host and infectivity prediction of Wuhan 2019 novel coronavirus using deep learning algorithm. bioRxiv 2020
37. Ji W, Wang W, Zhao X, Zai J, Li X. Homologous recombination within the spike glycoprotein of the newly identified coronavirus may boost cross-species transmission from snake to human. J Med Virol 2020;92, 433–440
38. Xiao KP, Zhai JP Feng YY, et al. Isolation and Characterization of 2019 -nCoV-like Coronavirus from Malayan Pangolins. bioRxiv 2020.02.17.951335
39. Lam T, Shum M, Zhu HZ, et al. Identification of 2019-nCoV related coronaviruses in Malayan pangolins in southern China. bioRxiv 2020.02.13.945485
40. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565‐574. doi:10.1016/S0140-6736(20)30251-8
41. Lu G, Wang Q, Gao GF. Bat-to-human: spike features determining 'host jump' of coronaviruses SARS-CoV, MERS-CoV, and beyond. Trends Microbiol. 2015;23(8):468‐478. doi:10.1016/j.tim.2015.06.003
42. Du L, He Y, Zhou Y, Liu S, Zheng BJ, Jiang S. The spike protein of SARS-CoV--a target for vaccine and therapeutic development. Nat Rev Microbiol. 2009;7(3):226‐236. doi:10.1038/nrmicro2090
43. Du L, Yang Y, Zhou Y, Lu L, Li F, Jiang S. MERS-CoV spike protein: a key target for antivirals. Expert Opin Ther Targets. 2017;21(2):131‐143. doi:10.1080/14728222.2017.1271415
44. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271‐280.e8. doi:10.1016/j.cell.2020.02.052
45. Wang Q, Zhang Y, Wu L, et al. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell. 2020;181(4):894‐904.e9. doi:10.1016/j.cell.2020.03.045
46. Xia S, Zhu Y, Liu M, et al. Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein [published online ahead of print, 2020 Feb 11]. Cell Mol Immunol. 2020;1‐3. doi:10.1038/s41423-020-0374-2
47. 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;395(10223):514‐523. doi:10.1016/S0140-6736(20)30154-9
48. Dietz K. The estimation of the basic reproduction number for infectious diseases. Stat Methods Med Res. 1993;2(1):23‐41. doi:10.1177/096228029300200103
49. Ridenhour B, Kowalik JM, Shay DK. Unraveling R0: considerations for public health applications. Am J Public Health. 2014;104(2):e32‐e41. doi:10.2105/AJPH.2013.301704
50. World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report-46, 7th March 2020. Available at: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200306-sitrep-46-covid-19.pdf?sfvrsn=96b04adf_4; last accessed March 16 2020
51. Lai A, Bergna A, Acciarri C, Galli M, Zehender G. Early phylogenetic estimate of the effective reproduction number of SARS-CoV-2 [published online ahead of print, 2020 Feb 25]. J Med Virol. 2020;10.1002/jmv.25723. doi:10.1002/jmv.25723
52. Liu Y, Gayle AA, Wilder-Smith A, Rocklöv J. The reproductive number of COVID-19 is higher compared to SARS coronavirus. J Travel Med. 2020;27(2):taaa021. doi:10.1093/jtm/taaa021
53. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631‐637. doi:10.1002/path.1570
54. Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020;14(2):185‐192. doi:10.1007/s11684-020-0754-0
55. Zhang H, Kang Z, Gong H, Xu D, Wang J, Li Z, et al. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. Preprint at https://www.biorxiv.org/content/10.1101/2020.01.30.927806v1 (2020)
56. Chai X, Hu L, Zhang Y, Han W, Lu Z, Ke A, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. Preprint at https://www.biorxiv.org/content/10.1101/2020.02.03.931766v1 (2020)
57. Lee PI, Hsueh PR. Emerging threats from zoonotic coronaviruses-from SARS and MERS to 2019-nCoV [published online ahead of print, 2020 Feb 4]. J Microbiol Immunol Infect. 2020;. doi:10.1016/j.jmii.2020.02.001
58. Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020;382(13):1199‐1207. doi:10.1056/NEJMoa2001316
59. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020;382(16):1564‐1567. doi:10.1056/NEJMc2004973
60. Lu CW, Liu XF, Jia ZF. 2019-nCoV transmission through the ocular surface must not be ignored. Lancet. 2020;395(10224):e39. doi:10.1016/S0140-6736(20)30313-5
61. Sun CB, Wang YY, Liu GH, Liu Z. Role of the Eye in Transmitting Human Coronavirus: What We Know and What We Do Not Know. Front Public Health. 2020;8:155. Published 2020 Apr 24. doi:10.3389/fpubh.2020.00155
62. Kampf G, Todt D, Pfaender S, Steinmann E. Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. J Hosp Infect. 2020;104(3):246‐251. doi:10.1016/j.jhin.2020.01.022
63. Guo ZD, Wang ZY, Zhang SF, et al. Aerosol and Surface Distribution of Severe Acute Respiratory Syndrome Coronavirus 2 in Hospital Wards, Wuhan, China, 2020 [published online ahead of print, 2020 Apr 10]. Emerg Infect Dis. 2020;26(7):10.3201/eid2607.200885. doi:10.3201/eid2607.200885
64. Yeo C, Kaushal S, Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible?. Lancet Gastroenterol Hepatol. 2020;5(4):335‐337. doi:10.1016/S2468-1253(20)30048-0
65. Chen Y, Chen L, Deng Q, et al. The presence of SARS-CoV-2 RNA in the feces of COVID-19 patients [published online ahead of print, 2020 Apr 3]. J Med Virol. 2020;10.1002/jmv.25825. doi:10.1002/jmv.25825
66. Holshue ML, DeBolt C, Lindquist S, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020;382(10):929‐936. doi:10.1056/NEJMoa2001191
67. Cai J, Xu J, Lin D, et al. A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features [published online ahead of print, 2020 Feb 28]. Clin Infect Dis. 2020;ciaa198. doi:10.1093/cid/ciaa198
68. Ong SWX, Tan YK, Chia PY, et al. Air, Surface Environmental, and Personal Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) From a Symptomatic Patient [published online ahead of print, 2020 Mar 4]. JAMA. 2020;323(16):1610‐1612. doi:10.1001/jama.2020.3227
69. Istituto Superiore di Sanità. Epidemia COVID-19. Aggiornamento nazionale. 20 maggio 2020 – ore 16.00. Available at: https://www.epicentro.iss.it/coronavirus/bollettino/bollettino-sorveglianza-integrata-covid-19_20-maggio-2020; last accessed May 24 2020
70. Yang P, Liu P, Li D, Zhao D. Corona Virus Disease 2019, a growing threat to children?. J Infect. 2020;80(6):671‐693. doi:10.1016/j.jinf.2020.02.024
71. Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020;382(13):1199‐1207. doi:10.1056/NEJMoa2001316
72. Dong Y, Mo XI, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020;16:16. doi:10.1542/peds.2020-0702
73. Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382(17):1663‐1665. doi:10.1056/NEJMc2005073
74. 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;382(14):1370‐1371. doi:10.1056/NEJMc2003717
75. Zheng F, Liao C, Fan QH, et al. Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China. Curr Med Sci. 2020;40(2):275‐280. doi:10.1007/s11596-020-2172-6
76. Cai J, Xu J, Lin D, et al. A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features [published online ahead of print, 2020 Feb 28]. Clin Infect Dis. 2020;ciaa198. doi:10.1093/cid/ciaa198
77. Xia W, Shao J, Guo Y, Peng X, Li Z, Hu D. Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults. Pediatr Pulmonol. 2020;55(5):1169‐1174. doi:10.1002/ppul.24718
78. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):1607‐1608. doi:10.1016/S0140-6736(20)31094-1
79. Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020;109(6):1088‐1095. doi:10.1111/apa.15270
80. Centers for Disease Control and Prevention. Coronavirus Disease 2019 in Children — United States, February 12–April 2, 2020. Available at: https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e4.htm#F2_down; last accessed May 24 2020
81. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 Among Children in China [published online ahead of print, 2020 Mar 16]. Pediatrics. 2020;e20200702. doi:10.1542/peds.2020-0702
82. Henry BM, Lippi G, Plebani M. Laboratory abnormalities in children with novel coronavirus disease 2019 [published online ahead of print, 2020 Mar 16]. Clin Chem Lab Med. 2020;/j/cclm.ahead-of-print/cclm-2020-0272/cclm-2020-0272.xml. doi:10.1515/cclm-2020-0272
83. Fang Y, Zhang H, Xie J, et al. Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR [published online ahead of print, 2020 Feb 19]. Radiology. 2020;200432. doi:10.1148/radiol.2020200432
84. Li W, Cui H, Li K, Fang Y, Li S. Chest computed tomography in children with COVID-19 respiratory infection. Pediatr Radiol. 2020;50(6):796‐799. doi:10.1007/s00247-020-04656-7
85. Duan YN, Zhu YQ, Tang LL, Qin J. CT features of novel coronavirus pneumonia (COVID-19) in children [published online ahead of print, 2020 Apr 14]. Eur Radiol. 2020;1‐7. doi:10.1007/s00330-020-06860-3
86. 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. Pediatr Infect Dis J. 2020;39(5):355‐368. doi:10.1097/INF.0000000000002660
87. Hon KL, Leung CW, Cheng WT, et al. Clinical presentations and outcome of severe acute respiratory syndrome in children. Lancet. 2003;361(9370):1701‐1703. doi:10.1016/s0140-6736(03)13364-8
88. Chen ZM, Fu JF, Shu Q, et al. Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus [published online ahead of print, 2020 Feb 5]. World J Pediatr. 2020;1‐7. doi:10.1007/s12519-020-00345-5
89. Tsou IY, Loh LE, Kaw GJ, Chan I, Chee TS. Severe acute respiratory syndrome (SARS) in a paediatric cluster in Singapore. Pediatr Radiol. 2004;34(1):43‐46. doi:10.1007/s00247-003-1042-2
90. Chen ZM, Fu JF, Shu Q, et al. Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus [published online ahead of print, 2020 Feb 5]. World J Pediatr. 2020;1‐7. doi:10.1007/s12519-020-00345-5
91. Jones VG, Mills M, Suarez D, et al. COVID-19 and Kawasaki Disease: Novel Virus and Novel Case [published online ahead of print, 2020 Apr 7]. Hosp Pediatr. 2020;hpeds.2020-0123. doi:10.1542/hpeds.2020-0123
92. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure [published online ahead of print, 2020 Apr 17]. Cell Host Microbe. 2020;S1931-3128(20)30236-5. doi:10.1016/j.chom.2020.04.009
93. Zhou Y, Fu B, Zheng X, et al. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe Covid-19 patients. Natl Sci Rev 2020 Mar 13. doi: 10.1093/nsr/nwaa041