Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults | Infectious Diseases | JAMA | JAMA Network
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    2 Comments for this article
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    Confounding Effects of Atopy and Intranasal Corticosteroids on ACE2
    Prof Brian Lipworth, MD | University of Dundee, Tayside Rhinology Mega-Clinic
    The nose is often the first portal of entry for SARS-CoV-2, which enters respiratory epithelial cells via ACE2 . The data from Bunyavanich et al (1) suggests that ACE2 activity in the nose is attenuated in younger children which might explain the lower prevalence of COVID-19 in younger children. There are however some issues in regard to their interpretation of the results. First, the 95% CI for log2-transformed ACE2 values are overlapping when comparing age groups <10 yo versus 10-17 yo, in turn suggesting there is no significant difference between the two groups especially after correcting the alpha error for multiple pairwise comparisons. Second they report that 50% of individuals in the overall cohort had concomitant asthma and that differences between age groups were observed after adjusting for gender and asthma. In such individuals <10 yo there would be a higher prevalence of atopy in regard to the presence of allergic eczema and allergic rhinitis. Since both atopy and topical corticosteroids both reduce airway epithelial ACE2 expression including the nose (2-4), these are likely to be relevant confounding factors which could contribute to lower ACE2 expression seen in the present study . It would therefore be pertinent to know if ACE2 expression remains lower in younger people after removing data for those subjects who were allergic or taking intranasal corticosteroids.

    References

    1. Bunyavanich S, Do A, Vicencio A. Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults. JAMA. 2020.
    2. Kimura H, Francisco D, Conway M, et al. Type 2 Inflammation Modulates ACE2 and TMPRSS2 in Airway Epithelial Cells. Journal of Allergy and Clinical Immunology.
    3. Jackson DJ, Busse WW, Bacharier LB, et al. Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2. Journal of Allergy and Clinical Immunology.
    4. Peters MC, Sajuthi S, Deford P, et al. COVID-19 Related Genes in Sputum Cells in Asthma: Relationship to Demographic Features and Corticosteroids. Am J Respir Crit Care Med. 2020.
    CONFLICT OF INTEREST: None Reported
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    Does Angiotensin-Converting Enzyme 2 Explain COVID-19 Incidence and Risk in Children?
    Akihiko Saitoh, MD, PhD | Niigata University
    We read with great interest the Research Letter describing lower nasal angiotensin-converting enzyme 2 (ACE2) gene expression in children than in adults, as this finding may clarify why children are less affected by coronavirus disease 2019 (COVID-19) (1). In our attempt to understand the pathogenesis and transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children and adults, the most interesting observations are that children infected with SARS-CoV-2 tend to be asymptomatic or to have mild disease and that they are less infectious than adults (2).

    Although the existing data suggest that SARS-CoV-2 infection rates are similar in
    children and adults, SARS-CoV-2 is less symptomatic in children, and few children with severe disease have been reported (2). However among children, COVID-19 severity differs in relation to age, and severe disease can develop in children younger than 4 years, particularly in infancy, the age group with the highest rate of hospitalization among children with COVID-19 (3). In addition, among children, the rate of severe or critical illness in those aged 1 to 5 years was reported to be more than 1.5 times the rates in older age groups (4).
     
    We were intrigued by the association between age and ACE2 expression in children younger than 10 years in this study and wondered if ACE2 expression increases with age in this group. A further study of infants and children younger than 4 years might help clarify the association of ACE2 expression with disease severity.

    Another important aspect of COVID-19 in children is SARS-CoV-2 viral load in the nasopharynx, which was reported to be similar to that in adults (5). However, most COVID-19 transmission is from adults to children, not from children to adults (2), a finding that cannot be solely explained by viral load in the nasopharynx.  Evaluating both viral load and ACE2 expression in the nasal cavity of patients with COVID-19 could help explain differences in COVID-19 transmissibility between children and adults.

    Although children seem to have less of a role than adults in SARS-CoV-2 transmission, there is an urgent need to understand COVID-19 pathogenesis and transmission in children, as they have been greatly affected by proactive school closures worldwide. This study helps children by shedding light on why they are less affected by COVID-19. Future studies of SARS-CoV-2 pathogenesis and the reasons for its lower transmissibility in children are clearly warranted.

    References

    1. Bunyavanich S, Do A, Vicencio A. Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults [published online May 20, 2020]. JAMA. doi:10.1001/jama.2020.8707
    2. Mehta NS, Mytton OT, Mullins EWS, et al. SARS-CoV-2 (COVID-19): What do we know about children? A systematic review [publisehd online May 11, 2020]. Clin Infect Dis. doi: 10.1093/cid/ciaa556
    3. CDC COVID-19 Response Team. Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):422-426.
    4. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 Among Children in China [published online March 16, 2020]. Pediatrics. doi:10.1542/peds.2020-0702
    5. Jones TC, Mühlemann B, Veith T, et al. An analysis of SARS-CoV-2 viral load by patient age. German Research network Zoonotic Infectious Diseases website. https://zoonosen.charite.de/fileadmin/user_upload/microsites/m_cc05/virologie-ccm/dateien_upload/Weitere_Dateien/analysis-of-SARS-CoV-2-viral-load-by-patient-age.pdf. Accessed May 24, 2020.
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    May 20, 2020

    Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults

    Author Affiliations
    • 1Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York
    • 2Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
    JAMA. 2020;323(23):2427-2429. doi:10.1001/jama.2020.8707

    Children account for less than 2% of identified cases of coronavirus disease 2019 (COVID-19).1,2 It is hypothesized that the lower risk among children is due to differential expression of angiotensin-converting enzyme 2 (ACE2),3 the receptor that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses for host entry.4 We investigated ACE2 gene expression in the nasal epithelium of children and adults.

    We conducted a retrospective examination of nasal epithelium from individuals aged 4 to 60 years encountered within the Mount Sinai Health System, New York, New York, during 2015-2018. Samples were collected from individuals with and without asthma for research on nasal biomarkers of asthma. The study was approved by the Mount Sinai institutional review board. Written informed consent was obtained from participants (or their parents for minors). Nasal epithelium was collected using a cytology brush that was immediately placed in RNA stabilization fluid and stored at −80 °C. RNA was isolated within 6 months. RNA samples were checked for quality and sequenced as a single batch in 2018. Sequence data processing included sequence alignment and normalization of gene expression counts across genes and samples.

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