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Editorial
May 20, 2020

Nasal ACE2 Levels and COVID-19 in Children

Author Affiliations
  • 1Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts
JAMA. 2020;323(23):2386-2387. doi:10.1001/jama.2020.8946

Coronavirus disease 2019 (COVID-19) has disproportionately affected certain vulnerable populations. Studies noted higher rates of certain comorbidities such as hypertension, diabetes mellitus, and chronic obstructive pulmonary disease in patients infected with COVID-19 with severe disease.1 Additionally, areas with more racial/ethnic minorities and higher rates of poverty have been shown to have higher rates of COVID-19 hospitalization and death.2 After adjustment for comorbidities, age has been independently associated with increased mortality due to COVID-19.3 However, limited attention has been given to children, who appear to have lower risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mortality.

In this issue of JAMA, Bunyavanich et al4 identify a possible factor that may be related to lower rates of SARS-CoV-2 infection in children. The authors evaluated gene expression in nasal epithelial samples collected as part of a study involving patients with asthma from 2015 to 2018. The nasal epithelium is one of the first sites of infection with SARS-CoV-2, and the investigators probed for the expression of the cell surface enzyme angiotensin-converting enzyme 2 (ACE2), which has been proven to bind to SARS-CoV-2 spike protein and promote internalization of the virus into human cells.5 Among a cohort of 305 patients aged 4 to 60 years, older children (10-17 years old; n = 185), young adults (18-24 years old; n = 46), and adults (≥25 years old; n = 29) all had higher expression of ACE2 in the nasal epithelium compared with younger children (4-9 years old; n = 45), and ACE2 expression was higher with each subsequent age group after adjusting for sex and asthma.

Numerous studies have highlighted the low rates of SARS-CoV-2 infection in children compared with adults. Children have been shown to have fewer and less severe symptoms compared with adults.6,7 This leads to the question of whether low rates of SARS-CoV-2 infection in children are due to low rates of testing in children, or if children are less susceptible to infection. An evaluation of 1286 close contacts of index cases in China found that infection rates in children were comparable with or slightly higher than in younger adults (aged 30-49 years) but were significantly lower than in older patients (aged ≥60 years).8 This finding suggests that children seem to have similar rates of becoming infected compared with middle-aged adults following close contact with a person infected with SARS-CoV-2. In contrast, a targeted screening approach in Iceland found SARS-CoV-2 in 6.7% of children younger than 10 years old (n = 564) compared with in 13.7% of people aged 10 years or older (n = 8635). A population-wide screening approach not restricted to people at risk of disease in the same study found no positive cases of SARS-CoV-2 among children under 10 years old, whereas 0.8% of people older than 10 years were positive for SARS-CoV-2.9 Although the true rate of acquiring SARS-CoV-2 infection among children of different age groups in the United States remains unclear, initial studies have suggested a lower incidence of SARS-CoV-2 infection in US children.7

While ACE2 binds to the receptor binding domain of SARS-CoV-2, a serine protease, TMPRSS2, is shown to cleave SARS-CoV-2 S protein, allowing for cell membrane fusion and endocytosis of the virus and subsequent viral replication. To better understand expression of these 2 key proteins, a number of single-cell RNA sequencing experiments have mapped them to various human cell types. One study using human and nonhuman primate tissue found ACE2 expression in the secretory cells of the nasal epithelia (upper respiratory tract) and in the type II pneumocytes of the lower respiratory tract.10 In fibrotic human lung tissue, only 1.4% of type II pneumocytes expressed ACE2, and 0.8% of type II pneumocytes expressed both ACE2 and TMPRSS2. In human ethmoid sinus surgical specimens representing upper respiratory epithelia, 1.3% of all secretory cells expressed ACE2 while 0.3% expressed both ACE2 and TMPRSS2 but were further enriched in secretory goblet cells.11 The spatial resolution offered by single-cell RNA sequencing highlights the limited number of cells in the respiratory tract that express ACE2. Further evaluation of ACE2 expression at the single-cell level in children could help explain whether a lower percentage of ACE2-expressing cells or a decrease in expression in ACE2 expression per cell is related to lower ACE2 expression in nasal epithelium, as noted in children identified by Bunyavanich et al.4

ACE2 has an important role in counterbalancing the effects of ACE. Angiotensin II, a product of ACE cleaving angiotensin I, can cause vasoconstriction, inflammation, and fibrosis by signaling through angiotensin II type 1 receptors. ACE2 can cleave angiotensin II to angiotensin 1-7, which can suppress inflammation and fibrosis and generate vasodilation by binding to the Mas receptor. Previous studies have found ACE2 to play a protective role in severe lung injury in ACE2 knockout mice.12 If ACE2 can mitigate lung injury but serves as a receptor for viral entry, then is more ACE2 or less ACE2 expression protective for children? In the nasal epithelium of the upper airway, lower ACE2 expression could be helpful in decreasing acquisition of SARS-CoV-2 infection. However, in the lower respiratory tract, it appears that decreased ACE2 expression could portend a higher risk of developing severe acute respiratory distress and lung injury.

Bunyavanich et al4 suggested that ACE2 expression in the nasal epithelium in their cohort does not reflect ACE2 expression in the pulmonary epithelium, and the expression of ACE2 in the lower respiratory tract is under different regulation. This emphasizes the importance of understanding the distribution of ACE2 in cells in different parts of the respiratory epithelium but also between cell-bound and plasma fractions. ACE2 is cleaved from the cell membrane on binding with SARS-CoV-2, releasing ACE2 into the plasma. The role of soluble ACE2 in neutralizing SARS-CoV-2 virus has recently been shown in vitro,13 but its activity in vivo is still to be determined. Ultimately, studying tissue expression of ACE2 in the lower respiratory tract of children may be helpful in understanding differences in the severity of COVID-19 among children compared with adults.

A new study called Human Epidemiology and Response to SARS-CoV-2 (HEROS), funded by the National Institute of Allergy and Infectious Diseases, is designed to prospectively follow 6000 children to determine risk factors for development of COVID-19.14 Data from this study could help identify whether the lower ACE2 expression identified by Bunyavanich et al4 correlates with lower rates of SARS-CoV-2 infection, and could serve to support the possibility that decreasing ACE2 expression in the nasal epithelium may be a potential therapeutic approach to mitigate transmission of COVID-19.

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Article Information

Corresponding Author: Ankit B. Patel, MD, PhD, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02132 (apatel38@bwh.harvard.edu).

Published Online: May 20, 2020. doi:10.1001/jama.2020.8946

Conflict of Interest Disclosures: Dr Patel reported receipt of grants from Relypsa and consulting fees from Third Rock Ventures. No other disclosures were reported.

References
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Mehra  MR, Desai  SS, Kuy  S, Henry  TD, Patel  AN.  Cardiovascular disease, drug therapy, and mortality in COVID-19.   N Engl J Med. Published online May 1, 2020. doi:10.1056/NEJMoa2007621PubMedGoogle Scholar
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Bunyavanich  S, Do  A, Vicencio  A.  Nasal gene expression of angiotensin-converting enzyme 2 in children and adults.   JAMA. Published online May 20, 2020. doi:10.1001/jama.2020.8707Google Scholar
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    2 Comments for this article
    EXPAND ALL
    Gene Expression vs Protein, and Asthma
    Dora Smith, None | None
    1. The original article mentioned that ACE2 gene expression is not the same thing as ACE receptors and they may not be correlated - but the editorial does not.

    2. The original article mentioned that 45% of the children in the study had asthma, and that having asthma was controlled for. However, the article does not report what relationship existed between ACE2 gene expression and asthma, and they surely noticed if there was such a relationship. This matters because people with asthma have lower ACE2 levels - gene expression or receptors - and are also, worldwide,
    about 1/5 as likely to be hospitalized with covid as anyone else.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Nasal ACE2 Levels and Fructose Consumption as a Risk Factor For Covid19
    Declan Waugh, BSc Env Science | Research Scientist
    I read the research letter by Bunyavanich et al. and accompanying editorial in JAMA with interest. The authors identified that ACE2 gene expression was significantly higher in older children, young adults and adults and suggested that lower ACE2 expression in children may be a possible factor that may be related to lower rates of SARS-CoV-2 infection in children. While the molecular mechanisms that mediate ACE2 expression are poorly understood, it has been observed that fructose metabolism increases ACE2 expression [1]. Moreover, fructose consumption is also directly implicated in the pathogenesis of hypertension, obesity, diabetes, kidney disease, cardiovascular disease, and metabolic syndrome [2]; all conditions associated with increased susceptibility to COVID19. In addition, ACE2 expression was shown to increase significantly in the lungs of rodents in animal models of diet-induced obesity [3], suggesting that the lungs of obese individuals may be more susceptible to SARS-COV-2 invasion. Of particular interest it has also been reported that the consumption of high fructose corn syrup is significantly higher in the United States and certain western countries than in Nordic counties or countries of the Asia-Pacific region including India, China, or Australia [4], where prevalence and mortality rates for COVID19 are also lower than the United States. In addition, a review of literature will show that several epidemiological studies in the United States have observed that fructose consumption is significantly lower in children < 6 years than older children and young adults. These findings may also elucidate, at least in part, a biological plausible mechanistic reason for the observations of Bunyavanich et al. that ACE2 gene expression was significantly lower in younger children compared to older children, young adults, and adults. Taken together, it is tempting to postulate that higher fructose-based diets in certain western countries may be a contributory factor to increased vulnerability to infection by SARS-COV2 and other RNA viruses that utilise ACE2 as its receptor for cell entry.

    Reference
    [1] Hernández-Díazcouder A, Romero-Nava R, Carbó R, Sánchez-Lozada LG, Sánchez-Muñoz F. High Fructose Intake and Adipogenesis. Int J Mol Sci. 2019,20, 2787. doi: 10.3390/ijms20112787
    [2] Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang D-H, et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr 2007; 86:899–906. doi: 10.1093/ajcn/86.4.899
    [3] Tilton SC, Waters KM, Karin NJ, Webb-Robertson BJ, Zangar RC, Lee KM, Bigelow DJ, Pounds JG, Corley RA. Diet-induced obesity reprograms the inflammatory response of the murine lung to inhaled endotoxin. Toxicol Appl Pharmacol. 2013, 267,137-48. doi: 10.1016/j.taap.2012.12.020.
    [4] Goran MI, Ulijaszek SJ, Ventura EE. High fructose corn syrup and diabetes prevalence: a global perspective. Glob Public Health. 2013;8(1):55‐64. doi:10.1080/17441692.2012.736257
    CONFLICT OF INTEREST: None Reported
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