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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 4  |  Page : 1115-1122

Immunological perspectives to understand the difference between children and adults in COVID-19


Department of Medical Microbiology and Immunology, Faculty of Medicine, Suez University, Suez, Egypt

Date of Submission02-Jun-2020
Date of Decision02-Sep-2020
Date of Acceptance11-Sep-2020
Date of Web Publication24-Dec-2020

Correspondence Address:
Mohamed A Sakr
Doctorate Degree (MD), Quesna, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_198_20

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  Abstract 


Objective
The aim was to review and summarize potential explanation for the difference between children and adults in susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which could help in suggestion of targets for future therapies.
Materials and methods
Systematic online search was applied using PubMed, Medscape, Science Direct, and WHO EMF databases with no date restrictions. English-language reports of the possible causes in the difference of immune response to SARS-CoV-2 infection in children from adults were included. Articles not reporting on the immune response to SARS-CoV-2 infection in children and adults were not included. Data were extracted on immunological mechanisms and other causes of health outcomes in Coronavirus Disease 2019 (COVID-19). Comparisons were made through a structured review, with the results tabulated. There were five studies about the role of angiotensin-converting enzyme 2 receptors, five studies about the role of the adaptive immune response, two studies about the role of telomere length, one study about the role of viral interference, two studies about the role of natural antibodies, and seven studies about other reasons for the difference between children and adults in susceptibility to SARS-CoV-2.
Findings
The most possible reasons for the difference between children and adults in susceptibility to COVID-19 include the expression and maturity of angiotensin-converting enzyme 2 receptors, the adaptive immune response to SARS-CoV-2 infection is qualitatively different in children from adults, shortened telomere length in adult leukocytes compared to children, viral interference with other viral infection in the respiratory tract, and more natural antibodies and lactoferrin with immunomodulatory characteristics in children.
Conclusion
Combination of some possibilities rather than one cause may explain the difference in pediatric and adult COVID-19 incidence, clinical presentation, and severity. More clinical trials on lactoferrin efficacy against SARS-CoV-2 infections should be done.

Keywords: angiotensin-converting enzyme 2, child, Coronavirus Disease 2019, lactoferrin, SARS-CoV-2


How to cite this article:
Sakr MA. Immunological perspectives to understand the difference between children and adults in COVID-19. Menoufia Med J 2020;33:1115-22

How to cite this URL:
Sakr MA. Immunological perspectives to understand the difference between children and adults in COVID-19. Menoufia Med J [serial online] 2020 [cited 2021 Mar 1];33:1115-22. Available from: http://www.mmj.eg.net/text.asp?2020/33/4/1115/304491




  Introduction Top


Coronavirus disease 2019 (COVID-19) is a newly emerging infectious disease with territorial expansion caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After its first occurrence from December 2019 in Wuhan of China, COVID-19 is of great public health concern[1].

COVID-19 is the third coronavirus outbreak in the last 20 years after the SARS-CoV and the Middle East respiratory syndrome MERS-CoV. The WHO has declared COVID-19 a global pandemic, as the number of countries with cases of the viral disease have been rising dramatically around the globe[2].

Infants and young children are usually susceptible to upper respiratory tract infection with viruses such as respiratory syncytial virus and influenza virus, because of their developing immune system[3]. However, In the early days of a COVID-19 infection outbreak, pediatric patients were rather rare, who were thought to be not susceptible to it[4].

Compared with adults, pediatric patients with COVID-19 showed distinctive characteristics in clinical presentation and computed tomography (CT) imaging. Pediatric patients tend to have milder clinical symptoms and fewer CT findings, and the prognosis is better. Most of the pediatric patients have recovered within 1–2 weeks after onset and rarely progress to lower respiratory tract infections[5],[6].

Therefore, the aim of this work was to review and summarize potential explanation for the difference between children and adults in susceptibility to SARS-CoV-2, which can help suggest goals for future treatments.


  Materials and methods Top


Data sources

A systematic search was conducted on the potential explanation for the difference between children and adults in susceptibility to SARS-CoV-2. This was applied using PubMed, Medscape, Science Direct, and WHO EMF Research databases. Reference lists were examined; manual and citation searches were carried out. The research focused on immunological mechanisms responsible for the difference between children and adults in susceptibility to COVID-19. No restrictions on date were applied.

Study selection

Eligible articles were published in peer-reviewed journals and written in English. Articles not reporting on the potential explanation for the difference between children and adults in susceptibility to SARS-CoV-2 in the title or abstract were not included. Full-text articles were screened, and the final selection decisions were made according to the following criteria: original studies, systematic reviews, or meta-analyses.

Data extraction

Articles not reporting on the immune response to SARS-CoV-2 virus infection in children and adults were not included. Letters, editorials, comments, news, and studies not within national research programmes or not focused on possible causes of the difference between children and adults COVID-19 outcomes were not included.

Data were extracted on immunological mechanisms and other causes of health outcomes in COVID-19 in children and adults. The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid.

US Preventive Services Task Force classification is as follows:

  1. Level I: evidence obtained from at least one properly designed randomized controlled trial
  2. Level II


    1. Level II-1: evidence obtained from well-designed controlled trials without randomization
    2. Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
    3. Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence


  3. Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.


Study quality assessment

The quality of all studies was assessed. Important assessment factors included were study design, evidence of power calculation eligibility criteria, adequate information, ethical approval, specified assessment measures, and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured systematic review was done with the results analyzed and tabulated. There were five studies about the role of the expression level and maturity of angiotensin-converting enzyme 2 (ACE-2) receptors for the difference between children and adults in susceptibility to SARS-CoV-2, four studies about the role of the adaptive immune response, two studies about the role of telomere length, one study about the role of viral interference, two studies about the role of natural antibodies, and seven studies about other possible reasons for the difference between children and adults in susceptibility to SARS-CoV-2.


  Results Top


Study selection and characteristics

In total, 120 potentially relevant publications were identified; 82 articles were excluded as they are away from our inclusion criteria [Figure 1]. A total of 38 studies were reviewed, as they met the inclusion criteria. Most of the studies described the potential explanation for the difference between children and adults in susceptibility to SARS-CoV-2. Most of the studies found that the immune response to SARS-CoV-2 virus infection is different to some extent in children from adults. Regarding these studies, one gene expression study[8], which comes in level II-3, reported that ACE-2 is highly expressed in alveolar type 2 cells of lung, esophageal upper epithelial cells, and absorptive enterocytes from ileum and colon. One comparative genetic analysis[9], which comes in level II-3, revealed that the expression level and expression pattern of human ACE-2 in different tissues might be critical for the outcome of SARS-CoV-2 infection. One experimental virus–cell interactions study[10], which comes in level II-3, found that SARS-CoV downregulates ACE-2 protein expression and induces ACE2 shedding from the cell surface. One gene expression study[11], which comes in level II-3, reported that a distinct age-related expression profile of ACE2 and TMPRSS2 genes in the peripheral blood mononuclear cells and T cells from healthy children and adults, as well as with smoking and underlying disease status, might contribute to the severity pattern of COVID-19?. One case series retrospective study[12], which comes in the second level regarding the pyramid of EBM, found that maturity and function of ACE-2 in children may be lower than in adults [Table 1].
Figure 1: Flow chart detailing the database searches, the number of abstracts screened, and the full texts retrieved in this systematic review. Based on four-phase flow diagram Moher et al.[7].

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Table 1: Role of the expression level and maturity of ACE-2 receptors for the difference between children and adults in susceptibility to SARS-CoV-2

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One case analysis study[13], which comes in the second level regarding the pyramid of EBM, showed that peripheral blood lymphocytes in children infected with SARS-CoV-2 remain mostly in normal range, suggesting less immune dysfunction. One randomized case–control study[14], which comes in level I or (level A), found that with ageing, continuous antigen stimulation is accompanied by the loss of expression of co-stimulatory molecules such as CD27 and CD28. One randomized case–control study[15], which comes in level I or (level A), reported that the accumulation of CD28 T cells is associated with the reduced overall immune response to infections in the elderly and could lead to a restriction of the space still available for functioning T cells. One case–control study[16], which comes in level II1, found that high serum concentrations of tumor necrosis factor-α, interleukin 6 (IL-6), and IL-10, which negatively regulate T-cell survival or proliferation, lead to diminishing T cells seen in COVID-19-infected patients [Table 2].
Table 2: Role of the adaptive immune response to SARS-CoV-2 virus infection in the difference in susceptibility between children and adults

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One prospective study[17], which comes in level II-2 or level B, and one case–control study[18], which comes in level II1, found that shortened telomere length in adults' leukocytes, especially lymphocytes, compared with children, results in poor immune response in adults compared with children and is associated with higher risk of infections. One experimental molecular study[19], which comes in level II-3, reported that the simultaneous presence of other viruses in the mucosa of lungs and airways, being common in young children, can let SARS-CoV-2 virus compete with them and limit its growth. One experimental cell study[20], which comes in level II-3, and one case–control study[21], which comes in level II1, found that children have more active innate immune response and natural antibodies than adults [Table 3].
Table 3: Role of telomere length, viral interference and natural antibodies in the difference in susceptibility between children and adults to SARS-CoV-2

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One randomized case–control study[22], which comes in level I or level A, founded that Bacillus Calmette–Guérin (BCG) vaccine has been shown to reduce morbidity and overall mortality to other respiratory infections that are often known to be caused by viruses through increasing the response of Th1 cells, shown by the increase of interferon-χ level. One prospective study[23], which comes to level II-2 or level B, revealed that innate immune cells can also develop enhanced resistance upon reinfection with the same or an unrelated pathogen through the epigenetic reprogramming process of the innate immune cells. One randomized case–control study[24], which comes in level I or level A; one experimental molecular study[25], which comes in level II-3; and two experimental virus–cell interaction studies[26],[27], which comes in level II-3, showed that the likelihood of a lower incidence and milder disease in children could be that they have high lactoferrin content with immunomodulatory and anti-inflammatory characteristics in breast milk or some infant formula feedings. One case series retrospective study[12], which comes in the second level regarding the pyramid of EBM, reported that infants can be infected by COVID-19 and children were unlikely to visit the high-risk areas where the early adult patients were known to have obtained COVID-19 [Table 4].
Table 4: Other possible reasons for the difference between children and adults in susceptibility to SARS-CoV-2

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  Discussion Top


SARS-CoV-2 is an emerging contagious pathogen. Compared with adults, pediatric patients with COVID-19 tend to have milder clinical symptoms and fewer CT findings, and the prognosis is better. Understanding why children generally are less vulnerable to severe COVID-19 would help to propose important protective mechanisms and suggest targets for future therapies to manage COVID-19-infected patients.

The possible reasons for the difference between children and adults in susceptibility to COVID-19

The expression level and maturity of angiotensin-converting enzyme 2 (ACE-2) receptors

The first potential explanation is that the expression level of ACE-2 may differ between adults and children. SARS-CoV-2 uses the SARS-coronavirus receptor, ACE2, for entry host cells. ACE-2 is a surface molecule highly expressed in alveolar type 2 cells of lung, esophageal upper epithelial cells, and absorptive enterocytes from ileum and colon, which indicated respiratory system and digestive system are a potential route for SARS-CoV-2 as described by Zhang et al. [8]. This corresponds to Cao et al.[9] which stated that the expression level and expression pattern of human ACE-2 in different tissues might be critical for the susceptibility, symptoms, and outcome of SARS-CoV-2 infection. Moreover, Glowacka et al.[10] showed that SARS-CoV downregulates ACE-2 protein expression and induces ACE2 shedding from the cell surface, and this process is required for cellular uptake of SARS-CoV.

Receptor repertoire such as ACE2 and TMPRSS2 potentially involved in the SARS-CoV-2 infection at the epithelial barriers and in the immune cells is diverse. A distinct age-related expression profile of ACE2 and TMPRSS2 genes in the peripheral blood mononuclear cells and T cells from healthy children and adults, as well as with smoking and underlying disease status, might contribute to the severity pattern and morbidity of COVID-19, as reported by Radzikowska et al. [11].

Several animal models revealed that ACE-2 expression in adults might be higher than that in children. The expression of ACE-2 was significantly lower in the neonatal sheep compared with that in the adult ones. This finding seems to indicate that lower ACE-2 expression might be correlated with the lower susceptibility of children to SARS-CoV-2. However, the expression of ACE-2 during the development of human children is not completely understood, as described by Li et al. [28].

Moreover, Dong et al.[12] hypothesized that children are less sensitive to COVID-19 because the maturity and function of ACE-2 in children may be lower than in adults.

In addition, many results in the animal studies have demonstrated increased ACE-2 activity in the male or ovariectomized model, suggesting a sex hormone effect. Moreover, the gene for the ACE-2 receptor is located on the X chromosome as reported by Walter et al. [29]. This may contribute to the difference in risk for worse outcomes and mortality between men and women both in the adult and the pediatric population[30].

The adaptive immune response to SARS-CoV-2 virus infection is qualitatively different in children from adults.

Gabriella et al.[31] stated that in SARS-CoV-2 infection, as for all viral infections, the adaptive immune response, virus-specific T cells, for cell-mediated immunity, and B-lymphocytes, for humoral immunity, play a key role.

Adult patients infected by SARS-CoV-2 that are hospitalized frequently manifest a lymphopenia, suggesting that cellular immune responses may be suppressed as reported by Raoult et al. [32]. However, peripheral blood lymphocytes in children infected with SARS-CoV-2, remain mostly in normal range, suggesting less immune dysfunction as proposed by Tan et al. [13].

Cristiani et al.[33] explained that in healthy children, this could be related to the fact that lymphocytes, especially natural killer cells, are constitutionally in greater amount than healthy adults. Lymphocyte count is very high in the first months of life and decreases in later childhood and in adolescence. Moreover, lymphocytes could be higher in children even owing to scheduled immunizations and frequently experienced viral infections in childhood, which is associated an everlasting immune system activation in the first years of life[33].

Li et al.[14] added that, with ageing, continuous antigen stimulation is accompanied by the loss of expression of co-stimulatory molecules such as CD27 and CD28. The accumulation of CD28 - T cells is associated with the reduced overall immune response to infections in the elderly and could lead to a restriction of the space still available for functioning T cells as reported by Saurwein-Teissl et al. [15].

Furthermore, high serum concentrations of tumor necrosis factor-α, IL-6, and IL-10, which negatively regulate T-cell survival or proliferation, lead to the diminishing of T cells seen in COVID-19-infected patients, as described by Diao et al. [16].

Shortened telomere length in adult leukocytes especially lymphocytes compared with children

Telomeres are DNA-protein complexes that protect the ends of chromosomes from degradation. Shorter leukocyte telomere length is associated with higher risk of infections as reported by Helby et al. [17].

Telomeres shorten with each mitotic cell division, but this shortening is partially compensated by the action of telomerase. However, Mendioroz et al.[18] found that telomerase expression levels in adult cells are not enough to preserve the original length of telomeres, resulting in the progressive shortening of chromosomes associated with aging and hence poor immune response compared with children.

Viral interference with other viral infection in the respiratory tract

Evidence suggests that infection of host with a virus can prevent or partially inhibit infection with another virus within the same individual, leading to viral interference[34]. When coinfection with multiple pathogens, competitive forms of pathogen–pathogen interactions occur, and perhaps the simultaneous presence of other viruses in the mucosa of lungs and airways, being common in young children, can let SARS-CoV-2 virus compete with them and limit its growth, as suggested by Nickbakhsh et al. [19].

More active innate immune response and natural antibodies in children

Other suggested reasons include children having a more active innate immune response, healthier respiratory tracts because they have not been exposed to as much cigarette smoke and air pollution as adults, and fewer underlying disorders, as explained by Kliegman et al. [35].

Moreover, Grimsholm et al.[20] reported that in humans, natural antibodies are produced by innate or immunoglobulin (Ig) M memory B cells (MBCs), whose frequency changes with age. A population of MBCs that is generated independently of the germinal centers. This complies with Aranburu et al. [21], who added that these natural MBCs, which are mostly abundant in children, of IgM isotype and generated independently of previous antigen exposures, have a broad reactivity and a variable affinity, but in adults, the innate MBCs is replaced with remodeled IgM MBCs.

Thus, the pediatric immune system is prepared and fit to react to novel antigen encounters, a function that might be diminished in adults and ineffective in elderly people aged 70 years or older[36].

Bacillus Calmette–Guérin (BCG) vaccine may have a role in induction of cross-protection and trained immunity

BCG vaccine has been shown to protect against early childhood tuberculosis, and most interestingly, is shown to reduce morbidity and overall mortality to other respiratory infections that are often known to be caused by viruses, and may be COVID-19, by increasing the response of T helper 1 (Th1) cells, shown by keeping the level of interferon-χ considerably high[22].

BCG is known to boost human innate immunity for prolonged periods following vaccination. This could be explained by a phenomenon known as trained immunity, which suggests that innate immune cells can also develop enhanced resistance upon reinfection with the same or an unrelated pathogen through the epigenetic reprogramming process of the innate immune cells such as monocytes as found by Kleinnijenhuis et al. [23]. This response is independent of adaptive immunity and driven by epigenetic modifications that influence gene expression in mononuclear phagocytes as explained by Kaufmann et al. [37].

Possibility for lower incidence and milder disease in children that they have high lactoferrin content with immunomodulatory and anti-inflammatory characteristics in breast milk or some infant formula feedings

Lactoferrin is a naturally occurring glycoprotein found in exocrine secretions and in the secondary granules of neutrophils. It has immunomodulatory characteristics ranging from innate immunity enhancement to potentiation of adaptive immune responsiveness and can control injury-induced inflammation and subsequent pathologies[38].

Lactoferrin, which is highly concentrated in human breast milk especially colostrum as well as often added to most infant formulas, reduces lower respiratory tract infections owing to its many antiviral properties, as reported by King et al. [24].

Florian et al.[25] describes the mechanism of action of lactoferrin, which starts in the early phase of the viral infection thus preventing entry of virus into the host cell, either by direct binding to virus particles or by blocking cellular receptors. Moreover, Milewska et al.[26] added that lactoferrin inhibits virus replication after entry of the virus into the cells by induction of interferons α/β production.

Lactoferrin has been studied against many numbers of viruses including SARS-CoV, which is closely related to SARS-CoV-2, and there is evidence that the binding of SARS-CoV to its entry receptor, ACE2 protein, is assisted by an attachment receptor, widely distributed cell-surface heparan sulfate proteoglycans Interestingly, lactoferrin can inhibit the binding of SARS-CoV to its functional receptor ACE2 protein by preventing the attachment of SARS-CoV to heparan sulfate proteoglycans, as reported by Lang et al. [27].

Children have fewer outdoor activities with closure of schools and are unlikely to visit the high-risk areas

On the contrary, Wei et al.[39] reported that infants can be infected by COVID-19 and consequently the number of COVID-19 pediatric patients may increase in the future and a lower number of pediatric patients at the beginning of a pandemic does not necessarily mean that children are less vulnerable to the infection with SARS-CoV-2. Moreover, Dong et al.[12] added that children were unlikely to visit the high-risk areas where the early adult patients were known to have obtained COVID-19.

In summary, the most possible reasons for the difference between children and adults in susceptibility to COVID-19 include the expression and maturity of ACE-2 receptors, the adaptive immune response to SARS-CoV-2 infection is qualitatively different in children from adults, shortened telomere length in adult leukocytes compared with children, viral interference with other viral infection in the respiratory tract, more natural antibodies and lactoferrin with immunomodulatory characteristics in children, and children were unlikely to visit the high-risk areas.


  Conclusion Top


Combination of some possibilities rather than one cause may explain the difference in pediatric and adult COVID-19 incidence, clinical presentation and severity. The immune response to SARS-CoV-2 virus infection is different to some extent in children from adults. Understanding why children generally are less vulnerable to severe COVID-19 would help to propose important protective mechanisms and suggest targets for future therapies to manage COVID-19-infected patients. More clinical trials on lactoferrin efficacy against SARS-CoV-2 viral infections should be done. More mechanisms for the difference in clinical features between children and adults remain to be determined.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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