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How does SARS-CoV-2 targets the elderly patients? A review on potential mechanisms increasing disease severity

Open AccessPublished:November 30, 2020DOI:https://doi.org/10.1016/j.ejim.2020.11.024

      Highlights

      • Especially the frail elderly show a high number of severe COVID-19.
      • Viral shedding may be increased in elderly patients.
      • Early identification is complicated due to atypical disease presentation.
      • Applying hygiene measures in patients with cognitive disorders is challenging.
      • The cardiorespiratory reserve is decreased increasing the risk of complications.
      • The aging immune system has a pro-inflammatory tendency, exaggerated by SARS-CoV-2.

      Abstract

      Importance: Among COVID-19 cases, especially the (frail) elderly show a high number of severe infections, hospital admissions, complications, and death. The highest mortality is found between 80 and 89 years old. Why do these patients have a higher risk of severe COVID-19? In this narrative review we address potential mechanisms regarding viral transmission, physical reserve and the immune system, increasing the severity of this infection in elderly patients.
      Observations: First, the spread of COVID-19 may be enhanced in elderly patients. Viral shedding may be increased, and early identification may be complicated due to atypical disease presentation and limited testing capacity. Applying hygiene and quarantine measures, especially in patients with cognitive disorders including dementia, can be challenging. Additionally, elderly patients have a decreased cardiorespiratory reserve and are more likely to have co-morbidity including atherosclerosis, rendering them more susceptible to complications. The aging innate and adaptive immune system is weakened, while there is a pro-inflammatory tendency. The effects of SARS-CoV-2 on the immune system on cytokine production and T-cells, further seem to aggravate this pro-inflammatory tendency, especially in patients with cardiovascular comorbidity, increasing disease severity.
      Conclusions and relevance: The combination of all factors mentioned above contribute to the disease severity of COVID-19 in the older patient. While larger studies of COVID-19 in elderly patients are needed, understanding the factors increasing disease severity may improve care and preventative measures to protect the elderly patient at risk for (severe) COVID-19 in the future.

      Keywords

      1. Introduction

      On November 18th 2020, there have been over 55 million confirmed cases of SARS-CoV-2 infection causing COVID-19, with up to 1.3 million deaths worldwide. In the Netherlands alone, there are up to 8,600 registered deaths, a number that is still on the rise. The risk of hospitalization and death increases with age,

      Dutch National Institute for Public Health and the Environment. https://www.rivm.nl/coronavirus-covid-19/grafieken, Accessed June 27th 2020.

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      Since polymerase chain reaction (PCR)-testing was limited in the beginning of the pandemic, especially in this patient group, it is likely that the total number of COVID-19-attributable cases and deaths are underestimated. During the (first) outbreak of the pandemic, the mortality rate in this group of patients increased from 1,160 to 2,400 deaths a week with a mortality excess of 53%.

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      2. Viral exposure

      2.1 Increased viral shedding

      One of the mechanisms explaining the large incidence in older COVID-19 patients, especially in nursing homes, might be increased viral shedding. In Influenza A and B infection, viral load is significantly higher in children <1 year and individuals > 65 years old, compared with other age groups.
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      2.2 Atypical presentation

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      2.3 Difficulty to ensure quarantine

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      Taken together, older patients may have higher viral shedding. Older and frail patients may present with atypical symptoms and may make it difficult to quickly identify infected individuals. Preventing spread of the infection by adequate hygiene measures and applying quarantine when needed may be difficult in patients with cognitive capabilities, especially when there is a shortage in testing and personal protective materials.

      3. Co-morbidity

      With aging, the prevalence of various diseases increases, e.g., respiratory diseases including chronic obstructive pulmonary disease, diabetes mellitus and cardiovascular disease (CVD). Over half of patients over 75 years old in the Netherlands have multiple chronic diseases.

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      The increase in co-morbidity and the decrease in physiological reserve in the elderly may increase the risk of severe (viral) infections and complications.

      3.1 Respiratory co-morbidity

      Aging is associated with a decrease in lung volumes, decreased respiratory muscle function (including the diaphragm) and cough strength.
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      3.2 Cardiovascular and cerebrovascular co-morbidity

      Pre-existing hypertension, diabetes, and cardiovascular disease are all associated with more severe COVID-19.
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      3.3 Frailty

      Frailty is defined as a geriatric syndrome characterized by an increased risk/vulnerability for developing adverse clinical outcomes like dependency and/or death. Frailty can be caused by and influenced by factors like comorbidity, decreased functional reserve, nutritional status, muscle weakness, physical activity, and mental state. Higher frailty scores, including in sepsis, are associated with worse patient outcomes like mortality and morbidity.
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      4. Dysfunctional immune response

      4.1 Reduced ACE2

      In viral infections, viral and host membranes fuse after binding with a receptor, viral genetic material enters the cell and the virus multiplies itself in the host cell. The spike protein receptor-binding domain of SARS-CoV-2 is a ligand of the receptor of ACE2.
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      4.2 Immunaging

      After infection with a virus, infected cells produce type I interferons (e.g., IFN-α and IFN-β), by transcription of the interferon genes induced by phosphorylation of interferon regulatory transcription factor (IRF) 3 and 7. These type I interferons lower the susceptibility of neighboring cells to viral infection and activate natural killer cells and Th1-lymphocytes, amplifying the anti-viral response. In human monocytes of older donors infected with influenza A, type 1 interferon production seems impaired with diminished IRF-3 and -7 phosphorylation, but pro-inflammatory TNF-α production was preserved.
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      • Dupuis G
      • Le Page A
      • Frost EH
      • Cohen AA
      • et al.
      Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes?.
      In a prospective population-based study of 1155 patients age 65-102 years, a stratified inflammatory index using IL-6 and TNF-α-receptor 1 levels could predict 10-year mortality.
      • Varadhan R
      • Yao W
      • Matteini A
      • Beamer BA
      • Xue QL
      • Yang H
      • et al.
      Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults.
      It remains to be determined whether this cytokine storm is the cause of or a symptom of severe COVID-19, or maybe even of aging. Taken together, diminished type I interferons production and pre-existing low-grade inflammation with pro-inflammatory cytokines might tilt the immune status of the elderly patient to a more pro-inflammatory status.

      4.3 Immunosenescence

      With aging, migration, chemotaxis and phagocytosis of the innate immune system including neutrophils, macrophages, and dendritic cells, decreases.
      • Franceschi C
      • Campisi J.
      Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.
      ,
      • Fulop T
      • Larbi A
      • Dupuis G
      • Le Page A
      • Frost EH
      • Cohen AA
      • et al.
      Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes?.
      ,
      • Crooke SN
      • Ovsyannikova IG
      • Poland GA
      • Kennedy RB
      Immunosenescence: A systems-level overview of immune cell biology and strategies for improving vaccine responses.
      While the number of circulating T-cells of the adaptive cellular immune system remains relatively constant with age, there is a shift in T-cell subpopulations leading to a decrease in naïve T-cells and increase in memory T-cells, which limits the response against novel infectious agents.
      • Crooke SN
      • Ovsyannikova IG
      • Poland GA
      • Kennedy RB
      Immunosenescence: A systems-level overview of immune cell biology and strategies for improving vaccine responses.
      ,
      • Moro-García MA
      • Alonso-Arias R
      • López-Larrea C
      When Aging Reaches CD4+ T-Cells: Phenotypic and Functional Changes.
      Expression of CD28, a costimulatory receptor in T-cells, decreases with age, what is associated with a weakened immune responses.
      • Crooke SN
      • Ovsyannikova IG
      • Poland GA
      • Kennedy RB
      Immunosenescence: A systems-level overview of immune cell biology and strategies for improving vaccine responses.
      ,
      • Moro-García MA
      • Alonso-Arias R
      • López-Larrea C
      When Aging Reaches CD4+ T-Cells: Phenotypic and Functional Changes.
      Higher TNF-α with aging inhibits CD28 expression, contributing to further T-cell dysregulation.
      • Bryl E
      • Vallejo AN
      • Weyand CM
      • Goronzy JJ
      Down-regulation of CD28 Expression by TNF-alpha.
      Further suppression of the adaptive immunity, is caused by lymphopenia, a hallmark phenomenon seen in COVID-19, reducing the number of total, CD4+, and CD8+ T cells.
      • Bektas A
      • Schurman SH
      • Sen R
      • Ferrucci L
      Aging, inflammation and the environment.
      In conclusion, both the innate and the adaptive cellular immune system of the older patient is weakened (immunosenescence), with a pro-inflammatory tendency (inflammaging), which seems to be intensified during COVID-19, increasing disease severity.
      • Fulop T
      • Larbi A
      • Dupuis G
      • Le Page A
      • Frost EH
      • Cohen AA
      • et al.
      Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes?.
      ,
      • Bektas A
      • Schurman SH
      • Sen R
      • Ferrucci L
      Aging, inflammation and the environment.
      • Molony RD
      • Malawista A
      • Montgomery RR
      Reduced dynamic range of antiviral innate immune responses in aging.
      • Keilich SR
      • Bartley JM
      • Haynes L
      Diminished immune responses with aging predispose older adults to common and uncommon influenza complications.

      5. Conclusion

      In this narrative review, we discuss several features of COVID-19 and aging to clarify the increased mortality in older patients, summarized in Figure 1. This review does not cover all of the aspects of COVID-19 and those of the aging immune system. There are still aspects unknown, and while it is theoretically plausible that changes seen in the aging immune system are causatively related to disease severity, further studies are required. Also, many of the studies on comorbidity and complications encompass relatively small numbers of elderly patients and need to be confirmed in prospective observational studies. Especially the frail elderly show a higher number of severe infections, requiring hospital admission, and leading to death. Elderly patients may show high viral shedding. Furthermore, ways to limit spread of the infection by early identification may be complicated due to atypical disease presentation and has been limited by lack of testing capacity in the recent past. Opportunities to apply quarantine measures in patients with cognitive disorders can be limited. Elderly patients have a decreased cardiorespiratory reserve and are more likely to have co-morbidity including atherosclerosis, rendering them more susceptible to complications. The aging innate and adaptive immune system is weakened, while there is a pro-inflammatory tendency. The combination of these factors contributes to the disease severity of COVID-19 in the older patient. Understanding these aspects may help to improve preventive measures and care of the older patient at risk for (severe) COVID-19 in the future.
      Figure 1
      Figure 1Factors contributing to disease severity of SARS-CoV-2 infection in the elderly. Abbreviations: CVD, cardiovascular disease; DM, diabetes mellitus; HT, hypertension; ACE-2, angiotensin converting enzyme 2; IL-6, interleukin 6.

      Declaration of Competing Interest

      The authors declare they have no conflict of interest.

      Acknowledgements

      The authors declare they have no conflict of interest.

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