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The current coronavirus disease 2019 (COVID-19) pneumonia outbreak, caused by the severe acute respiratory syndrome 2 (SARS-CoV-2) virus, is spreading globally at an accelerated rate, leading the World Health Organization (WHO) on March 11, 2020, to declare this infection as a global pandemic [1]. It has been emerged to be the third highly contagious coronavirus leading to an epidemic in the 21st century after severe acute respiratory syndrome (SARS-CoV) (outbreak in 2002) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (outbreak in 2012) [2]. The novel SARS-CoV-2 is a member of the Betacoronavirus genus, which also includes SARS-CoV and MERS-CoV, sharing with them the routes of transmission and clinical manifestations. SARS-CoV-2 can be transmitted from person-to-person [3]. The clinical spectrum of SARS-CoV-2 infection appears to be wide, ranging from mild upper respiratory tract infection to severe viral pneumonia that may progress to acute respiratory distress syndrome or multiorgan dysfunction and even death [4].
Like SARS-CoV and MERS-CoV, all individuals are generally susceptible to SARS-CoV-2 infection, but older people are more vulnerable to develop a severe infection, be at a greater risk of a cascade of complications, and admission to the intensive care unit (ICU) or even death in severe cases. Therefore, this article aims to focus on the clinical, laboratory, radiological features and clinical outcomes of older people with SARS-CoV-2 infection in order to investigate the predictive factors of fatal clinical outcome and thus providing some insights into the evidence for stratifying risk and helping to improve clinical practice and reduce mortality among them as illustrated in Fig. 1.
Fig. 1: Underlying mechanisms, clinical, laboratory, and imaging features of SARS-CoV-2 infection in older adults.
Methods Literature searchA literature research was conducted using keyword filters to select articles related to ‘clinical features’, ‘laboratory findings’, ‘imaging features’, ‘outcomes’ in combination with ‘SARS-CoV-2”, COVID-19’, ‘elderly’, ‘aging’, ‘older adults’ This research was carried out on articles published in the PubMed and Scopus databases for the English language from January 1, 2020 to May 31, 2020. We excluded all editorials, letters to the editor, and studies that discussed the psychological disorders and mental health among older adults during the COVID-19 pandemic. Table 1 summarizes the included studies addressing the characteristics of SARS-CoV-2 infection in older adults.
Table 1 - List of publications on older adults included in the review. Study Country origin Study design Study size Wang et al. [19] China Retrospective study 339 patients with COVID-19 admitted to Renmin Hospital of Wuhan University Liu et al. [20] China Retrospective study 56 patients Zhu et al. [21] China Retrospective study 72 symptomatic patients with COVID-19 Zhou et al. [22] China Retrospective, multicenter study 191 patients with laboratory confirmed COVID-19 (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) Deng et al. [23] China Retrospective study 109 fatal and 116 recovered COVID-19 cases admitted to two tertiary hospitals in Wuhan Huang et al. [24] China Retrospective study 36 nonsurvivors infected with SARS-CoV-2 in the Fifth Hospital of Wuhan Grasselli et al. [25] Italy Retrospective case series 1591 patients with confirmed COVID-19 referred for ICU admission Li et al. [26] China Retrospective study 204 patients diagnosed with COVID-19 in Renmin Hospital of Wuhan University Lian et al. [27] China Retrospective study 788 patients with confirmed COVID-19 Niu et al. [28] China Retrospective study 141 patients con-firmed with COVID-19 Guo et al. [29] China Retrospective, multicenter study 105 patients confirmed with COVID-19 Chen et al. [30] China Retrospective study 203 patients were diagnosed with COVID-19COVID-19, coronavirus disease 2019; ICU, intensive care unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Changes in lung anatomy and immune systems in older people increase their susceptibility to severe infection and hypoxia. Changes in the older people's lung anatomy and muscle atrophy leading to changes in the physiological functions of the respiratory system such as coughing and sneezing which are less efficient, making it difficult for them to clear the microbial pathogen, when infects the airways and reduced lung reserve [5]. In addition, the lung damage accumulated in older people from underlying chronic lung disease and habits like smoking or breathing polluted air can further increase their vulnerability, so when the microbial pathogen strikes, it can lead to severe pneumonia that may progress to respiratory failure. It was found that smoking and patients with chronic lung disease had a higher dipeptidyl peptidase IV (DPP4) expression, which was inversely correlated with lung function and diffusing capacity parameters [6]. Older people are physically frail and more likely to have one or more comorbidities and underlying chronic diseases that put them at a greater risk to suffer severely, develop more serious complications and also affect the disease prognosis. Hypertension, diabetes, cardiovascular disease, preexisting liver, and renal diseases, and cancer are the most common comorbidities among them. Angiotensin-converting enzyme 2 (ACE2) is highly expressed in type II alveolar cells (AT2), myocardium, kidney, gastrointestinal tract, and pancreas [7]. Recently, hypertension is emerging as a serious risk factor in older people with SARS-CoV-2 in particular, predisposing this population to increased COVID-19 disease severity and mortality. Hypertension is known to be associated with high levels of renin−angiotensin (RAS) [8], and when SARS-CoV-2 penetrates cells by binding to ACE2 in the lung [9], facilitating the virus replication, delaying virus clearance, and contributing to the severity of lung injury by reducing ACE2 cell surface expression, upregulating angiotensin II signaling, and compromising the anti-inflammatory function in RAS signaling [10]. Therefore, it is hypothesized that the increase in ACE2 levels with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) treatment is more likely to correct these changes [11]. Diabetes is another common co-morbidity among older people making them more vulnerable to COVID-19 disease severity and mortality. Diabetes can damage the nervous system, facilitate cellular binding and virus entry, and decrease the body's efforts to clear the virus from the lungs. Diabetes can also suppress immune cells by diminishing the function of T cell and increasing susceptibility to hyperinflammation and cytokine storm syndrome. Unlike hypertension, the link of diabetes to ACE2 expression levels in the lung in humans is still unknown, but it has been found that the type of diabetes treatment may affect ACE2 expression. It was suggested that administration of insulin downregulates ACE2 expression [12] whereas hypoglycemic agents such as thiazolidinediones (TZDs; pioglitazone) and glucagon-like peptide-1 (GLP-1) agonists (liraglutide) upregulate ACE2 expression [13].
Immune systemAge-related changes primarily affect the adaptive immune response, as evidenced by major defects in both cell-mediated immunity and humoral immune responses. In contrast, the innate immune response shows preservation to a greater degree even in extreme old age [14]. CD4+ T cells recognize and respond to neoantigens with aging as there is a gradual loss of T cell repertoire from naive CD8+ T cells [15]. Interleukin 6 (IL-6) production generally increases with increasing age. IL-4 production by CD4+ cells appears to decrease with age, but this is compensated by excess IL-4 synthesis by cytotoxic CD8+ cells and natural killer (NK) T cells [16]. On the other hand, production of IL-1, IL-3, tumor necrosis factor (TNF), interferon gamma (IFN-γ), IL-8, and IL-12 is generally intact and increases in the elderly. Thus, elderly patients generally have more prolonged proinflammatory responses than younger persons, which makes it difficult for them to clear microbial pathogens leading to poor outcomes and there is a dysfunction in signaling attenuation by counter-regulatory cytokines as IL-10 [17].
Demographic and clinical features of older people with severe acute respiratory syndrome coronavirus 2 infectionSARS-CoV-2 appears to discriminate not only by age but also by sex. It was found that older males are more susceptible to SARS-CoV-2 infection than older females as shown in Table 2. Similar to younger adults, SARS-CoV-2 appears to pose a particular threat to older males and has a unique prediction for them; this may be due to the biological, lifestyle, and behavior differences between males and females. Unlike the SARS-CoV outbreak, which was caused by a similar coronavirus. SARS-CoV was found to infect females more than males regarding WHO report from 30 different countries and areas [18].
Table 2 - Demographic and clinical characteristics of older adults with confirmed SARS-CoV-2 infection. Reference Older adults with SARS-CoV-2 infection Age in years Sex (male/female) Preexisting co-morbidities Main manifestations Wang et al. [19] 339/339 (100%) 71 ± 8 166/173 - Hypertension (40.8%)COVID-19, coronavirus disease 2019; ICU, intensive care unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Due to immune dysfunction, the high prevalence of underlying chronic health conditions and comorbidities is another propensity of SARS-CoV-2 infection in older people increasing their susceptibility to higher attack rates, adverse clinical outcomes, and death. The most common reported comorbidities among older people are hypertension, diabetes, cardiovascular diseases, and cerebrovascular diseases [19–30].
In older people with confirmed SARS-CoV-2, fever, cough, dyspnea, and fatigue are the most prevalent clinical presentations, which are consistent with the general symptoms of viral infection and pneumonia. Severe pneumonia may develop and progress into respiratory distress leading to hypoxia, respiratory failure, multiorgan failure, shock, and death.
Nonrespiratory symptoms of SARS-CoV-2 such as headache, sore throat, and gastrointestinal symptoms have been reported in older people. These symptoms should not be overlooked rather than waiting for respiratory symptoms to emerge, and high suspicion should be raised by clinicians who care for older people due to atypical presentation and disorders in this category. Similar to younger adults, the most common reported gastrointestinal symptoms among older people are diarrhea, vomiting, and abdominal pain during the course of the disease [19–24,26,27,29,30]. Evidence from previous SARS and MERS studies has found that coronavirus has a tropism to the gastrointestinal tract. These studies revealed that 10.6% of individuals with SARS and up to 30% of individuals with MERS had diarrhea [3]. Given that both SARS-CoV and MERS-CoV can be excreted through feces and remain viable under conditions conducive to transmission. In general, some individuals with SARS-CoV-2 develop diarrhea during their disease course but at a lower frequency compared to SARS. This indicates the possible tropism of SARS-CoV-2 to the gastrointestinal tract. Diarrhea results from the interaction between SARS-CoV-2 and ACE2 due to the receptor-binding domain on SARS-CoV-2 that can bind to human ACE2 with high affinity, leading to viral spread [31]. The viral receptor ACE2 is known to be highly expressed in alveolar AT2 cells in the lungs, but it is also found to be highly expressed in proximal and distal enterocytes resulting in malabsorption and diarrhea [32]. A recent study also demonstrated that SARS-CoV-2 RNA was detected in the patient's stool [33]. Another possible mechanism is changes in the composition and function of digestive tract flora mutually affecting the respiratory tract through immune regulation, the so-called “gut−lung axis” [34]. These data provide a potential alternative transmission route for SARS-CoV-2 through the fecal contents that could have a clear impact regarding transmission precautions.
Laboratory findings of older people with severe acute respiratory syndrome coronavirus 2 infectionSimilar to younger adults, lymphocytopenia, increase of inflammatory biomarkers (elevated C-reactive protein, elevated IL-6 level, elevated lactate dehydrogenase level (LDH) and high procalcitonin level), abnormal blood coagulation (increased d-dimer level), liver enzyme abnormalities [high aspartate aminotransferase (AST) and alanine transaminase (ALT) levels], and hypoalbuminemia are the most common reported laboratory abnormalities among older people as in Table 3[19,20,22–24,26,27,29,30].
Table 3 - Laboratory and radiographic findings of older adults with confirmed SARS-CoV-2 infection. Abnormal laboratory findings Imaging features Wang et al. [19] - LymphocytopeniaSARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Similar to previous studies of SARS-CoV and MERS-CoV in critically ill patients [35], Lymphocytopenia was found to be a prominent laboratory feature in patients with SARS-CoV-2. Since lymphocytes are the main target cells of viral infections, SARS-CoV viral particles can kill lymphocytes either by damaging the cytoplasmic components or apoptosis causing persistent consumption and/or insufficient regeneration of lymphocytes [35]. In addition, it was found that lymphocytopenia during SARS-CoV-2 may aggravate inflammatory responses, leading not only to pulmonary injury but also the injury of extra-pulmonary organs including the liver due to increased IL-6, IL-10, IL-2, and IFN-γ levels [36]. Therefore, the severity of lymphocytopenia may indicate either the severity of virus invasion or the status of the antiviral immunity, and thus can predict the disease severity and clinical outcomes.
Inflammatory responses triggered by a viral infection, evidenced by elevated C-reactive protein, elevated IL-6 levels, elevated LDH levels, and elevated procalcitonin levels, play a critical role in the severity of lung disease [37] in addition to the presence of abnormal blood coagulation function, which characterized by increased levels of d-dimer, is another common laboratory abnormality among older people. Increased d-dimer levels may be associated with fatal outcomes in patients with infection or sepsis and in patients on ventilators. The possible mechanisms of coagulation activation may be related to the persistent inflammatory response, induction of procoagulant factors, and hemodynamic changes, which predispose to ischemia and thrombosis. It was found that these laboratory abnormalities are similar to those previously reported in patients with SARS-CoV and MERS-CoV infections suggesting that SARS-CoV-2 infection is associated with a defect in cellular immunity, and coagulation activation. Therefore, close monitoring of dynamic changes in these inflammatory indices is mandatory to help judge the disease progression among older people, aiming to avoid a fatal outcome.
Apart from a lung injury, damage to other organs is of concern for SARS-CoV-2 infection. Liver injury may also occur among older people with SARS-CoV-2 that is characterized by abnormalities in liver enzymes (high AST and ALT levels) and hypoalbuminemia during the course of the disease. Currently, the mechanisms of liver injury are unclear; the liver injury may be related to virus-induced cytopathic effects on hepatocytes, immune-mediated inflammation, or drug hepatotoxicity [38,39]. There is also another suggestion that SARS-CoV-2 may directly bind to ACE2-positive cholangiocytes to dysregulate liver function [40,41]. However, further investigations are needed to find out whether SARS-CoV-2 may target the liver in a similar manner to SARS-CoV or other mechanisms that have a role in liver injury. Hypoalbuminemia may be another form of liver injury from SARS-CoV-2 due to impaired liver synthesis or a part of the disease pathophysiology as albumin is a negative acute-phase protein. There are multifactorial reasons for decreased albumin synthesis during inflammation and infection including increased leakage into the interstitial space, accelerated catabolism, and the effect of monocytic products such as IL-1 and IL-6, and TNFα [42]. Albumin is also an indicator of nutritional status of the body and can be observed in malnourished patients. Regardless of its cause, the hypoalbuminemia observed among the elderly may have a strong predictive value on morbidity and mortality as the body loses virus resistance, leading to disease progression and fatal clinical outcomes.
Chest imaging findings of older people with severe acute respiratory syndrome coronavirus 2 infectionThe most common reported chest radiologic abnormalities among older people are ground-glass opacities with or without consolidation, a single lung (single or multiple lobes) or both lungs may be affected or bilateral infiltrate, pleural thickening, and rarely pleural effusion [20–22,24,26,27,29,30] as shown in Table 3. It seems that older people are more prone to have extensive lung lobe involvement, interstitial changes, and pleural thickening. These chest radiologic findings are of great significance for early detection, early diagnosis, and improving prognosis. However, chest radiologic imaging studies of SARS-CoV-2 are preliminary and unknown aspects need to be further investigated.
Disease spectrum, complications, and clinical outcomes of older people with severe acute respiratory syndrome coronavirus 2 infectionSARS-CoV-2 presents unique features in these older people as evidenced by an increase in the proportion of severe-to-critical patients and fatality rate compared to the whole population as shown in Tables 4 and 5.
Table 4 - Spectrum of the disease and complications of older people with confirmed SARS-CoV-2 infection. Spectrum of disease Complications Wang et al. [19] - Moderate100 (29.5%)ARDS, acute respiratory distress syndrome; MOD, multiple organ damage; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
ICU, intensive care unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Concerning complications and mortality, the main complications include ARDS, bacterial infection, acute cardiac injury, acute kidney injury, and sepsis, followed eventually by multiple organ failure and death [19–24,26,27,29,30].
The development of ARDS is the most common complication among older adults. This may be due to lung aging associated with an inability of lung cells and multiple structural and functional changes in the respiratory tract, leading to decreased lung function, altered pulmonary remodeling, diminished regeneration, and increased susceptibility to lung disease [43].
Sepsis is another common complication, which may be directly caused by SARS-CoV-2 infection since bacterial infections are considered a leading cause of sepsis but viral infection can also cause sepsis syndrome. Further investigations are needed to understand the pathogenesis of sepsis in SARS-CoV-2 infection.
Severe acute respiratory syndrome coronavirus 2 fatality rate in older peopleEstimating the risk for hospitalization and the case fatality rate for SARS-CoV-2 in real-time during an epidemic is very challenging. Therefore, among those infected with SARS-CoV-2, the risk for hospitalization due to severe disease increases substantially with ag
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