Abstract
Morbidity and mortality rates during the COVID-19 pandemic have been particularly high among elderly people (>65 years). This review summarises some of the important physiological and clinical aspects in the background of augmented risk. Airway clearance provides defence against inhaled particles, including viruses. Some relevant studies have indicated that clearance from the small and large airways is slower in elderly people. Cough peak flow (the speed of expiratory airflow during coughing, or cough power) is another important parameter that reflects the defence capacity of the respiratory system. Age has likewise been shown to induce inspiratory and expiratory muscle weakness and, as a consequence, a low cough peak flow. In addition to the weakening of these non-specific defences in elderly people, the specific immune response against the SARS-CoV-2 virus has been found to be nearly blocked in aged mice, and the augmented synthesis of prostaglandin D2 (PGD2) was found to play a role in this phenomenon. Aged animals were protected from death by a specific antagonist of PGD2. Among aged people suffering from COVID-19, there were disproportionally more patients with low CD8 T lymphocyte counts and high plasma concentrations of interleukin 6 (IL-6). This combination of deficient cellular immunity and overt inflammatory response in COVID-19 has been identified as a significant risk factor of mortality.
The current COVID-19 pandemic (SARS-CoV-2–induced pneumonia) has affected more than 8% of the total Hungarian population [1], mostly elderly people (older than 65 years of age). This paper discusses some of the aspects of physiological ageing that increase the risk and severity of SARS-CoV-2–induced pneumonia. Since the risk of developing a lower airways infection is increased by the impaired clearance of inhaled pollutants or infectious agents from the small airways [2], data on small airways clearance during ageing will be summarised first. The outcome of a lower airways infection also depends on cough power [3], which in turn depends on the strength of the inspiratory and expiratory muscles [4]. Therefore, the second topic to be addressed is the impact of ageing on the strength of the respiratory muscles. Definitive protection against COVID-19 will be provided by adaptive or specific immunity to SARS-CoV-2. A great deal of important human and experimental data indicate that ageing is associated with an impaired adaptive immune response to this pathogen. The present review discusses some new immunological information on how ageing influences the anti-SARS-CoV-2–specific immunological and inflammatory response.
Measurements
Measurement of small airways clearance
“A technique has been developed [5] to deposit particles mainly in the smallest ciliated airways—that is, the bronchioles—using rather large particles (6 μm) and an extremely slow inhalation flow (0.05 L s−1)”. In the important study by Svartengren et al. [6], “all subjects inhaled monodisperse 6 μm Teflon particles labelled with 111Indium with an extremely slow inhalation flow (0.05 L s−1)”. Mean particle size ranged from 6.0 to 6.5 μm and inhalation flow varied between 0.043 and 0.050 L s−1. Radioactivity in the lungs was measured at 0, 24 and 48 h, as well as 1, 2 and 3 weeks after inhalation of the particles. Immediately after inhalation and 24 h later, radioactivity was measured using two 127 × 51 mm NaI detectors fitted with collimators [7]. Activity in the lungs was measured at 24 and 48 h and 1, 2 and 3 weeks after inhalation using a whole-body scanner [7].
Measurement of cough and respiratory muscle strength
In the study by Kaneko et al. [8], the 69 participants were ambulatory older adults aged ≥65 years. Individuals with lung disease or neurological diseases, air-flow limitation, a body mass index >30 kg m−2, and cognitive disorders that impeded direction-following abilities were excluded. Cough strength, as estimated by cough peak flow (CPF), was assessed using an oronasal mask connected to a portable peak flow meter. The subjects were seated and instructed to perform a volitional, maximum effort cough after inspiration to total lung capacity. Cough peak flow was measured three times with the subject in a sitting position, and the highest value was recorded. A CPF of 240 L min−1 was regarded as reduced, because, in an earlier study, a CPF of 242 L min−1 had been found to be the cut-off value for identifying patients with dysphagia at risk of aspiration pneumonia [3]. Respiratory muscle strength was assessed by measuring maximal inspiratory (PImax) and maximal expiratory (PEmax) pressure using a manometer. In line with the American Thoracic Society and European Respiratory Society guidelines [9], PImax and PEmax were measured with the subject in a sitting position and starting from residual volume and total lung capacity respectively. The measurements were repeated at least three times, and the highest value was recorded.
CD8 cells and IL-6 cytokine in ageing COVID-19 patients
Luo et al. [10] “retrospectively investigated the potential of immunological parameters as early predictors of COVID-19 pneumonia. A total of 1,018 patients with confirmed COVID-19 were enrolled in a two-centre retrospective study. The data collected included clinical features, laboratory tests, immunological tests, radiological findings, and outcomes. Univariate and multivariable logistic regression analyses were performed to evaluate factors associated with in-hospital mortality. Receiver operator characteristic (ROC) curves and survival curves were plotted to evaluate their clinical utility”. The materials and methodology of the experimental study on mice mentioned in the present review [11] will not be described here in detail.
Results
Ageing and small airways clearance
It was shown that patients with chronic bronchitis, with and without obstructed airways, typically had impaired mucociliary transport in their airways [12, 13]. Furthermore, patients with immotile cilia syndrome, a disease caused by absent or extremely slow mucociliary clearance in the airways, had similar signs and symptoms in the airways as patients with chronic bronchitis [14, 15]. These findings indicate that impaired mucociliary clearance is a pathogenicity factor of the development of chronic bronchitis. In a frequently cited paper [16], long-term clearance (typically up to 21 days) from the small airways was studied in 46 non-smoking, healthy subjects with a wide age distribution (mean [range] 42 [19–81]) years. Thirteen of the subjects were aged 24 years, eight were aged 25–29 years, seven 30–49 years, nine 50–64 years, and nine 65 years. Pulmonary function (mean ± SD [range]) was normal, with a forced expiratory volume in one second (FEV1) of 105 ± 16% of predicted (78–149), and an FEV1/forced vital capacity (FVC) of 80 ± 6.7% of predicted (64–99).
Figure 1 shows that late clearance (between 24 h and 21 days after inhalation) is significantly dependent on age. Although not shown in the figure, ageing is also associated with reduced FVC and FEV1. These two lung function parameters have been shown to be related to the late clearance of inhaled Teflon particles. Multiple regression analysis has, however, revealed that age independently predicts slower late small airways clearance.
Clearance (%) as a function of age. Clearance is estimated as the difference in retention at 24 h and 21 days; 24-h retention is 100%. The correlation between clearance at 1–21 days vs. age (r) = 0.70 [17].
Citation: Developments in Health Sciences 4, 4; 10.1556/2066.2022.00056
These observations may be clinically relevant, since small airways clearance is associated with increased risk of developing a lower airways infection [14, 15]. Subjects with cystic fibrosis and FEV1 <70% have been found to have worse long-term clearance compared to subjects with FEV1 >70% [17]. This indicates a potential association between small airways clearance and the development of airway obstruction.
Ageing, cough peak flow and respiratory muscle strength
Effective cough depends on sufficient respiratory muscle strength to increase lung volume and generate high expiratory flow [4]. Respiratory muscle strength and lung volume decline with age, and respiratory muscle weakness and reduced chest and abdominal wall mobility limit lung volume [18, 19]. Reduced lung volume restricts the volume of air that can be inhaled. This reduces positive intrathoracic pressure, which in turn reduces CPF [19]. In addition to age-related effects, poor physical performance and physical inactivity have an adverse impact on respiratory muscle strength [20] and lung volume [21, 22] in older adults. Objective assessments of physical activity may thus help in identifying factors that affect CPF and in formulating strategies to mitigate the risk of pulmonary complications in older adults. Kaneko et al. [8] therefore tested factors that contribute to CPF, and the relationship between CPF and respiratory muscle function in older adults.
Their findings indicated that vital capacity (VC), PImax and PEmax were significantly correlated with CPF. During multiple linear regression analysis with a dependent variable (CPF) and independent variables (FVC, PImax, PEmax), FVC and PImax were shown to be independently associated with CPF. Other authors [23] have also tested how ageing influences PImax. Figure 2 shows that PImax decreases with age (between 30–39 and 80–90 years). These findings underline that the ageing-related risks of pneumonia include weaker respiratory muscles, which lead to weakness of cough.
Increased age is associated with decreased maximal inspiratory pressure [24]
Citation: Developments in Health Sciences 4, 4; 10.1556/2066.2022.00056
Ageing and the development of SARS-CoV-2–specific immunity: experimental and clinical observations
Rates of morbidity and mortality associated with respiratory viral infections are highest among elderly people. While T lymphocytes are necessary for viral clearance, many age-dependent intrinsic T-cell defects have been documented. The development of robust T-cell responses in the lungs requires respiratory dendritic cells (rDCs), which process antigens and migrate to the draining lymph nodes (DLNs). Zhao et al. [11] showed that “increases in prostaglandin D2 (PGD2) expression in mouse lungs with ageing were correlated with a progressive impairment in rDC migration to the DLNs. Decreased rDC migration resulted in diminished CD8 T-cell responses and more severe clinical disease in older mice infected with respiratory viruses. Diminished rDC migration was associated with virus-specific defects in T-cell responses and was not a result of cell-intrinsic defects but rather reflected the observed age-dependent increases in PGD2 expression. Blocking PGD2 function with small-molecule antagonists enhanced rDC migration, T-cell responses, and survival”. This effect was correlated with the upregulation on rDCs of CCR7, a chemokine receptor involved in DC chemotaxis. The findings suggest that inhibiting PGD2 function may be a useful approach to enhance T-cell responses against respiratory viruses in older humans.
Ageing, CD8 cells and IL-6 cytokine in COVID-19 [11]
The findings indicate that “counts of all T lymphocyte subsets were markedly lower in non-survivors than survivors, especially CD8+ T cells”. Among all tested cytokines, IL-6 was elevated most significantly, with a greater than ten-fold upward trend. “Using multivariate logistic regression analysis, IL-6 levels of more than 20 pg mL−1 and CD8+ T-cell counts lower than 165 cells/μL were found to be associated with in-hospital mortality after adjusting for confounding factors. Groups with IL-6 levels of more than 20 pg mL−1 and CD8+ T-cell counts lower than 165 cells/μL contained a higher percentage of older patients” (Table 1).
Increased age in COVID-19 pneumonia patients tends to be associated with higher IL-6 concentration and lower CD8 lymphocyte count [11]
| Group 1 (n = 487) | Group 2 (n = 98) | Group 3 (n = 203) | Group 4 (n = 230) | P value | |
| Increased IL-6 | − | + | − | + | |
| Reduced CD8 cells | − | − | + | + | |
| Age (years) | 56 (43–65) | 61 (51–70) | 62 (53–69) | 68 (62–77) | <0.001 |
Conclusions
The summarised data provide convincing explanations as to why ageing people are at increased risk of morbidity and mortality following SARS-CoV-2 infection. The reviewed research data prove that the clearance of small particles (such as viruses) from the airways, cough power, as well as the specific antiviral immune response, become weaker with ageing. In addition, weak non-specific defence and adaptive immunity will be combined with an overt inflammatory response in elderly people exposed to the infection. Vaccination against the coronavirus is thus especially important among elderly people.
Authors' contribution
NA.
Ethical approval
NA.
Conflicts of interest/Funding
The author declares no conflict of interest and no financial support was received for this study.
Acknowledgements
NA.
References
- 1.↑
koronavirus.gov.hu [Internet]. Budapest: Government of Hungary; [cited 2021 Aug 10]. Available from: http://koronavirus.gov.hu.
- 2.↑
Svartengren M , Svartengren K , Europe E , et al. Long-term clearance from small airways in patients with chronic bronchitis experimental and theoretical data. Exp Lung Res. 2004;30:333–353. https://doi.org/10.1080/01902140490449436.
- 3.↑
Bianchi C , Baiardi P , Khirani S , Cantarella G . Cough peak flow as a predictor of pulmonary morbidity in patients with dysphagia. Am J Phys Med Rehabil. 2012;91:783–788. https://doi.org/10.1097/PHM.0b013e3182556701.
- 4.↑
McCool FD . Global physiology and pathophysiology of cough: ACCP evidence-based clinical practice guidelines. Chest 2006;129:48S–53S. https://doi.org/10.1378/chest.129.1_suppl.48S.
- 5.↑
Anderson M , Philipson K , Svartengren M , Camner P . Human deposition and clearance of 6-micron particles inhaled with an extremely slow flow rate. Exp Lung Res. 1995;21:187–195. https://doi.org/10.3109/01902149509031753.
- 6.↑
Svartengren M , Falk R , Philipson K . Long-term clearance from small airways decreases with age. Eur Respir J. 2005;26:609–615. https://doi.org/10.1183/09031936.05.00002105.
- 7.↑
Falk R , Magi A , Swedjemark GA . Whole-body measurement techniques at the Swedish National Institute of Radiation Protection. Acta Radiol Suppl. 1971;310:94–113.
- 8.↑
Kaneko H , Suzuki A . Effect of chest and abdominal wall mobility and respiratory muscle strength on forced vital capacity in older adults. Respir Physiol Neurobiol. 2017;246:47–52. https://doi.org/10.1016/j.resp.2017.08.004.
- 9.↑
American Thoracic Society/European Respiratory Society . ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit Care Med. 2002;166:518–624. https://doi.org/10.1164/rccm.166.4.518.
- 10.↑
Luo M , Jing Liu J , Jiang W , Yue S , Liu H , Wei S . IL-6 and CD8+ T cell counts combined are an early predictor of in-hospital mortality of patients with COVID-19. J Clin Invest Insight. 2020;5:e139024. https://doi.org/10.1172/jci.insight.139024.
- 11.↑
Zhao J , Zhao J , Legge K , Perlman S . Age-related increases in PGD2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J Clin Invest. 2011;121:4921–4930. https://doi.org/10.1172/JCI59777.
- 12.↑
Santa Cruz R , Landa J , Hirsch J , Sackner MA . Tracheal mucous velocity in normal man and patients with obstructive lung disease; effect of terbutaline. Am Rev Respir Dis. 1974;109:458–463. https://doi.org/10.1164/arrd.1974.109.4.458.
- 13.↑
Matthys H , Vastag E , Köhler D , Daikeler G , Fisher J . Mucociliary clearance in patients with chronic bronchitis and bronchial carcinoma. Respiration. 1983;44:329–337. https://doi.org/10.1159/000194565.
- 14.↑
Camner P , Mossberg B , Afzelius BA . Evidence of congenitally nonfunctioning cilia in the tracheobronchial tract in two subjects. Am Rev Respir Dis. 1975;112:807–809. https://doi.org/10.1164/arrd.1975.112.6.807.
- 15.↑
Mossberg B , Afzelius B , Eliasson R , Camner P . On the pathogenesis of obstructive lung disease. A study on the immotile cilia syndrome. Scand J Resp Dis. 1978;59:55–65.
- 16.↑
Svartengren K , Ericsson CH , Svartengren M , Mossberg B , Philipson K , Camner P . Deposition and clearance in large and small airways in chronic bronchitis. Exp Lung Res. 1996;22:555–576. https://doi.org/10.3109/01902149609046042.
- 17.↑
Lindstrom M , Camner P , Falk R , Hjelte L , Philipson K , Svartengren M . Long-term clearance from small ciliated airways in patients with cystic fibrosis. Eur Respir J. 2005;25:317–323. https://doi.org/10.1183/09031936.05.00120103.
- 18.↑
Janssens JP . Aging of the respiratory system: impact on pulmonary function tests and adaptation to exertion. Clin Chest Med. 2005;26:469–484. https://doi.org/10.1016/j.ccm.2005.05.004.
- 19.↑
Smith JA , Aliverti A , Quaranta M , et al. Chest wall dynamics during voluntary and induced cough in healthy volunteers. J Physiol. 2012;590:563–574. https://doi.org/10.1113/jphysiol.2011.213157.
- 20.↑
Buchman AS , Wilson RS , Boyle PA , Tang Y , Fleischman DA , Bennett DA . Physical activity and leg strength predict decline in mobility performance in older persons. J Am Geriatr Soc. 2007;55:1618–1623. https://doi.org/10.1111/j.1532-5415.2007.01359.x.
- 21.↑
Sillanpää E , Stenroth L , Bijlsma AY , et al. Associations between muscle strength, spirometric pulmonary function and mobility in healthy older adults. Age (Dordr). 2014;36:9667. https://doi.org/10.1007/s11357-014-9667-7.
- 22.↑
Freitas FS , Ibiapina CC , Alvim CG , Britto RR , Parreira VF . Relationship between cough strength and functional level in elderly. Rev Bras Fisioter. 2010;14:470–476. [Article in English, Portuguese].
- 23.↑
Enright PL , Adams AB , Boyle PJ , Sherrill DL . Spirometry and maximal respiratory pressure references from healthy Minnesota 65- to 85-year-old women and men. Chest. 1995;108:663–669. https://doi.org/10.1378/chest.108.3.663. Erratum in: Chest. 1995;108:1776.
- 24.↑
Kelley RC , Ferreira LF . Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology. Heart Fail Rev 2016;22(2):191–207. Available from: https://doi.org/10.1007/s10741-016-9549-4.
