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Ageing and respiratory infections: The airway of ageing Kamran Haq, Janet E. McElhaney ∗ Advanced Medical Research Institute of Canada, Sudbury, ON, Canada P3E 5J1

a r t i c l e

i n f o

Article history: Available online xxx Keywords: Ageing Influenza Vaccines Immunity

a b s t r a c t Respiratory infections are a leading cause of infectious disease burden worldwide especially among the elderly. Furthermore, a direct relationship between ageing and susceptibility to infections has been reported, which may be caused by impaired immune function, frailty and degree of exposure to infectious diseases. Many complex changes, including structural and age-associated decline in immunity are associated with increased pulmonary diseases worldwide and result in a high age-related disease burden. The common respiratory infections that present serious risks for the elderly include influenza, respiratory syncytial virus, and a number of bacterial pathogens including pneumococcus and tuberculosis. Vaccines are available for a limited number of these pathogens including influenza, pneumococcal and pertussis vaccines. This mini review article examines the age-related changes in immune function that predispose the elderly population to respiratory infections and potential loss of vaccine efficacy with a focus on ageing and influenza infections. © 2014 Published by Elsevier B.V.

1. Introduction Ageing is a complex and continuous biological process. It is a natural process that impairs several physiological systems, including the immune system and results in increased susceptibility to infectious, autoimmune and neoplastic diseases [1]. While there is no universal definition for ageing, World Health Organization and most clinical/geriatric references define the chronological age of 65 years as a definition of ‘elderly’ among developed countries; we do have to keep in mind that the rate of ageing varies between individuals and populations [2]. Ageing is a complex and multifactorial process which is not clearly understood yet. However, some characteristics of the ageing process are well accepted such as its universality among living organisms, irreversibility, frailty and eventually results in death. The rate of ageing also varies between individuals and groups based on pre-determined genetic factors or by environmental factors such as nutrition, exercise, health and lifestyle. The number of adults aged 65+ is expected to increase from 600 million to an estimated 2 billion by 2050, with over 25% of the population over 65 years in developed countries [3]. In parallel, World Health Organization also estimate that respiratory tract

∗ Corresponding author at: Advanced Medical Research Institute of Canada, 41 Ramsey Lake Road, Sudbury, ON, Canada P3E 5J1. Tel.: +1 705 523 7100x2725; fax: +1 705 523 7079. E-mail addresses: [email protected], [email protected] (J.E. McElhaney).

infections are the most common infectious cause of death in the world, with almost 3.5 million deaths yearly. The most common of all respiratory diseases is asthma with 235 million people globally suffering from asthma, and more than 3 million people died of chronic obstructive pulmonary disease (COPD) in 2005; 90% of these deaths occurred in low and middle income countries [4]. Given this trend, and the rapidly growing 65+ population, particularly in low income countries, emphasis on the overall quality of life of the older person represents a major public health challenge and is now a global issue. Research studies have now shown that systemic immunity gradually declines with advancing age as a consequence of the natural ageing process. This progressive decline in both the innate and adaptive immune systems is associated with biological ageing and is collectively defined as ‘immunosenescence’. Clinical consequences of immunosenescence include increased prevalence of cancer, autoimmune and chronic diseases, and poor responses to vaccination and increased vulnerability to common respiratory infections such as influenza [1,5,6]. Other than immune senescence, other structural changes also occur in the lung and the chest wall as a consequence of the ageing process which gradually lead to a decline in measures of lung function [7] and mechanical barriers at the mucosal surfaces. These structural changes include muscles, ribs and spine causing a decrease in the size of the thoracic cavity which impacts in normal lung function. Ageing has been shown to affect inspiratory and expiratory respiratory muscle strength, which is associated with poor cough strength and the ability to clear particles from the lung. These physiological changes are involved

http://dx.doi.org/10.1016/j.imlet.2014.06.009 0165-2478/© 2014 Published by Elsevier B.V.

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in exacerbating respiratory infections and poor outcomes in the elderly. Undoubtedly, there are many infections that present risks but we have chosen to highlight influenza virus infections. This mini review explores age-related immunologic changes in the respiratory system and their consequences.

Table 1 Alterations in innate and adaptive effectors associate with ageing. Cells

Effect of ageing

Refs.

T cells

Increase in ratio of CD4+ /CD8+ cells in BAL fluid Decreased clonal diversity of naïve T cells Increase in memory T cells Increased proportion of Treg cells Increased production of cytokines (e.g. IL-10, TGF-␤, IL-17)

[12,40]

B cells

Decrease in naive B cells Change in antibody repertoire Decline in specific B cell response to vaccines

[53,55]

NK cells

Increase in cells numbers Diminished cytotoxicity and secretion of cytokines/chemokines

[35]

Neutrophils

Reduced migration response to stimulants Decrease in expression of CD16

[37]

DC

No change in antigen uptake, processing, presentation

[24,25]

AM

Increased numbers Decrease in phagocytosis Dysregulation of cytokine/chemokines and reduced NO secretion

[62,63]

1.1. Immunosenescence and inflammaging Over an individual’s lifetime, we are exposed to a number of prevalent persistent reactivating herpesviruses that include herpes simplex virus (HSV), Epstein–Barr virus (EBV), varicella zoster virus (VZV) and cytomegalovirus (CMV) which may result in latent infections that can reactivate later in life. Among these, chronic CMV infection has been suggested as the key stimulus driving the process of immunosenescence [8]. Given that >90% of 80+ year olds are CMV positive, inflammatory changes which include increased concentrations of pro-inflammatory cytokines and various acute-phase proteins, suggest that ageing is also associated with a chronic lowgrade pro-inflammatory state, despite the absence of any particular disease [9,10]. An emerging theory is that this state of “inflammaging” is a consequence of lifetime exposure to antigenic load, and it drives a number of adverse changes including those related to immunosenescence [11]. This association is also observed in bronchoalveolar lavage fluid (BAL) from older adults, which contains high levels of proinflammatory cytokines compared to young adults [12]. However, other theories have eliminated the key role of CMV as the driving source of inflammaging [13], and others suggest the role of increased adiposity with age or decreased production of sex steroids as driving forces [14,15]. The consequences of inflammaging are tissue damage, production of reactive oxygen species, and release of cytokines which result in a pro-inflammatory state [16]. These changes may lead to overall suppression of the inflammatory response that is needed to fight an acute respiratory infection. Therefore, novel immunotherapies including vaccines designed to improve the regulation of inflammatory responses would appear to be key strategies for promoting healthy ageing in older people with chronic viral infections. 2. Ageing and respiratory immune response Respiratory illnesses including asthma, tuberculosis, bronchiolitis, emphysema, influenza, and pneumonia are common at all ages; however, there is a higher incidence of respiratory infections among adults of 65+ years. Mucosal surfaces in the respiratory, gastrointestinal and urogenital tracts, represent the most critical portals of pathogen entry including bacteria and viruses. After initial infection of epithelial cells, pathogens may replicate and promote disease at the mucosal site or invade neighbouring cells and spread systemically. Constant exposure of our respiratory tract to pathogens and allergens result in various kinds of infections and allergies which may or may not be harmful, however among the elderly these exposures can injure the lung and adversely impact repair. Traditionally, respiratory infections (acute to chronic infections) are divided into upper respiratory infections (e.g. common cold, sinusitis, tonsillitis, pharyngitis, laryngitis) and lower respiratory infections (e.g. pneumonia, bronchitis, tuberculosis). Influenza and respiratory syncytial virus (RSV) can affect both the upper and lower respiratory system. Since these infections are commonly complicated by bronchitis or pneumonia, adults 65+ years are recommended to be immunized with pneumococcal and influenza vaccines. Efforts continue to be focused on developing an RSV vaccine to reduce the significant morbidity of this virus in older adults, particularly those with COPD [17–19]. Immune senescence caused by the ageing process is associated with activation of both innate and adaptive immune responses

[41] [48] [49]

Abbreviations: BAL, broncial alveolar lavage fluid; Treg, regulatory T cells; IL, interleukin; TGF, transforming growth factor; CD, cluster of differentiation; DC; Dendritic cells; AM, alveolar macrophage.

(Table 1). The effect of immunosenescence on the innate immune system is primarily characterized by compromised functioning of neutrophils, monocytes, and dendritic cells. Whereas thymic involution and reduced responsiveness to new antigens, owing to a reduced ratio of naïve:memory T cells, characterizes senescence of the adaptive immune system. Generally, some key features of immunosenescence include a shift in T-cell populations with an increase in memory T cells and diminished output of naïve T cells, increased autoimmune responses and a chronic low-grade inflammation triggered by non-specific innate immunity [20,21]. 2.1. Ageing and Innate immunity The innate immune system, which includes a diverse group of cell types including dendritic cells (DC), natural killer (NK) cells, macrophages/monocytes and neutrophils, is affected at multiple levels during the ageing process [22]. The number and functional properties of DCs and the cytotoxic capacity of NK cells decline among the elderly when compared to young adults [23]. DCs are a specialized population of mononuclear cells responsible for recognition and uptake of pathogens for antigen presentation, and can be divided into two subsets both of which are found in the respiratory tract: myeloid (mDC) and plasmacytoid (pDC). These DC subsets have different functions in the immune response and are rapidly recruited as immature DCs following exposure to pathogens or inflammatory stimuli. In order to activate B- and T cells, DCs have to migrate from the site of infection to draining lymph nodes (LN) where T cell priming occurs. Studies have reported that with ageing antigen uptake, processing and presentation by DCs to stimulate naïve CD8+ T cells is well retained [24,25], whereas others have reported a diminished ability to induce naïve T cell proliferation [26–28]. Several murine studies have demonstrated poor migration and homing of DCs [27,29]. pDCs are critical type I interferon (IFN) producers via Toll-like receptors (TLR) 7 and 9 in response to viral and bacterial infections. Studies have demonstrated decreased toll-like receptors (TLR) function of pDCs and mDCs from older

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(65+ years) compared to younger adults. Others studies examining pDCs demonstrated that ageing was associated with a decrease in the number of pDC as well as lower expression of TLR9. Additionally, the capacity of mDC and pDC to produce pro-inflammatory cytokines after TLR stimulation is reduced [30,31]. Recent evidence demonstrated that myeloid-derived suppressor cell subsets, which can suppress T cell responses, are increased in the serum of frail elderly as with pro-inflammatory cytokines required for their differentiation, resulting in immune dysfunction [32]. Similarly, there is a decline in the number of specialized DCs (Langerhans cells) located at mucosal epithelial sites (primary site of respiratory infections) and function with ageing [33,34]. This decline in number and function of DC contribute to a weak immune response for activating effector and memory T cells as well as initiating influenza-specific responses in the lymph node (LN) and infection site. During early viral infection, activation of NK cells elicit the effector functions of cytokine production and target cell lysis via perforin/granzyme and other cytotoxic factors. Several alterations due to immune senescence have been described in NK cell function in the elderly. In older adults, the absolute numbers of NK cells are shown to increase; however, their cytotoxicity is attenuated due to inefficient signal transduction, increased expression of killer-inhibitory receptors and decreased secretion of cytokines/chemokines [35]. CMV seropositivity among the elderly significantly increases the percentage of NK cells in peripheral blood, and has various effects on the different subsets of NK cells [36]. Influenza infection of DC results in activation various receptors and release of cytokines that prompt a subset of NK cells (invariant NK T cells; iNKT) to produce immunomodulatory cytokines that can enhance inflammatory responses in the airways. Neutrophils rapidly migrate to sites of infection in response to distinct pro-inflammatory chemoattractants released by other cells. In vitro studies of neutrophils from older adults show a significant reduction in the migration response to granulocyte macrophage colony stimulating factor (GM-CSF) or peptide stimulation due to a decrease in expression of CD16, a marker of neutrophil functional capacity and viability [37]. In older adults, bacterial products that stimulate cytokines and other inflammatory mediators including lipopolysaccharide (LPS), IL-2, GM-CSF, G-CSF are less able to induce anti-apoptotic signals in neutrophils following stimulation [38]. This study describes neutrophil and macrophage impairment to respiratory burst and reactive nitrogen intermediates which results in poor ability to destroy bacterial pathogens. Examining neutrophils in frail elders living in nursing homes, a dysregulation in the expression of TLR4, ␤2 integrins and chemokines was reported, which may predispose the elderly to bacterial infections [39]. These observations may have important mechanistic links to age-related changes in the respiratory microbiome but the research is in its early stages and cause-effect relationships have yet to be established.

of influenza illness [43–45]. The increase in the memory T cell pool (CD8+ CD28− T cells) is mainly specific and associated with CMV seropositivity [46], however a direct link between changes in CD8+ T cells in relation to CMV seropositivity has yet to be made. Influenza-related studies showing that CD4+ T cell functionality declines in the elderly are also supported by poor antibody and CD4+ T cell responses to trivalent influenza vaccine (TIV) [40,47]. While there is also a general increase in memory CD4+ T cell phenotype in older adults, the number of circulating influenza-specific CD4+ T cells does not change with ageing. Studies examining the effect of ageing on number and function of regulatory T cells (Treg) reported an imbalance in Treg (CD4+ FoxP3+ ) responses known to suppress proliferation and activation of T cells, and production of interleukin (IL)-17. Higher frequencies of immunosuppressive Treg cells are observed in the elderly [48] and in vitro studies show that Treg express high levels of IL-10 and TGF-␤ [49]. This increase could contribute to a higher suppressive effect eventually leading to the decrease in immune function and response to vaccines [50]. Interestingly, IL-17 producing T helper cells (Th17) may also contribute to the dysregulated cytokine production observed in the older population. Murine studies show that aberrant IL-17a production in response to viral infection stimulates neutrophil-dependent processes which contribute to mortality [51]. Th17 cells are critical in mediating vaccine-induced immunity against several mucosal infectious diseases, and studies by Lee et al. [52] have reported a reduced number in the elderly. The decline in humoral responses to respiratory infections is best exemplified by decreased influenza vaccine efficacy, which drops from 70-90% in those under 65 years of age to 30–40% over the age of 65 [50]. Upon infection, naïve B cells that recognize cognate antigens are activated and form germinal centres where switching and maturation occurs. These populations of memory B cells and antibody secreting cells help promote pathogen clearance during primary infection. Similar to T cell responses in the elderly, the humoral responses clearly declines with age due to reduced naïve B cell numbers or repertoire diversity [53]. Evidence of poor responses or inability to respond to new antigens comes from measurement of changes in specific antibody levels post vaccination. Studies comparing antibody responses to influenza and pneumococcal vaccines among adults (65 years), demonstrated reduced levels of immunoglobulin M (IgM) and IgA and weak changes to the repertoire in older adults [54]. A study over two influenza seasons, 2008–2010, demonstrated that specific B cell response to influenza vaccine decrease with age [55]. These age-related decreases in the diversity and quality of antibody response may affect the ability to clear pathogen and provide protection in the initial infection by respiratory pathogens.

2.2. Ageing and Adaptive immunity

The disease burden of influenza worldwide is currently estimated to be 3–5 million cases of severe disease and between 250,000 and 500,000 deaths annually [56]. Approximately 25% of elderly patients suffer from complications due to influenza. Hospitalization and death rates from influenza are rising in spite of widespread vaccination programmes which have been implemented in many countries. The cause of high infection rates among the elderly can be attributed to the lack of vaccination programmes in low and middle income countries, genetic re-assortment (‘antigenic shift’) and mutations (‘antigenic drift’) that lead to a mismatch with influenza vaccine strains, and most importantly, the decline in cell-mediated immune function that is poorly stimulated by current influenza vaccines. The rising impact of influenza in the over 65 population can be attributed the effects of immune senescence and ageing of the population, but also to the dramatic increase in

Several cross-sectional and longitudinal studies have demonstrated the impact of ageing on adaptive immunity. The main age-associated differences include: decreased clonal diversity of naïve T cells, increase in memory T cells and altered T cell signalling [reviewed in 40,41]. As we age, expression of various inhibitory receptors are enhanced and co-stimulatory as well as tumour necrosis factor (TNF) receptors decreased [42]. Progressive loss of naïve CD8+ T cells and increase of memory T cells, especially in memory CD8+ T cells, has been demonstrated among the elderly as a result of thymic involution and decreased lymphopoiesis in the bone marrow. CD8+ T cells have been linked to poor antibody responses to influenza vaccination but CD8+ T cell responses appear to be a better correlate of protection against and severity

2.3. Influenza in elderly

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high-risk chronic conditions that impact on influenza outcomes among the elderly [57]; the constant threat of the emergence of a novel influenza subtype is even a greater risk to the population. Among community-dwelling older adults, increasing age has been shown to correlate with increased risk of hospitalization due to secondary infections or pneumonia and influenza [58]. Both cell-mediated and humoral immune responses play key roles in influenza virus clearance and protection. CD4+ and CD8+ T cells are required for influenza virus clearance during primary infection in the mucosal tissues, in addition humoral responses also aid in virus clearance [59]. Age-related changes in the mucosal immune system result in a shift in the proportion of distinct T cell subsets and a decrease in total B cell populations. Meyer et al. [12] observed a higher ratio of CD4+ /CD8+ T cells in BAL fluid when comparing older to younger adults. In young adults, correlates of protection based on CD4+ [60] and CD8+ [61] T cell responses to peptides derived from the internal proteins (matrix and nucleoprotein) of influenza point to the importance of including these antigens in novel strategies to improve influenza outcomes in older adults including the development of “universal” vaccines. With a decrease in B cell numbers, the reduction in antibody-secreting and antigen-binding capacity can contribute to increased pathogen infection of the host cell and a less robust immune response. In ageing adults, the proportion of Treg cells is increased in older adults and may suppress the immune response to respiratory viral infections [5]. Ageing is associated with increased numbers of NK cells and also increases serum levels of proinflammatory cytokines [35]. Similarly, ageing is also associated with an increase in the number of phagocytes, macrophages and neutrophils. Alveolar macrophages which reside on the respiratory epithelium are the first cells encountered by pathogens or antigens in the respiratory airway, and are an important component of the mucosal immune system. Their numbers are increased with age, however they have been shown to have decreased phagocytic potential, inefficient chemotaxis and can also contribute to “inflammaging”, the heightened and potentially pathologic production of inflammatory mediators leading to tissue destruction [62,63].

3. Therapeutic strategies and prevention in the elderly A major health issue among the older adults is the increasing prevalence and severity of some infectious diseases, which partly reflects the age-related decline in immune function. For example, influenza is associated with severe complications and secondary infections in the elderly and contributes to the four leading causes of global mortality with the highest rates in older adults. Vaccination is of crucial importance in preventing infection and protecting the vulnerable elderly population from respiratory infections for which vaccines are available. Annual vaccination against influenza is recommended in most developed countries for persons with underlying chronic conditions and older adults over the age of 60 [64]. Vaccination has shown a reduction in influenza-specific hospitalizations by 27–45% and mortality up to 50% [65]. Although vaccination remains the most effective method of preventing many infections, we face some challenges related to the limited efficacy of vaccines observed among the elderly [66]. Thus, there is an urgent need to develop strategies for improving vaccine efficacy and therapies to boost immunity in the elderly. Various strategies to improve vaccines-mediated protection include: using a higher dose compared to standard doses, changing vaccine formulation by addition of adjuvants, using alternate routes of immunization, and universal vaccine strategies which target conserved pathogen regions. RSV remains an important but often unrecognized respiratory pathogen causing serious illness in the elderly [17,19]. Vaccines against RSV infection developed to elicit long-lived protective immunity have been unsuccessful, and at present there is no

approved vaccine to protect against RSV [67]. Currently, a recombinant monoclonal antibody, palivizumab (Synagis® ) is used to prevent serious RSV infections; however its use is limited due to its cost. Research is also focussing on DNA and subunit vaccines, which can confer long lasting protection, however, efficient delivery systems will be required to increase the efficacy of DNA/protein vaccines. A recent murine study reported protective efficacy for up to a year when using a truncated form of the fusion (F) protein in combination with adjuvants such as TLR agonists and an immunostimulatory peptide [68]. Vaccination against pneumococcal infection is recommended for all adults age 65 years and older. Currently, there are two effective vaccines to protect adults against pneumococcal diseases; a pneumococcal polysaccharide vaccine (PPSV) that contains purified capsular polysaccharide antigen from different types of pneumococcal bacteria, and a pneumococcal conjugate vaccine (PCV). A 23-valent PPSV is the recommended vaccine for clinical use in adults aged 65+ years to prevent against invasive pneumococcal diseases (IPD) [69]. Early published results of the recent Dutch PCV13 trial suggest that this vaccine offers protection against both IPD and non-invasive pneumococcal pneumonia in immunocompetent community-dwelling adults ≥65 years. However, protection is limited to those pneumococcal serotypes contained in the 23 serotypes in PPSV and 13 serotypes in PCV [70]. Further research is needed to develop pneumococcal vaccines that provide crossprotective immunity against current and emerging serotypes not contained in the vaccine. This is particularly important for frail elderly whose immune systems may be compromised by the effects of chronic underlying diseases, beyond those related to ageing and immune senescence. 4. Conclusion Respiratory infections remain the most common cause of mortality and morbidity in the elderly worldwide, and emerging infections such as pandemic influenza pose new threats. Many physiological changes, including immunological changes that affect proper functioning of the pulmonary system result in higher susceptibility to respiratory infections. A decline in functional responses of the innate and adaptive components may increase the susceptibility to acute respiratory infections in the elderly, and increase the likelihood of severe illness and secondary infections. Vaccinations provide efficient protection from many infectious diseases, however, the age-related decline in the immune system presents a significant challenge to developing new and more effective vaccines for the older population. Additional research to better understand how age-related changes interact with the effect of chronic infections and diseases are needed to develop new vaccines with enhanced protection among older adults. Conflict of interest Janet McElhaney has participated on advisory boards for GlaxoSmithKline, Sanofi Pasteur, Novartis, and Med-Immune, on data monitoring boards for Sanofi Pasteur, and has participated in clinical trials sponsored by Merck, GlaxoSmithKline and Sanofi Pasteur; and has received honoraria and travel and accommodation reimbursements for presentations sponsored by Merck, GlaxoSmithKline and Sanofi Pasteur, and travel reimbursement for participation on a publication steering committee for GlaxoSmithKline. References [1] McElhaney JE, Effros RB. Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 2009;21:418–24.

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Please cite this article in press as: Haq K, McElhaney JE. Ageing and respiratory infections: The airway of ageing. Immunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.06.009