09 Geriatrics

SECTION 9

Geriatrics 76.

Telomere and Ageing VN Mishra, Nalini Mishra, Ishan

353

77.

The Immunity in Elderly Jyotirmoy Pal, Pradip Kumar Chowdhury

356

78.

Atrial Fibrillation in Elderly Vijay Garg, Raman Parashar, Aadish Kumar Jain, AK Pancholia

362

79.

Infections in Elderly Gandharba Ray, L Ravi Kumar

368

C H A P T E R

76

WHAT IS AGEING?

Over the years Ageing has been defined by scientific thinkers, workers and organizations in their own way, from the biological standpoint most definitions of aging indicate that it is a progressive process associated with declines in structure and function, impaired maintenance and repair systems, increased susceptibility to disease and death in near future. Ageing is not inevitable, indeed there are some species of plants and animals that do not appear to age as they undergo an extremely slow aging process termed “negligible senescence” conversely there are some living creatures that undergo programmed death immediately after reproduction such as annual plants and semelparous animals. However majority of others from yeast to humans undergo a gradual aging process leading to death that is surprisingly similar at the cellular and biochemical level.

Ageing is particularly apparent in organisms where growth is completed before reproduction commences, such as insects, birds and many mammals including humans. Understanding ageing is demanding, time consuming and to be honest we are still not well equipped mentally and technically to understand this complex puzzle of Life and Death, the biggest secret of nature.

There is little evidence that death is programmed into our genes and substantial evidence that it is malleable, it is proved by the fact that lifespan has been lengthened by a variety of means in many living species including human beings. Recent studies on mice have shown a 20% rise in life expectancy in mice following genetic modification.

THEORIES OF AGEING

One has to agree with the logic that all living creatures have only two options to maintain their existence: immortality or reproduction. It seems that in the situation of ever changing environment, they have adopted strategy of reproduction combined with a finite lifespan which has proved to be successful. Many evolutionary theories related to aging are linked by their attempts to explain this interaction between reproduction and longevity.

Most of the mainstream aging theories stem from the fact that evolution is driven by early reproductive success whereas there is minimal selection pressure for late life reproduction or post reproductive survival. Aging is seen as the random degeneration resulting from the inability of evolution to prevent it i.e. the non adaptive consequence of evolutionary neglect. This conclusion is supported by recent studies that restricted reproduction to later life in the fruit fly Drosophila melanogaster thus permitting

Telomere and Ageing VN Mishra, Nalini Mishra, Ishan

natural selection to operate on later life traits leading to an increase in longevity It seems that there is still no consensus about the mechanism of ageing but there is general agreement that it is unlikely that any single mechanism would explain the process. Following quote by some anonymous worker explains the fact that how complex the process is and how little we know about it till now “Rather than getting closer to understanding the systems (of ageing), science is getting further away, because we are learning it’s more complicated than we thought it was.” Many theories have been put forward by workers from time to time to explain why and how ageing happens. These are not mutually exclusive theories but differ in the perspectives of their analysis.

One of the important theories of ageing is “Telomere Shortening theory of ageing.”

WHAT IS TELOMERE?

Telomeres are the strands of DNA with same repetitive nucleotide sequences at each end of a chromosome. Telomeres have been compared with the plastic tips on shoelaces, because they keep chromosome ends from fraying and sticking to each other or from fusion with neighbouring chromosomes which would scramble an organism’s genetic information. Its name is derived from the Greek nouns telos means ‘end’ and merοs means ‘part.’ For vertebrates the sequence of nucleotides in telomeres is TTAGGG. Because of the way in which DNA is replicated, the length of the telomeres shortens each time the cell divides. Consequently, the length of telomeres in the cells of older people tends to be shorter than in younger people. In human white blood cells length of telomere ranges from 8,000 base pairs in newborns to 3,000 base pairs in adults and as low as 1,500 in elderly people. (An entire chromosome has about 150 million base pairs.) Each time it divides, an average cell loses 30 to 200 base pairs from the ends of its telomeres.

In 1965 Leonard Hayflick’s showed the limit to which cells duplicate themselves before aging. Hayflick established what subsequently is called the Hayflick limit, which states that a cell can divide forty to sixty times before it cannot divide further and begins to age. Although Blackburn helped discover telomeres in 1975 two years before in 1973, Olovnikov had hypothesized the existence of telomerase, the length of telomeres, and their connections to cellular aging during his study on the Hayflick Limit, later on Blackburn isolated and cloned telomeres in Tetrahymena DNA. Blackburn with the help of Carol Greider identified telomerase in 1984 and isolated it from

354

Tetrahymena in 1989. This discovery was so important that Blackburn, Jack Szostak, and Carol Greider received the Nobel Prize in Medicine in 2009 for their work to identify and isolate telomeres and telomerase. Telomere shortening has been identified as a factor that could contribute to ageing. However, the relationship is not a simple one and although short telomeres may contribute to early ageing, they are not a good predictor of how long an individual will live or how healthy they will be before they die. Research into this field is still at an early stage.

GERIATRICS

WHAT IS TELOMERASE?

Telomerase is a ribonucleoprotein DNA polymerase complex that maintains telomere length. The complex comprises the protein human Telomerase Reverse Transcriptase (hTERT) and a catalytic RNA (TERC). In the absence of telomerase activity telomeres progressively shorten. Telomerase activity is absent in most normal human somatic cells because of the lack of expression of TERT whereas TERC is usually present. Without telomerase, telomere shortening eventually limits the growth of cells, leading to senescence. Expression of TERT in cells that otherwise lack telomerase activity cause cells to bypass senescence and crisis, such cells are usually termed “immortalized.” The absence of telomerase activity in most human somatic cells results in telomere shortening during aging. Telomerase activity can be restored to human cells by hTERT gene transduction or potentially via drug therapy.

CAN TELOMERASE REVERSE AGEING PROCESS?

It is becoming apparent that reversing shortening of telomeres through temporary activation of telomerase may be a potent means to slow aging. This could possibly extend human life by increasing Hayflick limit. Three routes have been proposed to reverse telomere shortening: drugs, gene therapy, or metabolic suppression, so-called, torpor/hibernation. So far these ideas have not been proven in humans. Turbill in the year 2013 demonstrated that telomere shortening is reversed during hibernation and thus aging is slowed in rodents prolonging life span. In recently conducted studies on mice it has also been demonstrated that telomere extension could successfully reverse some signs of aging. Those mice that were engineered to lack the enzyme telomerase became prematurely decrepit but they bounced back to health when the enzyme was replaced. The finding hints that some disorders characterized by early ageing could be treated by boosting telomerase activity. It also offers the possibility that normal human ageing could be slowed by reawakening the enzyme in cells where it has stopped working. This has implications for thinking about telomerase as a serious anti ageing intervention.

Other scientists however point out that mice lacking telomerase are a poor stand in for the normal ageing process. Moreover, ramping up telomerase in humans could potentially encourage the growth of tumours.

Role of Telomere Extension in Reversing Aging in Cultured Human Cells

Scientists working at the Stanford University have developed a new procedure which involves the use of a modified type of RNA, this can quickly and efficiently increase the length of human telomeres, human cultured fibroblast cells treated with this procedure behave as if they are much younger than untreated cells, multiplying with abandon in the laboratory dish rather than stagnating or dying. Skin cells with telomeres lengthened by this procedure were able to divide up to 40 more times than those cells which were untreated. This will improve the ability of researchers to generate large numbers of cells for study or drug development. This research may show the new path to treat diseases caused by shortened telomeres in the coming days.

TELOMERE AND LIFE STYLE MODIFICATIONS

Some of the lifestyle factors which increase risk of developing cancer have also been associated with shortened telomeres including stress, smoking, physical inactivity and diet high in refined sugars. Diet and physical activity influence inflammation and oxidative stress. These factors are thought to influence telomere maintenance. Psychological stress has also been linked to cell aging, and telomere shortening appears to be accelerated in people living more stressful lives. In a study by Epen on peripheral blood mononuclear cells from healthy premenopausal women, women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age related changes. In 2012 Blackburn published the influence of lifestyle on the length of telomeres and cellular aging in humans. He found that stress, nutrition and personality influence the length of telomeres and telomerase enzyme activity. The authors noted that those who perceived events as less stressful had longer telomere lengths compared to individuals who perceived events as more stressful behaviours, smoking or eating processed meats also correlated with shorter than normal telomere lengths. Also those who took vitamin C or E supplements had longer than normal telomere lengths. The results of Blackburn and her team’s experiment verified that environmental factors affect the length of telomeres.

It has been suggested that a combination of lifestyle modifications, including healthy diet, exercise and stress reduction, have the potential to increase telomere length, reverse cellular aging, and reduce the risk for aging related diseases. In a recent clinical trial on early prostate cancer patients comprehensive lifestyle changes resulted in a short term increase in telomerase activity and long term modification in telomere length. Lifestyle modifications have the potential to naturally regulate telomere maintenance without promoting tumorigenesis.

TELOMERE AND CANCER

Telomeres are critical for maintaining genomic integrity.

but perhaps telomere shortening might play some role in aging and age-related diseases. They might be contributors or intermediaries by enhancing the effects of other types of molecular cellular damage. Reactivation of telomerase could be useful in some forms of cell therapy but safety issues are a concern as activation of telomerase removes barrier to the continued growth and developing cancers. Lack of telomerase activity provides a tumour suppressor function. Targeting the telomeres and/or telomerase by itself does not seem to have effect on human aging at present but it might be helpful in the case of some specific pathologies. It is unquestionable that cellular senescence and telomere biology are important in understanding pathogenesis of cancers and it may be of some help in developing newer anti cancer treatments in near future.

1.

Quite often these cells escape death by making more telomerase enzyme, which prevents the telomeres from getting shorter. Measuring telomerase may be a way to detect cancer. And if we could learn how to stop telomerase, we might be able to fight cancer by making cancer cells age and die. In one experiment, researchers blocked telomerase activity in human breast and prostate cancer cells growing in the laboratory, prompting the tumour cells to die. But there are risks. Blocking telomerase could impair fertility; wound healing, and production of blood cells and immune system cells.

A 2013 pilot study from University of California San Francisco on early stage prostate cancer studied the lifestyle changes and experienced a significant increase in telomere length of approximately ten percent. Cancer cells require a mechanism to maintain their telomeric DNA in order to continue dividing indefinitely (immortalization).

A mechanism for telomere elongation or maintenance is one of the key steps in cellular immortalization and can be used as a diagnostic marker in the clinic. The largest comparative study of telomeres and telomerase, involving over 60 mammalian species found that smaller, short lived species tend to have long telomeres and high levels of telomerase. This suggests that short telomeres and suppression of telomerase are necessary for the evolution of large body sizes and longevity, presumably by suppressing cancer.

Finch C. E. 1990 Longevity, senescence and genome Chicago, IL: University of Chicago Press.

2.

Vaupel J. W., Baudisch A., Dolling M.et al. The case for negative senescence. Theor Popul Biol 2004; 65:339–351.

3.

National Institutes of Health. Single gene change increases mouse lifespan by 20 percent [Internet]. 2013. http://www. nih.gov/news/health/aug2013/nhlbi-29.htm

4.

Bernardes de JB, Vera E, Schneeberger K, et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med 2012; 4:691–704.

5.

Sadava D, Hillis D, Heller C, & Berenbaum M. (2011). Life: The science of biology. (9th ed.) Sunderland, MA: Sinauer Associates Inc.

6.

Peter J. Hornsby. Telomerase and the aging process. Exp Gerontol 2007; 42:575–581.

7.

Shay J, Wright W. Hallmarks of telomeres in ageing research. J Pathol 2007; 211:114–23.

8.

Turbill C, Ruf T, Smith S, et al. Seasonal variation in telomere length of a hibernating rodent. Biology Letters.

2013; 9:20121095.

9.

Wentzensen, IM; Mirabello, L; Pfeiffer, RM; et al. “The association of telomere length and cancer: a metaanalysis”. Cancer Epidemiol Biomarkers Prev 2011; 20:1238– 1250.

CONCLUSION

Telomere plays an important role in natural senescence and aging. Telomerase is probably not the sole factor in determining differences in aging rate among various species. Cellular senescence is primarily caused by cumulative effect of various kinds of cellular stress

REFERENCES

the

10. Lin, Jue, Elizabeth B et al. “Telomeres and lifestyle factors: roles in cellular Aging.” Mutation Research 2012; 730:85–9.

11. Ornish, D; Lin, J; Chan, JM; et al. “Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study”. Lancet Oncol 2013; 14:1112–20.

12. Willeit P, Willeit J, Mayr A, et al. “Telomere length and risk of incident cancer and cancer mortality”. JAMA 2010; 304:69–75.

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CHAPTER 76

Studies have shown that telomere dysfunction or shortening is commonly acquired during the process of tumour development. Short telomeres can lead to genomic instability, chromosome loss and the formation of non reciprocal translocations. It has been observed that telomeres in tumour cells and their precursor lesions are significantly shorter than surrounding normal tissue. As a cell begins to become cancerous, it divides more often and its telomeres become very short. If its telomeres get too short, the cell may die. Observational studies have found shortened telomeres in many cancers including pancreatic, bone, prostate, bladder, lung, kidney, head and neck. In addition, people with many types of cancer have been found to possess shorter leukocyte telomeres than healthy controls. Recent meta-analyses suggest 1.4 to 3.0 fold increased risk of cancer for those with the shortest vs longest telomeres. However the increase in risk varies by age, sex, tumour type and differences in lifestyle factors.

The Immunity in Elderly

C H A P T E R

77

Jyotirmoy Pal, Pradip Kumar Chowdhury

INTRODUCTION

There is an increasing awareness that many chronic infections and diseases impact on the immune system. The immune system is a very dynamic network, consisting of various innate and adaptive cells and indirect messaging mediated by soluble factors. The changes in immune profiles translate into obvious signs of immunological aging that are more profound in diseases. In the current decades, there is an increase in the aged population across the world. According to the WHO, the proportion of old individuals (age > 60 years) will rise to 22% of the world population.57Â In this context, it is very important to improve our knowledge of aging and its associated diseases to fight with the burden of diseases and to promote healthy aging.

BASICS OF IMMUNITY

Immunity is the state of protection, against any substance that is recognized as foreign by the body. The immune system is composed of two major subdivisions, the innate or nonspecific immune system and the acquired or specific immune system (Figure 1).

Innate Immunity- Innate or nonspecific immunity is a primary defense mechanism against invading organisms, involves barriers that keep harmful materials from entering the body. It is a key element of the immune response including several cellular components such as macrophages, natural killer (NK) cells, and neutrophils, which provide rapid first-line defense against pathogens.

Acquired or adaptive Immunity- Acquired immunity is immunity that develops with exposure to various antigens, specific to that antigen and acts as a second line of defense and its response can be antibody mediated (humoral), cell mediated (cellular), or both. Active Immunity- Active immunity is induced after contact with foreign antigens (eg, microorganism or their products). This contact may consist of clinical or subclinical infection, immunization IMMUNITY

INNATE (inborn) Gerietic factors

ACQUIRED

ACTIVE Own antibodies

NATURAL Exposure to infectious agent

ARTIFICIAL Immunization

PASSIVE Ready-made antibodies

NATURAL Maternal antibodies

ARTIFICIAL Antibodies from other sources

Fig. 1: Schematic presentation of the immune system (Source: http://futuresurgeon0607.blogspot.com/)

or transplantation of foreign cells. In all these instances the host actively produces antibodies. However, protection is delayed until antibody production reaches an effective level. Passive Immunity- Passive immunity is achieved by administration of preformed antibodies. It provides prompt protection against certain viruses (eg, HBV) in non immunized individuals but does not provide longlasting protection.

Cell-mediated Immunity- It is the type of immunity that functions in defense against fungi, parasites, bacteria, and viruses inside host system and against tissue transplants, with highly specialized cells that circulate in the blood and available in local tissue site.

Humoral Immunity- This is the component of the immune system that involves antibodies secreted by B cells and circulates as soluble proteins in blood.

Cells in the Immune System- All cells of the immune system originate from a hematopoietic stem cell in the bone marrow, which gives rise to two major lineages, a myeloid and a lymphoid progenitor cells. These progenitor cells subsequently give rise to the myeloid cells (monocytes, macrophages, dendritic cells, megakaryocyte and granulocytes) and lymphoid cells (T cells, B cells and natural killer (NK) cells) respectively. These cells make up the cellular components of the innate (non-specific) and adaptive (specific) immune systems (Figure 2).

IMMUNOSENESCENCE

The term 'immunosenescence' is used to describe loss of immune functions in elderly people (age > 65 years). Though it involves both the innate and adaptive immune system,2 the important contributor is the changes observed in adaptive immunity, including T and B lymphocytes. The antigen-specific immunity is impaired with aging partly due to alterations in the innate immunity. Although its mechanisms are not very clear, it has been associated with increased susceptibility to diseases, infections and poor response to treatments and vaccination.1 The ability of maintaining receptor diversity is reduced with aging and this is paralleled by the reduction in the number of circulating naĂŻve T-cells (CD45RA+CCR7+CD28+CD27+).3,4 This can be explained by the phenomenon of involution of the thymus, where T-cell maturation occurs. This is associated with increased number of memory cells due to pathogens encountered during the course of life.5 Another hypothesis to explain immunosenescence partly is the telomere length. The telomere shortening primarily identified in highly differentiated effector memory CD8+ T cells, most of which are CD28− T cells.6 The loss of telomeric repeats is associated with loss of proliferative capacity and

T-cell

T-cell Cytokines

Thymus

357

Cytokines

B-cells

Plasma cell

Inflammation via PMN, etc.

Differentiation of cytotoxic T-cells

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(CD45RA+CCR7+CD28+CD27+).[3,4] T-cell nescence: This can be immunosenescence' is used to describe explained by the phenomenon of involution of the T-cells Cytokines une functions in elderly people (age > 65 thymus, where T-cell maturation occurs. This is Bone marrow ough it involves both the innate and associated with increased number of memory cells cell[2] the important Cytokines immune stem system, due to pathogens encountered during the course of [5] life.specific Another hypothesis to explain is the changes observed in adaptive Antigen T-cell immunosenescence partly is the telomere length. including T and B lymphocytes. The interaction The telomere shortening primarily identified in ecific immunity is impaired with aging Cytokines highly differentiated effector memory CD8+ T cells, to alterations in the innate immunity. s mechanisms are not very clear, it has most of which are CD28− T cells.[6] The loss of ciated with increased susceptibility to telomeric repeats T-cell is associated with loss of infections and poor response to APC (e.gproliferative capacity and replicative senescence. and vaccination.[1] The ability of macrophage) Despite this evidence the telomere length is not the shortest in the highly differentiated T g receptor diversity is reduced with [7] specifica more Cytokines cells,Antigen his is paralleled by the reduction in the suggesting complex relationship interaction of circulating naïve T-cells between telomeres and senescence.

Macrophage activation

Antibody production

Fig. 2: Schematic diagram of the cellular interactions in the immune response. APC: Antigen presenting cell Fig. 2: Schematic diagram of the cellular interactions in the immune response. APC: Antigen presenting cell

With aging, monocytes increased in numbers.8 Defective Toll-like receptor (TLR) function has been studied in Susceptibility to diseases and comorbidities monocytes, where the production of IL-6 and TNF-α ↔ Immune erosion + + 9 + [3,4] Immunosenescence: CCR7by+CD28 CD27 ). has aThis b reduced (CD45RA when induced TLR1/2.

Aging general can suppressive effect on dendritic cell function.

Neutrophils KLRG-1/CD57 T-cells The term 'immunosenescence' is used to describe explained by the phenomenon of involution of th show reduced functions, like slowed response to Clonal ↔ Persistent infections loss of immune functions in elderly people (age > 65 thymus, where T-cell maturation occurs. This chemotaxis, phagocytosis, generation of superoxide, Expansion years).

Though both the innate and alterations associated increased of lipid memory cel in signal with transduction andnumber membrane ↔ TCR diversity it involves CMV specific T-cells [2] 10 ↔ Anti-CMV control rafts with aging.

This age-related decline in neutrophil adaptive immune system, the due to pathogens encountered during the course o important functions is explained partly by the decreased Fc-γ receptor life.[5] Another contributor is the changes observed in adaptive hypothesis to expla Telomerase activity Inflammation expression.11 Some events associated with signaling and immunity, including T and B lymphocytes.

The immunosenescence partly is the telomere ↔ Telomere length ↔ Multifactorial activation may also interfere with neutrophil functions. length dehydroepiandrosterone sulfate (DHES) antigen-specific immunity is impaired with aging For example, The the telomere shortening primarily identified Thymic output levels are highly reduced with aging (adrenopause) partly due to alterations the innate immunity. highly differentiated effector memory CD8+ T cell ↔ Newly emigrant naïvein T-cells that could highly impact neutrophil −activation.[6] The Although its mechanisms are not very clear, it has DHES increases most ofsuperoxide which are CD28 by T cells.

The loss o generation neutrophils ? Stimulus been associated with increased susceptibility to via a PKC-β/p47(phox) telomeric repeats associated with loss o pathwayis12 that suggests altered ↔ Innate immunity: PMN, monocytes and DC effect due to modulation of neutrophil diseases, infections and poor response to antibactericidal proliferative capacity and replicative senescenc activity.

[1]

treatments and vaccination. The ability of Despite this evidence the telomere length is not th Aging T AND B CELLS IN AGINGin the highly differentiated shortest maintaining receptor diversity is reduced with omponents of immunosenescence: The items depicted on left side show decline with age,There while items the are onseveral memory subsets in the CD4 and [7] cells, suggesting and this is paralleled by the DC: reduction in PMN: the CD8 a more complex relationsh Fig.age.

3: The components immunosenescence: The items upregulationaging with ? Unknown; CMV:ofCytomegalovirus; Dendritic cell; Polymorphonuclear compartments. Based on surface markers depicted on left decline with age, while items TCR: T-cell receptor. number of side show circulating naïve T-cells used to between telomeres and are senescence. distinguish these, there central memory

on the right show upregulation with age. ? Unknown; CMV: (CCR7+CD45RA−CD45RO+CD28+CD27+), effector memory Cytomegalovirus; DC: Dendritic cell; PMN: Polymorphonuclear (CCR7−CD45RA−CD45RO+CD28+/-CD27+/-) and late increased in numbers.[8] Defectivedifferentiated Toll-like receptor(CCR7−CD45RA+CD45ROlowCD28−CD27−) neutrophil; TCR: T-cell receptor munity in Aging:

(TLR) function has been studied in The monocytes, of the innate immune system, like cells. frequency of CD28− T cells, which is often replicative senescence.

Despite this evidence the telomere where the production of IL-6 and TNF-α reduced , monocytes/macrophages and dendritic associated to aging of the immune system, encompass length not that the shortest highly differentiated T Aging a general induced

by TLR1/2.[9] rgo changes with isaging lead to in thewhen bothhasthe effector memory and T-effector memory recells,7 With suggesting a more complex relationship suppressive effect between on dendritic cell function. mmune function. aging, monocytes expressing CD45RA (TEMRA) cells and discrepancies

telomeres and senescence.

exists between CD4 and CD8 T cells.13 Some markers are associated lack of functionality of T cells. CD57 and Susceptibility to diseases and with comorbidities INNATE IMMUNITY IN AGING KLRG-1 are associated lack of proliferative response The cells of the innate immune system, like neutrophils, ↔ Immunewith erosion and are considered as markers of replicative senescence. monocytes/macrophages and dendritic cells undergo These cells lack expression of costimulatory molecules changes with aging that lead to impaired immune function. like CD28 and CD27. A majority of the expanded cells are

358

CMV Seropositive

1. Inflammation ↑↑↑ Aging: ↔

2. Comorbidities ↑↑↑

↔

3. Resilience ↓↓↓

IRP High % CD8+ CD28CMV Sero-positivity Low B-cell numbers CD4:CD8 < 1

Mortality ↑↑↑ ↔

Morbidity ↑↑↑ Quality of life ↓↓↓

CMV Seronegative

1. Inflammation ↑ Aging: ↔

2. Comorbidities ↑

Mortality ↑ No IRP

GERIATRICS

3. Resilience ↓

Morbidity ↑ Quality of life ↑

Fig. 4: The Impact of cytomegalovirus infection on immunity and health. With aging there is an elevated proinflammatory profile that is enhanced by CMV infection. Associated co morbidities and poor resilience will add up to the existing condition and may lead individuals to be at risk later in life, as suggested by the IRP. This will be reflected into different mortality, morbidity and quality of life grades. +: Present; +++: Very high; --- : Very low; CMV: Cytomegalovirus; IRP: Immune Risk Profile. Source: Aging Health @2013 Future Medicine Ltd. expressing CD57, KLRG-1 or both suggesting antigenspecific T-cell expansion leads to an increased proportion of replicative senescent cells. Both the number and the function of B cells are reduced with aging. The senescent B cells also exhibit increased production of low-affinity antibodies due to decreased isotype switching from IgG to IgM antibodies.16 These lead to increased susceptibility to diseases, reduced responses to vaccination and increased incidence of cancer in aged populations.14,15 Reductions in B-cell lymphopoiesis in old age could contribute to reduce tumor immunosurveillance. So it appears that loss of B-cell diversity is strongly associated with poor health rather than age.17

increase in the proportion of memory T cells. The most observable phenotypic and functional changes are seen in the subsets of CD8+ T-cell. The continuous stimulation of memory cells by specific persistent antigens like CMV leads to their progressive exhaustion characterized by the loss of costimulatory molecules (CD28 and CD27), shortening of telomeres and terminal differentiation (CD45RA+CD57+). The presence of CMV and CMVspecific T cells hinders the response to co-infections such as EBV.21 The accumulation of these virus-specific CD8+ T cells compromises immune function and restricts the overall immune repertoire in elderly. CMV infection has been associated with the Immune Risk Profile (IRP), a cluster of parameters predicting mortality in the elderly.

Apart from CMV seropositivity, increased numbers of CD8+CD28− T cells, an inverted CD4:CD8 ratio (<1) and low B-cell counts are part of the IRP.22 CD8+CD28− T cells also exhibit suppressor activities which may alter antigen presentation and changes in dendritic cell function with aging.23 In contrast the CD4+ T cells are less affected by replicative senescence. The memory CD4+ T-cell response is impaired with aging.24 Overall, CD8+, CD4+ and putative antigen presenting cell (APC) changes with an altered interaction between these cells lead to reduced vaccine efficacy.

ALZHEIMER’S DISEASE (AD)

INFECTIOUS DISEASES

Alzheimer’s disease (AD) is an age-related neurological disorder that leads to progressive dementia. AD is histopathologically characterized by extracellular amyloid plaques formed by amyloid-β (Aβ) peptide and by intracellular neurofibrillary tangles. The inflammation resulting from deposits of highly aggregated Aβ fibrils plays an important role in the pathogenesis of AD.25 In the brain, microglia express MHC class I and II molecules after activation by neurodegeneration or ischemia.26 By contrast, microglia activation in the brain of AD patients is caused by Aβ and the activated microglia cluster at sites of Aβ deposition.27 The microglia from elderly donors show changes in their cytoplasmic structure, leading to functional defects and development of AD in the elderly, but it still remains unknown how the activation of microglia is influenced by age and senescence.27

The lifelong exposure to pathogens leads to a relative

There are several types of cardiovascular diseases associated with aging. The higher prevalence of coronary disease, hypertension, diabetes, ventricular hypertrophy, fibrosis and senescence of cardiac cells lead to events that may predict more severe cardiac failure with aging.28,29 The atherosclerotic plaques are composed of activated helper T cells, γ/δ T cells, macrophages, smooth muscle cells and CD1a+ dendritic cells, whereas B cells and NK cells are absent.30 These cells induce a proinflammatory milieu that contributes sustained inflammation and the development of the lesions. Innate cells like neutrophils participate in the development of ischemic stroke. CD4+ T cells modulate immune response by secreting type-2 cytokines (IL-4 and IL-10) or type-1 cytokines (IL-12, IFN-γ and TNF-α). The majority of the T cells present in atherosclerotic plaques are memory cells lacking CD28 expression. These cells have a poor proliferative capacity but a higher proinflammatory/cytotoxic (IFN-γ

IMMUNITY IN AGE-RELATED DISEASES

To understand the relationship between diseases in the elderly and the immune system the following diseases are discussed below: The aged immune system is not as efficient in recognizing and eliminating new invaders or in preventing their spread. Age-associated alterations in systemic immunity contribute to the increased incidence and severity of infectious diseases in elderly.18 The organisms such as bacteria, viruses, fungi or parasites often encounter less resistance after invading the elderly. CMV is asymptomatic in most individuals and only in rare cases CMV disease develops.19 The prevalence for CMV varies from 45 to 100% according to age, location and hygiene conditions. CMV prevalence is lower in Europe/USA and higher in Africa/Asia but significant differences exist within large countries.19 In aged people CMV specific CD8+ T cells increased and circulating naive T cells are decreased. The risk of influenza-related death increases exponentially after 65 years.20 CMV and influenza per se is not directly inducing death, but the events associated with these diseases are detrimental, especially in elderly with poor resilience (Figure 4).

CARDIOVASCULAR DISEASES

and TNF-α) profile that sustain local inflammation and disease progression.13

CANCER

DIABETES

Type 2 diabetes has become an epidemic especially in the elderly37 with the majority in the 45–64 years.38 With aging the body composition is changed such as sarcopenia and fat accumulation.38 The reduced muscle bulk with lack of motility (sedentary lifestyle) leads to decrease energy expenditure favoring fat accumulation. Other risk factors are insufficient exercise, smoking, alcohol, weight gain and an unbalanced diet.39 There is a strong link between inflammation, diabetes and metabolic syndrome. The study of Hjelmesæth et al strongly suggests that CMV infection and the associated events can initiate/accelerate the onset of diabetes.40 CMV seropositivity is associated with glucose regulation in elderly.41 Therefore diabetes and metabolic syndrome influence immunosenescence.

Some vitamins and mineral supplementation can help in augmenting immunity, such as vitamin A helps to maintain the epithelial integrity of the respiratory and gastrointestinal tracts, thereby reduces the risk of influenza and gastrointestinal infection; vitamin D enhances activation of Toll like receptors (TLRs) and increases cathelicide production, which contributes to the destruction of intracellular organism. Zinc has a role in helping phagocytosis, and maintenance of the complement cascade. While malnutrition has detrimental effect on immunity, caloric restriction has positive effect on T cell function. So a balanced diet approach would be justified.45,46

EXERCISE AND LIFESTYLE MODIFICATION

Moderate exercise helps to maintain the physical functions and cardiovascular fitness improves the T helper immune responses. Smoking and alcohol consumption should be stopped and lipid profile should be within normal range to maintain a healthy immune system.

Vaccinations: Vaccinations are a reliable and costeffective method for prevention of infections. The elderly people not able to respond optimally to vaccination due to reduced thymic output of naive T cells, increasing memory T cells but their progressive replicative senescence,47 and imbalance between pro- and antiinflammatory cytokines. Apart from changes in T cells a latent CMV infection and physical frailty also impact on the outcome of vaccinations. Physical frailty such as slow walking speed, low physical activity and weight loss have been associated with reduced antibody response to vaccination and post vaccination influenza infection.48 The strategies to improve the effectiveness of vaccines in elderly individuals include: a.

Using adjuvant: TLR-4 agonist, glucopyranosyl lipid adjuvant stable emulsion, improves the antigen-presenting capacity of dendritic cells by improving T-cell immune response by increasing the production of proinflammatory cytokines when added to influenza split-virus vaccine.49

b.

Broadening the cross-reactivity of strains: The use of MF59 adjuvenated vaccine offers a broader range of protection for multiple strains.50

c.

Changing the route of administration: Intradermal injection improves immunogenicity in elderly individuals.51

INFLAMMATION & AGING

Inflammation in aging is often referred to as low-grade inflammation.42 A set of proinflammatory mediators such as RANTES, MIP-1α, MCP-1, CRP, IL-6, IL-8 and TNF-α have been identified in aging. Among these, CRP, IL-6 and TNF-α are often associated with comorbidities such as cardiovascular diseases, atherosclerosis, dementia and diabetes. These association studies did not enable to predict disease onset in the elderly at the inflammatory level. Furthermore, studies have shown that higher levels of proinflammatory molecules are not always associated with poor health, since centenarians show higher IL-6 levels.43 This suggests that inflammation in aging is probably a sign of unsuccessful aging associated with diseases.

REVERSING IMMUNITY

Many strategies such as caloric restriction, hormone therapy, cytokine therapy or stem cell approaches have been demonstrated to restore immunity in animal models, but may prove difficult to perform in humans due to lack of consensus.44 The following approaches are employed to reverse the immunity in elderly with justified manner.

Reversing thymic involution and increasing thymopoiesis

Eexogenous administration of keratinocyte growth factor induces the production of IL-7 on thymic epithelial cells, thereby increasing thymic output in murine models.52,53 By in vivo administration of FGF-7, the senescence-associated gene Ink4a can be repressed in involuted thymus to generate T-cell progenitors.52 The T-cell functions can be restored by promoting 4–1BB, or blocking PD-1 and supplementing with cytokine cocktails. Blockade of 4–1BB highly reduces the production of key cytokines such as IFN-γ and TNF-α.54 Cytokines play a pivotal role in T-cell survival, homeostasis and activation. Recent study

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The incidence of cancer increases with advancing age.31 This is due to the cumulative events such as exposure to carcinogens, mutations and reduced immune functions.

In healthy elderly people, the killing, proliferative and response of NK cells to triggering are reduced.32,33 The reduced killing may be due to the altered perforin release and interaction at the immunological synapse site of the target cells.34 This mechanism can explain why elderly individuals are more susceptible to cancers. The immunecompromised individuals (e.g., HIV patients) are more susceptible to non-Hodgkin’s lymphoma (NHL) and cervical cancer.35 The tumor induced local inflammation suppresses the adaptive immune system favoring tumor development.36 The elderly people are less susceptible to acute lymphoblastic leukemia (ALL) due to reduced thymopoiesis and more susceptible to chronic lymphocytic leukemia (CLL) due to immunosenescence. Moreover tumors often express Fas Iigand which induces apoptosis of T cells through Fas receptor. Therefore elevation of Fas receptor with aging contributes tumor growth.

NUTRITIONAL INTERVENTION

360

showed that IL-15 preferentially promote proliferation of CD28null CD4+ T cells over the CD28+CD4+ T cells. IL15 also enhances the cytotoxic activity in a short-term manner by increasing IFN-γ, granzyme B and perforin production.55 Further studies are necessary to understand the impact of different cytokine cocktails on other T-cell subsets and not only on CD28null T cells.56

GERIATRICS

CONCLUSION

Immunesenescence is a major challenge against active ageing which is the major determinant for susceptibility to diseases and may also be a cornerstone in sustaining chronic conditions due to the associated proinflammatory profile. Notably the putative alterations in T- and B-cell interaction are still poorly understood in pathological situations and in subclinical condition like age-associated low-grade inflammation. The Immunosenescence has the direct effect on development of frequent and severe infection, which further increases morbidity, disability and death in elderly population. Overwhelming detrimental effect of weaning immunity precipitates aggressive malignancy in them. Thymic rejuvenation is attractive, but still requires cautious interpretation.

Vaccination is an effective measure but efficacy decreased with advancing ageing, which mandates discovery of new and augmented vaccination strategy. Lifestyle modification, nutritional supplementation, caloric restriction but avoiding malnutrition through balanced diet may be employed to augment immunity in elderly.

Telomerase based approach and gene therapy could be the future prospects.

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van Duin D, Mohanty S, Thomas V et al. Age-associated defect in human TLR-1/2 function. J Immunol 2007; 178:970– 975.

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11. Butcher SK, Chahal H, Nayak L et al. Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J Leukoc Biol 2001; 70:881–886.

12. Radford DJ, Wang K, McNelis JC et al. Dehdyroepiandrosterone sulfate directly activates protein kinase C-beta to increase human neutrophil superoxide generation. Mol Endocrinol 2010; 24:813–821.

13. Appay V, van Lier RA, Sallusto F, Roederer M. Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytometry A 2008; 73:975–983.

14. Signer RA, Montecino-Rodriguez E, Dorshkind K. Aging, B lymphopoiesis, and patterns of leukemogenesis. Exp Gerontol 2007; 42:391–395.

15. Weiskopf D, Weinberger B, Grubeck-Loebenstein B. The aging of the immune system. Transpl Int 2009; 22:1041– 1050.

16. Kogut I, Scholz JL, Cancro MP, Cambier JC. B cell maintenance and function in aging. Semin Immunol 2012; 24:342–349.

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18. Castle SC. Clinical relevance of age-related immune dysfunction. Clin Infect Dis 2000; 31:578–585.

19. Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 2010; 20:202–213.

20. Thompson WW, Shay DK, Weintraub E et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003; 289:179–186.

21. Khan N, Hislop A, Gudgeon N et al. Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J Immunol 2004; 173:7481–7489.

22. Wikby A, Johansson B, Olsson J, Lofgren S, Nilsson BO, Ferguson F. Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp Gerontol 2002; 37:445–453.

23. Agrawal A, Agrawal S, Tay J, Gupta S. Biology of dendritic cells in aging. J Clin Immunol 2008; 28:14–20.

24. Kang I, Hong MS, Nolasco H et al. Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine. J Immunol 2004; 173:673–681.

25. Akiyama H, Barger S, Barnum S et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000; 21:383–421. *Demonstrated the relationship between the proinflammatory milieu and Alzheimer’s disease.

26. McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Rev 1995; 21:195–218.

27. Streit WJ, Sammons NW, Kuhns AJ, Sparks DL. Dystrophic microglia in the aging human brain. Glia 2004; 45:208–212.

43. Sansoni P, Vescovini R, Fagnoni F et al. The immune system in extreme longevity. Exp Gerontol 2008; 43:61–65.

28. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease. Circulation 2003; 107:346–354.

44. Dorshkind K, Montecino-Rodriguez E, Signer RA.The ageing immune system: is it ever too old to become young again? Nat Rev Immunol 2009; 9:57–62.

29. Chen W, Frangogiannis NG. The role of inflammatory and fibrogenic pathways in heart failure associated with aging. Heart Fail Rev 2010; 15:415–422.

31. Myers CE, Mirza NN, Lustgarten J. Immunity, cancer and aging: lessons from mouse models. Aging Dis 2011; 2:512– 523.

32. Borrego F, Alonso MC, Galiani MD et al. NK phenotypic markers and IL2 response in NK cells from elderly people.

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33. Kutza J, Muraskoz DM. Age-associated decline in IL-2 and IL-12 induction of LAK cell activity of human PBMC samples. Mech Ageing Dev 1996; 90:209–222.

34. Hazeldine J, Hampson P, Lord JM. Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity. Aging Cell 2012; 11:751–759.

35. Caceres W, Cruz-Amy M, Diaz-Melendez V. AIDS-related malignancies: revisited. PR Health Sci J 2010; 29:70–75.

36. Soudja SM, Wehbe M, Mas A et al. Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice. Cancer Res 2010; 70:3515–3525.

37. Yoon KH, Lee JH, Kim JW et al. Epidemic obesity and Type 2 diabetes in Asia. Lancet 2006; 368:1681–1688.

38. Kesavadev JD, Short KR, Nair KS. Diabetes in old age: an emerging epidemic. J Assoc Physicians India 2003; 51:1083– 1094.

39. Tuomilehto J, Lindstrom J, Eriksson JG et al. Prevention of Type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344:1343–1350.

40. Leung Ki EL, Venetz JP, Meylan P, Lamoth F, Ruiz J, Pascual M. Cytomegalovirus infection and new-onset posttransplant diabetes mellitus. Clin Transplant 2008; 22:245– 249.

41. Chen S, Jm de Craen A, Raz Y et al. Cytomegalovirus seropositivity is associated with glucose regulation in the oldest old. Results from the Leiden 85-plus study. Immun Ageing 2012; 9:18.

42. De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflammageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 2005; 579:2035–2039. *Demonstrates the link between chronic stimulation of the immune system by viruses, its related inflammation and longevity.

45. Ongradi J, Kovesdi V. Factors that may impact on immunosenescence: an appraisal. Immun Ageing 2010; 7: 7.

46. Centers for Disease Control and Prevention. MMWR 2009; 58:1091-1095 47. Effros RB, Boucher N, Porter V et al. Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp Gerontol 1994; 29:601–609.

48. Yao X, Hamilton RG, Weng NP et al. Frailty is associated with impairment of vaccine-induced antibody response and increase in postvaccination influenza infection in community-dwelling older adults. Vaccine 2011; 29:5015– 5021.

49. McElhaney JE, Zhou X, Talbot HK et al. The unmet need in the elderly: how immunosenescence, CMV infection, comorbidities and frailty are a challenge for the development of more effective influenza vaccines. Vaccine 2012; 30:2060– 2067.

50. Fragapane E, Gasparini R, Schioppa F, Laghi-Pasini F, Montomoli E, Banzhoff A. A heterologous MF59adjuvanted H5N1 prepandemic influenza booster vaccine induces a robust, cross-reactive immune response in adults and the elderly. Clin Vaccine Immunol 2010; 17:1817–1879.

51. Holland D, Booy R, De Looze F et al. Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis 2008; 198:650–658.

52. Min D, Panoskaltsis-Mortari A, Kuro OM, Hollander GA, Blazar BR, Weinberg KI. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 2007; 109:2529–2537.

53. Berent-Maoz B, Montecino-Rodriguez E, Signer RA, Dorshkind K. Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a. Blood 2012; 119:5715–5721.

54. Dumitriu IE, Baruah P, Finlayson CJ et al. High levels of costimulatory receptors OX40 and 4–1BB characterize CD4+CD28null T cells in patients with acute coronary syndrome. Circ Res 2012; 110:857–869.

55. Alonso-Arias R, Moro-García MA, Vidal-Castiñeira JR et al. IL-15 preferentially enhances functional properties and antigen-specific responses of CD4+CD28(null) compared to CD4+CD28+ T cells. Aging Cell 2011; 10:844–852.

56. Chu NR, DeBenedette MA, Stiernholm BJ, Barber BH, Watts TH. Role of IL-12 and 4–1BB ligand in cytokine production by CD28+ and CD28- T cells. J Immunol 1997; 158:3081–3089. Website: 57. WHO. Ageing and life course. www.who.int/ageing/en/ index.html

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30. Waltner-Romen M, Falkensammer G, Rabl W, Wick G. A previously unrecognized site of local accumulation of mononuclear cells. The vascular-associated lymphoid tissue. J Histochem Cytochem 1998; 46:1347–1350.

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Atrial Fibrillation in Elderly

C H A P T E R

78

Vijay Garg, Raman Parashar, Aadish Kumar Jain, AK Pancholia

•

Feeling of palpitations

In atrial fibrillation the electrical flow is chaotic causing the heartbeat to become irregular. Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and accounts for 1/3 of hospital admissions for cardiac rhythm disturbances.

•

Shortness of breath

•

Chest pain

•

Fatigue or exercise intolerance

PREVELANCE OF AF IN ELDERLY

The goals in the treatment and management of AF are, first, to prevent thromboembolic episodes, mainly strokes,

INTRODUCTION

For both men and women, prevalence and incidence of AF were disproportionately higher in developed nations compared with developing nations. The reported annual incidence of AF in men and women in the age group of 55–64 years has been reported to be 0.003% and 0.001% respectively, which increases to 0.038 in men and 0.031 in women in the 85–94 age group. In general, the incidence of AF is 0.1% per year in the population below forty years and increases to 2% in those older than 80 years.

MANAGEMENT AND TREATMENT

Table 1: Cardiovascular Morbidity and Mortality Associated with Atrial Fibrillation Event

Association with AF

Death

Increased mortality, especially cardiovascular mortality due to sudden death, heart faiure or stroke

Stroke

20-30% of all strokes are due to AF. A growing number of patients with stroke are diagnosed with ‘silent’, paroxysymal AF.

Hospitalizations

10-40% of AF patients are hospitalized every year.

Quality of life

Quality of life is impaired in AF patients independent of other cardiovascular conditions

Left ventricular dysfunction and heart failure

Left ventricular dysfunction is found in 20-30% of all AF patients.

AF causes or aggravates LV dysfunction in many AF patients, while other have completely preserved LV function despite long-standing AF

Cognitive decline and vascular dementia

Cognitive decline and vascular dementia can develop even in anticoagulated AF patients. Brain white matter lesions are more common in AF patients than in patients without AF.

PATHOPHYSIOLOGY OF AF (FIGURE 1)

Aging heart, characterized by myocardial fibrosis and atrial dilation, is a proper soil for AF to flourish. AF creates electrical and structural remodeling in the atria by shortening, mismatching, and lengthening the effective refractory period (increase of dispersion), depressing the intra-atrial conduction, and depriving its contractile function.

SIGN AND SYMPTOMS

When heart goes into atrial fibrillation patient may experience dangerous and frightening symptoms. AF may cause symptoms such as: •

Dizziness

Fig. 1: Risk Factor for Atrial Fibrillation

which leads to a considerable reduction in mortality, and second, to improve the quality of life, by reducing the symptoms and hospitalizations (Table 1). The first goal is achieved using anticoagulant therapy, and the second is achieved through rhythm or rate control.

Newer techniques such as catheter ablation are rapidly establishing their role in treatment.

Anticoagulation therapy in elderly patients

The ATRIA1 and BAFTA17 studies have shown that elderly patients with AF benefited by the use of anticoagulation therapy. OACs have reduced the thromboembolic risk in these patients when compared to aspirin. The OACs used in these studies were vitamin K antagonists

Table 2: CHADS2 and CHA2DS2VASc Score CHADS2 -> CHA2 DS2 VASc

CHADS2 Risk

Score

CHA2DS2-VASc Risk

Score

CHF

1

CHF or LVEF ≤ 40%

1

Hypertension

1

Hypertension

1

Age > 75

1

Age ≥ 75

2

Diabetes

1

Diabetes

1

Stroke or TIA

2

Stroke / TIA / Thromboembolism

2

Vascular Disease

1

Age 65-74

1

Female

1

INR should be monitored regularly, even if the patient is stable, and every one of them must keep an INR diary.

Elderly patients are prone to injuries and falls, and thus the fear of bleeding is considerable in them. The HASBLED19 and HEMMORR2HAGES20 scores are valuable tools in evaluating these patients’ bleeding risk (Table 4).

VKAs are connected to serum albumin. In the elderly patients, serum albumin levels often drop dramatically

Table 3: Therapeutic Recommendations Risk category

CHA2DS2-VASc score

One ‘major’ risk factor or ≥ 2 ‘ clinically relevant nonmajor’ risk factors

≥2

Recommended antithrombotic therapy OACa

One ‘clinically relevant nonmajor’ risk factor

1

Either OACa or aspirin 75325 mg daily.

Preferred: OAC rather than aspirin.

No risk factors

0

Either aspirin 75-325 mg daily or no antithrombotic therapy.

Preferred: no antithrombotic therapy rather tha aspirin.

Table 4: Bleeding Risk Scores in AF Atria

HAS-BLED

HEMORR2HAGES

Anemia

3

HT

1

Hepatic or renal disease

1

Severe renal disease

3

Abnormal renal or liver function

1

Ethanol abuse

1

Age ≥ 75 years

2

Stroke

1

Malignancy

1

Any prior haemorrhage

1

Bleeding

1

Older age (> 75 years)

1

HT

1

Labile INR

1

Reduced platelet count or function

1

Elderly (> 65 years)

1

Rebleeding

2

Drug or alcohol use

1

HT

1

Anemia

1

Genetic factors

1

Excessive fall risk

1

Stroke

1

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Elderly patients should be administered anticoagulation therapy for AF. Both CHADS2 and the newer CHA2DS2VASc scores emphasize the importance of increased age in the evaluation of thromboembolic risk (Table 2). Patients with CHADS2 >= 2 should receive oral anticoagulation (OAC). Patients with score 1 are subject to the physician’s opinion to receive anticoagulants or aspirin. Using the newer CHA2DS2- VASc score, all patients older than 75 years should receive OAC, unless there is a strong contraindication (Table 3).

(VKAs), especially warfarin. Maintaining an international normalized ratio (INR) between 2.0 and 3.0 is the target for thromboembolic protection. The revised guidelines by Japanese Circulation Society (JCS) suggest a target INR of 1.6–2.6 for patients with nonvalvular AF and aged >= 70.18 .

due to inflammation or malnutrition and lack of protein in their diets. VKA overdose is frequent in these situations and hence INR should be monitored closely, every 15–21 days (Figure 2).

364

GERIATRICS

Novel oral anticoagulants (NOACS), on the contrary, do not require INR monitoring and are rapidly getting popular even among the elderly. NOACS currently used in clinical practice include dabigatran which is a direct thrombin inhibitor, and rivaroxaban, apixaban, and edoxaban which are direct factor Xa inhibitors.

Fig. 2: Management of Atrial Fibrillation

In patients 75 years or older with AF after an acute coronary syndrome and revascularization, triple antithrombotic therapy (aspirin, clopidogrel plus oral anticoagulant) for a minimum of 4 weeks and up to a maximum of 6 months should be administered. Because of the high risk of bleeding in the elderly, the duration of this therapy should not last more than 4 weeks, and bare metal stent should be selected. Afterward, patients will continue treatment with dual therapy (antiplatelet agent plus oral anticoagulant) for 1 year (Figure 3). In such a case, clopidogrel plus VKA seems to have a better hemorrhagic profile than clopidogrel plus acetylsalicylic acid plus VKA, with no inferiority to stent thrombosis.

Patients 75 years or older with AF with stable CAD who underwent revascularization should receive triple therapy for 2–4 weeks and proceed to dual therapy for 1–12 months (Figure 4). Bare metal stenting should be preferred (Figure 5) in such a case also. In patients without a revascularization procedure, a single treatment

Fig. 3: Antithrombotic therapy after an acute coronary syndrome in atrial fibrillation patients requiring anticoagulation

365

CHAPTER 78 Fig. 4 : Antithrombotic therapy after elective percutaneous intervention in atrial fibrillation patients requiring anticoagulation

Fig. 5: Initiation or Resumption of Anticoagulation in Atrial Fibrillation Patients after an Intracranial Bleed

GERIATRICS

366

Fig. 6: Acute Heart Rate Control in Atrial Fibrillation with VKAs or NOAC seems to be sufficient. It should be noted that newer antiplatelets are not yet approved in triple therapy and prasugrel is contraindicated in patients aged 75 and over.

PERCUTANEOUS LEFT ATRIAL APPENDAGE CLOSURE

Many patients, particularly the elderly, cannot tolerate or even refuse to receive chronic anticoagulation therapy. As an alternative to systemic anticoagulation, a new invasive procedure has been evolved, the percutaneous left atrial appendage (LAA) closure. Approximately 90% of the left atrial thrombi originate from the LAA, and its successful occlusion can significantly reduce the thromboembolic risk. Patients with nonvalvular AF, at high stroke risk and contraindications for OACs are possible candidates for this technique.

ANTIARRHYTHMIC DRUGS IN ELDERLY PATIENTS

Rate control : In the elderly patients, especially the asymptomatic ones, rate control is the first-line therapy. β-blockers are the most effective at achieving that goal (Figure 6). Digoxin is recommended in acute heart failure, but has been proven to be an independent risk factor for death in patients without heart failure and should be used cautiously in the elderly in whom renal function is delicate.

Rhythm control : In an elderly patient with recurrences of AF despite receiving rhythm control medication, further attempts at restoring sinus rhythm are not suggested.

Cardioversion, whether electrical or pharmaceutical, is related to serious side effects in the elderly and unless AF <= 48 hours, and OAC must be documented for at least 3 weeks. Amiodarone is the safest choice in pharmaceutical cardioversion in the elderly (Figure 7).

CATHETER ABLATION OF AF IN THE ELDERLY

Left atrial catheter ablation has proven to be a considerable therapeutic option in maintaining sinus rhythm in patients suffering from AF. Catheter ablation is strongly contraindicated in patients with thrombus in the left atrium or in patients who cannot receive anticoagulation for at least 6â&#x20AC;&#x201C;8 weeks after the procedure. Evolution in AF, ablation techniques and improved efficacy have given the elderly patients an alternative treatment for AF. Recent studies, have demonstrated similar rates of success and adverse events using radiofrequency catheter ablation between the elderly and younger patients.

BENEFIT OF YOGA IN PATIENT WITH ATRIAL FIBRILLATION

It was found that patients who did yoga had a better quality of life, lower heart rate and lower blood pressure than patients who did not do yoga. If could be that the deep breathing balances the parasympathetic and sympathetic nervous system, leading to less variation in heart rate. The breathing and movement may have beneficial effects on blood pressure.

CONCLUSION

Over the past decades, novel medications and therapies

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Fig. 7: Rhythm control management of recent onset atrial fibrillation have been administered to the elderly patients with AF. This subgroup of patients who were neglected and undertreated now occupy the center stage. Therapies must be tailored to elderly patients, with particular attention to structural heart disease and renal failure.

Elderly patients are at increased risk for thromboembolic events. Thromboembolic protection is therefore of major importance in this population. Newer anticoagulants are increasing in popularity among the elderly patients without renal failure. Elderly patients with contraindications to OAC are possible candidates for percutaneous LAA closure.

REFERENCES

1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001; 285:2370–2375.

2. Kistler P, Sanders P, Fynn S, et al. Electrophysiologic and electroanatomic changes in the human atrium associated with age. J Am Coll Cardiol 2004; 44:109–116.

3. Lakshminarayan K, Solid CA, Collins AJ, Anderson DC, Herzog CA. Atrial fibrillation and stroke in the general medicare population: a 10-year perspective (1992 to 2002).

Stroke 2006; 37:1969–1974.

4. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Study. Circulation 1998; 98:946– 952.

5. Fazekas T. The concise history of atrial fibrillation. Orvostort Kozl 2007; 53:37–68.

6. Wann LS, Curtis AB, Ellenbogen KA, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/ AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines.

Circulation 2013; 127:1916–1926.

7. Lu Z, Scherlag BJ, Lin J, et al. Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing. Circ Arrhythm Electrophysiol 2008; 1:184–192.

8. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 2008; 51:802–809.

9. Everett TH 4th, Olgin JE. Atrial fibrosis and the mechanisms of atrial fibrillation. Heart Rhythm 2007; 4(3 Suppl):S24–S27.

10. Xiao Y, Yang KQ, Yang YK, et al. Clinical characteristics and prognosis of end-stage hypertrophic cardiomyopathy.

Chin Med J (Engl) 2015; 128:1483–1489.

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79

ABSTRACT

Infections are common cause of morbidity and mortality in older patients despite advances in antibiotic therapy.

They account for one third of all deaths in people of 65 years and older. As the population of older adults increase the clinicians are seeing increasing number of cases of infectious diseases in older adults – particularly nosocomial and health-care associated infections. Early detection of infection can be difficult in older adults due to the frequent absence of typical signs and symptoms. The absence of fever does not exclude infection, the absence of respiratory symptoms does not exclude pneumonia and without dysuria there can be UTI. Instead of classic symptoms of infection older adults may present with confusion, delirium, anorexia, falls and general decline in functional status. Estimated 90% of deaths in pneumonia occurs in people 65 years and above. Mortality resulting from influenza primarily occur in elderly and UTI is the most common of bacteraemia in older adults. Tuberculosis and HIV infection is very difficult to treat in older patients because of there low immunity and organ dysfunction.

Tropical disease like malaria and diarrhoea become most fatal in this age group. Therefore physicians should be most careful while treating elderly people with infection.

INTRODUCTION

Despite advances in antibiotic therapy infectious diseases continue to be a major cause of mortality in older adults.

The diagnostic and therapeutic advances of managing infections in older adults create special challenges for physicians, still then early diagnosis and treatment in these patients are essential because of higher incidence of morbidity and mortality. Many signs and symptom of infection that are common in younger adults particularly fever and leucocytosis present less frequently or not at all in older adults1. While 60 percent of older adults with serious infections develop leucocytosis, its absence doesnot rule out infectious process. Because frail old adults found to have poor body temperature response, elevations in body temperature of 1.10 C from their normal base line temperature should be considered a febrile response.

Changes caused by infection in the elderly are subtle and nonspecific complaints may be the only sign of infection.

Elderly patients with infection may present with cognitive impairment or a change in mental status, frank delirium occurs in 50% of older adults with infections. Further move anorexia, functional decline, falls, weight loss or

Infections in Elderly Gandharba Ray, L Ravi Kumar

a slight increase in respiratory rate may be only sign indicating infection in older patients.

Demographic picture in developing countries2 : Demographic aging is now well established and the elderly population (age >65yrs ) will exceed 1 billion persons in 2030. At present the proportion of elderly persons in developed countries are much more than the same population in developing countries but this proportion is changing. This fast changing pace in demographic structure results from phenomenon called demographic transition in which the successive or concomitant reduction in the death and birth rates results in the former boosting population size and the latter increasing the proportion of elderly individuals. At present the increase in elderly population of developing countries is dramatically faster than the increase observed in the industrialised countries. Because aging is associated with higher prevalence of chronic and debilitating disease leading to disability, healthcare needs will be increased among the aging population and will place more pressure on the already constrained healthcare resources of developing countries.

What is the role of infection in the death of elderly individuals? Statistics from the WHO suggest that in Europe and United states is 5% of population > 60 years old will die as a consequences of infection compared with 20% in Africa. In the developing world the infectious diseases of death are respiratory infection, diarrhoeal disease, tuberculosis, malaria and AIDS, which together represent >90% of deaths. The remaining 10% are due to tropical disease and various other infections. In industrialised countries respiratory tract infections, bloodstream infections, urinary tract infections and infections of digestive system represent 90% of infection related deaths, other disease such as tuberculosis, hepatitis B and C, diarrhoeal disease and AIDS represents nearly all remaining 10%. As already stated by Kalache in 1996, many infectious diseases” no longer kill but neither do day die”. This aphorism is also reminds that the impact of infectious diseases should not be only measured by mortality rate, but also morbidity and quality of life, particularly in the aging population. These parameters are much more difficult to acess objectively, but understanding them will be increasingly important in the future.

BACTERIAL PNEUMONIA

Pneumonia and influenza combined are the 6th leading cause of death in United States, and 90% of these deaths

Table 1: Empirical antibiotic therapy for community acquired pneumonia Out Patients 1. previously healthy and no antibiotic in past 3months. clarithromycin or azithromycin, Doxycycline

2.

comorbidities and antibiotic in past 3 months

•

moxifloxacin or levofloxacin or gemifloxacin

•

Amoxicillin clavulunate or cefpodoxime plus macrolide.

ceftriaxone

or

In patient, Non ICU 1. parenteral moxifloxacin or levofloxacin 2.

parenteral ceftrixone, ampicillin, cefotaxime, ertapenem plus macrolide

In patient ICU

1.

ceftroioxone, ampicillin -sulbactum, cefotaxime + azithromycin or fluroquinolon

Special Concerns a.

Pseudomonas –piperacillin –Tazobactum, cefipime, impenem, meropenem plus

Ciprofloxacin or levofloxacin

b.

Betalactam +amioglycoside +azithromycin

c.

Betalactam + aminoglycoside + antipneumococcal fluroquinolone

INFLUENZA

CA-MRSA: Linozolid or Vancomycin Empiric Antibiotic Treatment for health care associated Pneumonia Patients without risk factor for MRD pathogens •

Ceftriaxone or Cefotaxime

•

Moxifloxacin, ciprofloxacin or levofloxacin

•

Ampicillin /sulbactam

•

Ertapenem

In addition to the choice of antibiotic adequate hydration and oxygenation must also be assured. The duration of treatment for S. pneumonia is 10 days but the gram – ve and a typical organism long duration treatment is required.

Patients with risk factors for MRD pathogens 1.

A Beta-lactam, Ceftazidime or cefipime or piperacillin /tazobactum or Imipenem or merepenem plus

2.

Gram negative coverage, Gentamycin tobramycin or amikacin, Ciprofloxacin levofloxacin plus

3.

Gram +ve coverage. Linozolid or vancomycin

or or

occur in the adults 65years and older. Changes in the pulmonary reserve, decrease cough reflex, decrease elasticity of alveoli and poor ventilation, all of which lead to diminished cough and airway patency-cause older adults susceptible to pneumonia. Because the diagnosis of pneumonia in older adults is difficult to make since the signs and symptoms can be subtle, the initiation of antibiotics therapy is often delayed, which may

It is a common respiratory infection that has enormous impact world wide and causes significant morbidity and mortality in older adults. Of deaths resulting from influenza, 80%-90% occur in adults 65 years and older. Older adults can benefit most from vaccination, early detection and aggressive therapy. The signs and symptoms of influenza infection in older adults are similar to those occurring in younger patients, again a febrile response may be absent. It is typically associated with headache, fever chills, muscle aches, malaise, cough and sore throat. Older adults may develop persistent weakness for longer period and risk of complications such as pneumonia are high. Diagnosis is done by RTPCR, RIDTS, C Rapid influenza diagnostic test, virus culture in tissue and antibody titre in paired sera. Four antiviral agents available and approved for prevention and treatment-Amantadine, Rimantadine, Zanamivir and Oseltamivir. They must be taken within 48hrs of onset of symptoms. Janamivir and oseltamivir are not approved for prophylactic use. These type of drugs also require dosage modification in elderly persons with renal impairment.

TUBERCULOSIS

The low disease fighting capacity of elderly patients which is partially attributable to deregulation of immune system and greater secretion of macrophage pro-inflammatory cytokines in response to antigenic challenge also leads to greater or longer lasting metabolic changes in this population3. Whilst no change was found in T-cell function in very healthy elderly individuals without nutritional deficit, micronutrient deficiency has

369

CHAPTER 79

•

contribute to higher mortality rates. Diagnosis is made by gram- stain and culture and radiological examination of chest. Besides urinary antigen test for Legionella, PCR, IgM serology, CRP and procalcitonin tests are also done for pneumonia. Regardless of the age bacterial causes of pneumonia can only be identified in 20% – 50 % of patients. In the absence of specific bacterial etiology, pharmacotherapy of pneumonia is initially empiric and directed at likely causative pathogens. In older patients viruses, Hemophylus influenzae, gram negative bacilli and Staphylococcus aureus, Moraxilla catarrhalis, Legionella and Mycoplasma are less common but important causes of pneumonia in elderly because the bacterium may not be covered by traditional empiric antibiotic regimens.

Gram negative bacteria are responsible for more infection in elderly than younger adults. Therefore in older patients empiric antibiotic therapy should include the coverage for gram +ve and gram –ve and atypical organism. (Table 1 summerises the option for initial antibiotic therapy for pneumonia).

GERIATRICS

370

been shown to lower immunity resulting in susceptibility to infection.

The incidence of tuberculosis is increasing in developing countries. The presentation is atypical with more disseminated disease and more frequent lower lobe involvement in case of pulmonary tuberculosis. Drug induced hepatitis and infection with other drugs may be relevant problems. The difficulty faced by the elderly population in obtaining access to health care may lead to an exclusion from treatment. In Taiwan rates of drug resistance have been found in elderly population that are higher than general population.

URINARY TRACT INFECTION IN ELDERLY

UTI is one of the most prevailing causes of infectious diseases among the geriatric population in both genders.

Due to their anatomy and reproductive physiology, women are more susceptible. However between females and males the ratio varies from geriatric( 50:1) to younger( 2:1) population. Previous studies showed that UTI is often erroneously diagnosed with around 40% of hospitalised elderly admissions due to nonspecific symptoms. UTI was caused due to urinary urinary incontinence previous history, urogenital surgery and diabetes mellitus4. In the study conducted in South India by R. K. Venkatesh et. al5 (2016), 106 patients had UTI. Diabetes and hypertension were the most common co- morbidities. Urine culture and sensitivity was done and 50 patients had culture positivity (Table 2) and sensitivity pattern as per (Table 3). The clinical outcome of UTI treatment patients is accordingly to Figure 1. This study clearly suggests that E coli is the common organism of UTI in elderly and the prefer use of antibiotics according to the sensitivity pattern improves outcome. In a study conducted in Tamil naidu in three medical colleges the risk factors among subjects with UTI was as per Table 4.6 Careful attention should be paid to appropriate dosing in the elderly. Renal impairment is common in this age group and often unrecognized. So the calculated GFR should be determined in all patients and the dosage adjustment of various drugs should be done7.

SKIN INFECTION

Herpes zoster: Infection with herpes zoster caused by Improved

Stable 5%

DAMA 4% 2%

DARA

Died

Methycillin resistant Staphylococcus aureus: MRSA present a major problem for elderly patients especially those in the institutional settings. The most common reservoir of MRSA colonization are nasal mucosa and oropharynx. Skin contamination from persons already colonised in these areas may also be source of MRSA infection. Vancomycin is the drug of choice for MRSA infection. Older adults require dosage adjustment basing on their renal function. Staffs and patients who are MRSA carriers should be isolated and topical mupirocin should be applied to the colonised areas. The following table shows the MRSA therapeutic option.

MRSA PREVENTION

1%

24% 64%

DARA-Discharged against referral advice DAMA-Discharged against medical advice

Fig. 1

Worsened

a reactivation of varicella virus dormant in dorsal root ganglia is also common in older adults. As cellular immunity wanes with advancing age, clinical reactivation of virus can occur. The hall mark herpes zoster is skin lesions that progress from discrete patches of erythema to grouped vesicles in a dermatomal pattern that postulate and crust within 7 to 10 days. Diagnosis of suspicious lesions can be confirmed by giant cells noted on Tzank test preparation of lesion scrapings, DNA â&#x20AC;&#x201C;PCR or a positive viral culture of vesicular fluid. Pain is the most common symptom associated with herpes zoster, and it can be debilitating in frail elderly patients. Post herpetic neuralgia develops in 10-70% of the patients and can be difficult to treat. In immune-compromised patients there may be cutaneous dissemination, pneumonitis, meningo- encephalitis, transverse myelitis and other serious complication. Immune- competent patients can be treated with oral acyclovir at a dosage of 800mg five times daily for 7-10 days. However valacyclovir and famcyclovir are superior in terms of pharmacokinetics and pharmacodynamics and should be used preferentially.

Famcyclovir is given at a dose of 500mg three times for 7days. Valacyclovir is given at a dose of 1gm three times for 5-7days. In severely immune-compromised patients the treatment should be started with IV acyclovir which prevents the occurrence of visceral complications. The dose is 10mg/kg 8hourly for 7 days. Acute neuritis and post herpetic neuralgia can be treated with gabapentin, pregabalin, amitriptyline hydrochloride, liodocaine (patches) and flufenazine hydrochloride. In one study glucocorticoid therapy administered early in the course of herpes zoster significantly accelerated the quality of life and reduced the analgesic medication8.

1.

Carefull hand washing

2.

Isolation of infected patients.

3.

Removal of colonized catheters

4.

Eradication of nasal carriage with mupirocin

ORAL THERAPY FOR MILD INFECTIONS

1.

clindamycin

2.

TMP-SMX

3.

minocyclin

4.

Doxycycline

371

Table 2: Most prevalent organisms in Urinary tract tract infections Type of microbe

Number of isolates

Percentage of isolates

E coli

24

48

Klebisiella pneumonia

5

10

Pseudomonas aeruginosa

2

4

Serratiasps

1

2

Citrobacterkoseri

1

2

Enterococcus sps

8

16

MRSA

3

6

Staphylococcus aureus

2

4

MSSA

1

2

Candida sps

3

6

Total

50

100

Gram Positive bacteria (28%)

Fungus (6%)

Table 3: Sensitivity pattern of the antibiotics used in UTI patients Antibiotic

Sensitive

(%)

Resistance

(%)

Netilmicin

24

100

0

0

Amikacin

24

100

0

0

Imipenem

22

100

0

0

Cofeperazone-Sulbactam

21

95.5

1

4.5

Piperacillin-Tazobactam

17

77.2

5

22.8

Gentamicin

14

58.3

10

41.7

Cotrimoxazole

6

25

18

75

Norfloxacin

3

15

17

85

Amoxicillin-Clavulanic acid

2

8.3

22

91.7

Ampicillin/Amoxicillin

2

8.3

22

91.7

Cefotaxime/Ceftriaxone

2

8.3

22

91.7

Cefuroxime

2

8.3

22

91.7

Cefpirome, Cefepime

1

4.5

21

95.5

Aztreonam

0

0

22

100

Ticarcillin-Clavulanic acid

0

0

14

100

Cefazolin/Cefodroxil

0

0

4

100

Ciprofloxacin/Levofloxacin

0

0

4

100

Table 4: Frequency of risk factors among the subjects with UTI Risk factor

Culture positive

Culture negative

No.

%

No.

%

Diabetes

14

50%

21

29.10%

Catheterisation

12

42.80%

21

29.10%

Renal stones

8

28.50%

7

9.70%

Immuno suppression

5

17.80%

15

20.80%

Incontinence

6

21.40%

14

19.40%

None of the above

3

10.70%

25

34.70%

5.

linezolid, tedizolid

3.

Tecoplanin

4.

Ceftaroline

1.

Vacomycin

5.

Tedizolid

2.

Daptomycin

6.

Dalbavamcin

FOR SERIOUS INFECTION, PARENTAL THERAPY

CHAPTER 79

Organism

Gram Negative bacteria (66%)

372

Table 5: Management of infections caused by VRE Endovascular Infections 1.

Daptomycin +Aminoglycoside 2.

Qunupristin –dalfopristin+another active agent

3.

Linozolid

4.

High dose amphicillin +Aminoglycoside

GERIATRICS

Non endovascular bacterimia 1.

High dose daptomycin +aninoglycoside

MALARIA

+another

agent

2.

Quinupristin + Dalfopristin+another active agent

3.

Linozolid

Meningitis 1.

Linozolid+CSF penetrating active agent 2.

Q/D +another active agent

3.

High dose daftomycin +CSF penetrating active agent

UTI 1.

Fastomycin

2.

Nitrofurantoin

3.

Ampicillin or Amoxicillin

VANCOMYCIN RESISTANT ENTEROCOCCI

VRE present a major problem in old patients especially when an outbreak occurs in institutional settings. They are the 2nd most common organism in nosocomial urinary tract and wound infection and 3rd most common cause of nosocomial bacterium in United States. They have become resistant to vancomycin since 1988 leading to high mortality. Because of the high level of antibiotic resistance prevention of outbreaks and spread of VRE is crucial. The following table 5 shows the management of infection caused by VRE.

AIDS

is low(5-10%). The route of infection is homosexual transmission and nosocomial infection plays a major role.

They have a short survival than the younger population.

They are also many times deprived of adequate medical care.

The number of elderly patients with HIV infection is increasing throughout the world. In industrialised countries patients aged >50years account for 10-15% of HIV infection. In developing countries the incidence

Malaria is a major cause of morbility and mortality in elderly population. Higher parasite loads and higher proportion of severe forms have been reported to be associated with malaria among elderly individual without immunity as compared with younger adult population. In various studies in endemic area it was seen that in severe malaria in elderly, fever was absent in 40% of cases, coinfection with other organism was present in 40% with the overall mortality higher.

REFERENCES

1.

Charles p, mouton MD, MS and Oralia V. Bazaldua, Phrama. D Bashrava Pieree etal-common infection In older adults. American family physician 2001; 63:257-268.

2.

Gietan Gavazzi, Francosis Hermannand Karl –Heinz Kraouse –Aging and infectious disease in the developing world clinic infectious disease 2004; 39:83-91.

3.

Sonia Menon, Rodolfo rossi, Leon Nshimyumukiza etal. -Convegence of diabetes mellitus protein energy malnutrition and TB epidemic the neglected elderly population; BMC infectious disease 2016; 16:361-365.

4.

Vasudevon R. Urinary tract infection Accors view of infection and associated risk factors J Microbiology Exp 2014; 1:00008.

5.

R. K. Venkatesh, MM. prabhu, K. Nandakumari etal, Urinary Tract infection trasmitant pattern of elderly patients in tertiary hospital set up in south India:Aprospective study – J young Parm 2016; 8:108-113.

6.

Rejiltha IM, Susilathangam G, Velvizhi G-UTI in elderly – Aclinical and microbiological study Indian J A applied medical research 2014; 4:465-467.

7.

Andrea core –Smith and Michael Almond Management of UTI in elderly. Trends in Urology GYnaecology and sexual health 2007; 4:31-34.

8.

Richard J. Whitlay. Varicella –Zoster virus infection – chapter 217, Harrisons principle of Internal medicine vol 2 Editors Dennis L. Kasper Etal 19th edition 2, Mc Graw Hill Education New York P 1183-1186.