Frailty: challenges and progress

Peter Crome and Frank Lally

Key points

Frailty in older people is characterized by deteriorating health and increasing need for support.

Frailty has the features of a ‘geriatric giant’ as originally defined by Isaacs.

The identification of frail older people is important for medical intervention and for strategic planning.

The clinical definition of frailty is still being debated but may include the following aspects:

• a distinct phenotypical profile

• a frailty index defined by the accumulation of deficits

• genetic and biochemical predisposition.

There is no specific treatment for frailty but there are treatments for the diseases that contribute to it.

1 Introduction

Frailty, in the context of older people, is a relatively new word to be included in the medical lexicon. The word is derived from the Latin fragilis and defined by the dictionary as ‘easily broken or destroyed’, ‘in poor health; weak’, and ‘morally weak, easily tempted’ (1). Despite these rather derogatory and demeaning definitions it has been accepted by the medical community as a way of identifying mainly older people at risk of further decline although the word itself and its concept has its critics (2). A potential pathway to frailty with trigger factors is depicted in Figure 7.1 which is essentially a synopsis of the literature on frailty.

**Fig. 7.1** Potential steps leading to frailty.

Factors (boxes) acting either alone or synergistically to reduce physiological capacity leading to increased dependency. This may initially lead to a pre-frail state before tipping into the frailty syndrome leading to further functional decline.

The heterogeneity in health status in older people has been recognized since biblical times. The desirability to define different groups of older people has come more recently from different directions. Within the health community these have arisen from the desire to identify groups of older people who are most at risk of deteriorating health or function. The potential advantages of identifying such people are to allow therapeutic interventions at an individual level and to help plan health and social care services at a population level. Nevertheless, how to define frailty and how best to identify frail individuals has not been resolved.

2 Definitions

One of the earliest attempts to define the difference between fit and frail was that of Woodhouse et al. (3). The essential components of the frail person they described were that such people were older, dependent on others for activities of daily living, and often in institutional care. They may not have overt disease but minor abnormalities detected by investigations, and they may be on regular medication. Among the diseases associated with frailty were neurodegenerative conditions (Alzheimer’s, Parkinsonism), and arthritis, fractures, and osteoporosis. Both the distinction and the overlap between frailty and chronic diseases continue to be debated (4). Woodhouse and colleagues also drew attention to the physiological changes in later life and the implications for drug therapy. The development of analytical techniques to measure drug pharmacokinetics has allowed major differences to be identified between young and old people. However, it became clear that these differences, which were identified by studying younger volunteers and older hospital patients, were not due to age alone but also to other factors which would now be subsumed into the frailty paradigm. The connection between frailty and prescribing has been a continuing theme of the frailty debate (5).

2.1 Phenotypes and deficits

A standard definition of frailty has yet to emerge but two distinct approaches have been suggested: the phenotype and the frailty index. These are in addition to the global clinical impression, which itself may be refined by tools such as the Canadian Study of Health and Aging Frailty Score (6). A recent Delphi consensus approach failed to reach agreement on a specific set of clinical or laboratory biomarkers, although there was agreement on the value of screening for frailty. Consensus was also obtained that the domains of physical performance (including gait speed and mobility), nutritional status, mental health, and cognition should form part of any definition (7).

Fried et al. were the first to estabterm1lish a frailty phenotype (8) based on a standardized assessment of physical health and has recently been described as rule based (9). Fried defined frailty as comprising three or more of the following characteristics:

unintentional weight loss

self-reported exhaustion

weak grip strength

slow walking speed

low physical activity.

Using data from the Cardiovascular Health Study of more than 5,000 participants, they found that the presence of frailty for over three years predicted falls, worsening mobility, first hospitalization, and death, with hazard ratios of 2.06, 2.68, 2.25, and 6.47, respectively. People with only one or two of the phenotype factors were at lower risk of adverse outcomes. Fried also drew attention to the difference between frailty (as defined by the phenotype), co-morbidity (presence of many medical conditions), and disability (lack of independence). Subsequently the predictive validity of the phenotype was confirmed by Fried and colleagues using data from the Women’s Health and Aging Study (10). The criteria are shown in table 7.1.

Table 7.1 The Fried criteria of frailty

Feature	Measurement
Shrinking (sarcopenia)	Unintentional weight loss (>4.5 kg)
Weakness	Lowest quintile of grip strength
Exhaustion	Self-reported using Center of Epidemiological Studies—depression scale
Slow walking speed	Lowest quintile over 15 feet
Low physical activity	kcal/week in lowest quintile

While Fried’s methods of identifying frailty may be suitabterm1le for epidemiological studies, they are not really practical in the acutely ill or for individuals with severe disability. Additionally they do not take account of psychological, emotional, or cognitive factors that have been shown to have negative health impacts. Simpler criteria have been proposed such as those of Ensrud et al. (11) in which three factors are measured: weight loss of more than 5% between tests, self-reported exhaustion using the Geriatric Depression Scale, and inability to get out of a chair five times without using the arm. However, the latter test may present difficulties for many older people and the height of the chair would be a factor. Montesanto et al. suggested that different populations, such as the older people they studied in Calabria, may represent a unique group with different phenotypical domains identifying frailty (12). Their model employed cognitive functioning, functional activity, physical performance, degree of depression, and self-reported health.

An alternative to the phenotype approach is the frailty index, defined by the accumulation of deficits, which can be physical or mental health diseases, disabilities, or abnormal laboratory findings (13). The more of these deficits a person has, the greater the risk of being frail. A number of such frailty indices have been suggested. Searle et al. (14) proposed a set of criteria that need to be present in constructing a frailty index. According to the authors the criteria must

be health-related (e.g. not age-related baldness)

in general increase in prevalence with age

not become ubiquitous at too early an age (e.g. presbyopia)

be broad, covering a number of body systems.

They also described a validating process including the determination of cut-off scores based on data from the Yale Precipitating Events Project. Both binary and continuous variables were included. Examples of deficits included are help with bathing, feeling happy, heart attack, and low mini mental state examination. Examples of deficits excluded because they did not meet the Searle et al. (14) criteria are being admitted to hospital in the past year (not age-related) and measured vision. Two European studies that employed a 40-item frailty index confirmed the predictive value of this approach (15, 16). They found that men have a higher mortality rate than women despite having a lower frailty index (15). It has also been suggested that higher physiological functioning in youth may be at the expense of greater susceptibility in later life (17).

The influence of excluding people with disability and subdividing a frailty index into physical health, mental health, and social frailty phenotypes was explored in a study of community-dwelling people over 75 (18). The four-year hazard ratio for death was 3.09 and 2.69 for the physical social types, respectively. The social phenotype, however, did not predict mortality. The frailty index has also been suggested as a way of determining frailty in mouse models (19).

Of course, it must be stated that the presence or absence of frailty is not the only marker of reduced life expectancy or deteriorating function. The presence of advanced cancer is an obvious example of a marker unrelated to frailty.

3 Frailty and the immune system

Discussion of the pathophysiological factors reported to be associated with frailty would require a book in its own right. For this reason the authors aim to provide an overview of the burgeoning literature that covers frailty-related immunological and inflammatory predictors with some key references.

Figure 7.2 illustrates some of the potential immunological pathways that may lead to frailty. The illustration is a synopsis of the literature on the subject and gives some of the main factors that have been reported and in which there is still active research interest.

**Fig. 7.2** Possible mechanisms of immune dysregulation leading to frailty.

It has been recognized for a long time that as the body ages there are associated biological changes. The term coined for age-related changes to the immune system is immunosenescence. Immunosenescence affects both the innate and adaptive arms of the immune system. This can lead to changes to white cell populations such as neutrophils and natural killer (NK) cells (innate), as well as to T-lymphocyte subsets (adaptive) such as T-memory cells that allow rapid response to specific antigens already recognized by the system. Other factors can also modify the immune system, such as physical insult and stress. It is recognized that both conditions can lead to depression, which itself is an immune modulator.

The effects of lifestyle choices on our bodies are now well known; factors such as poor diet, excess alcohol, and increased visceral fat have all been implicated. These can cause fluctuations in the levels of circulating cytokines leading to imbalance and/or increased oxidative stress by the production of free radicals, which can have effects on cellular processes and DNA regulation and may lead to cell death (apoptosis).

Chronic inflammation in older people (inflammaging) can also cause a rise in circulating pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin 1 (IL-1). C-reactive protein, a marker of inflammation, is often raised in frail or pre-frail individuals.

Many researchers have suggested that a viral infection earlier in life can predispose an individual to immune dysregulation later in life. One often-cited candidate is cytomegalovirus (CMV). This is a common herpes virus and causes little harm at the time of infection. However, it remains within cells and the immune response to it appears to remain raised, thereby placing a burden on the immune system. CMV has been directly associated with frailty in several studies (20, 21).

The upshot is that some or all of these factors can play a part in compromising or regulating the immune system. Lowering responses in the innate arm of the system can lead to increased risk of infections, as cells such as neutrophils and NK cells are not working as they should. Similarly, the immunocompromised individual is unable to produce an adequate response to vaccines such as the influenza vaccine often given to older people during winter months. This adds not only to the physiological burden but also has service and financial implications.

For further reading, some general references on frailty and inflammation are (22–24) and immunosenescence (25

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