Frailty

Frailty – 7 Interesting Facts

Frailty is a clinical syndrome resulting from aging-related dysregulation of multiple physiologic systems leading to a loss of physiologic reserve and markedly increased vulnerability to stressors such as acute illness, injury, and medical interventions. This ultimately leads to increased risk of adverse health outcomes
Frailty exists on a spectrum from prefrailty to mild symptoms to severe limitations and then ultimately failure to thrive and a premorbid state
2 major conceptual models of frailty include physical frailty syndrome, defined by physiologic alterations, and deficit accumulation frailty, defined by an accumulation of chronic disorders that can impair functioning and increase vulnerability
Physical manifestations of frailty include weakness, slowed walking speed, low physical activity, low energy or exhaustion, and weight loss. Balance may be poor and patients have an increased risk of falls
Diagnosis is based on clinical scoring systems, the most common being the frailty phenotype (or Fried frailty tool) and the frailty index⁴⁵¹⁶
There are no specific treatments, but effective preventive and treatment interventions include maintaining muscle mass and strength through resistance exercise or a multicomponent exercise program. Dietary protein supplementation may also be beneficial⁴⁰⁴³
Management by a multidisciplinary team, when possible, is optimal

Alarm Signs and Symptoms

Symptoms that may indicate a new life-threatening stressor include:
- Acute worsening weakness
- Decreased food intake
- Falls
- Fever
- Shortness of breath

Introduction

Frailty is a clinical syndrome of aging-related dysregulation of multiple physiologic systems leading to loss of physiologic reserve and thus markedly increased vulnerability to stressors with increased risk of adverse health outcomes¹²
- Stressors include acute illness, surgical or medical interventions, and trauma
- Adverse outcomes include procedural complications, falls, institutionalization, disability, and death
Physical frailty and index frailty are the 2 major conceptual models of frailty
- These models form the basis of frailty measurement tools and diagnosis³
Physical frailty, also known as phenotypic or syndromic frailty, is a clinical syndrome with 5 components: weight loss, exhaustion, weakness, slowness, and low level of physical activity
- Results from energy dysregulation in multiple systems⁴⁵
  - Physical frailty is the most commonly used definition of frailty⁶
  - Sarcopenia is a loss of muscle mass and strength and is a major component of physical frailty
Index frailty, also known as deficit accumulation frailty, defines frailty based on the accumulation of multiple disorders and impairments that each increase the risk of mortality and disability⁷⁸
- These deficits include disabilities, diseases, physical and cognitive impairments, psychosocial difficulties, geriatric syndromes (eg, falls, delirium, urinary incontinence), and laboratory, imaging, or electrodiagnostic abnormalities
- Rationale for the deficit accumulation model is that the more deficits an individual has, the greater their risk of an adverse health outcome
- The frailty index is a score calculated by adding together the number of impairments and conditions an individual has⁷
Frailty exists on a spectrum ranging from prefrailty to frailty to failure to thrive
Prefrailty refers to people who fulfill some but not all criteria for frailty
- Such people are at risk for developing frailty
- Prefrailty may involve physical or index frailty
Failure to thrive is a syndrome manifested by decreased appetite, poor nutrition and inactivity associated with weight loss greater than 5% of baseline, cognitive and functional decline, depression, and malnutrition

Epidemiology

Prevalence of frailty varies with the population studied and frailty instrument used
A systematic review of prevalence of frailty in adults aged 50 years and older across 62 countries revealed that the pooled prevalence of physical frailty was 12% compared to 24% for index frailty⁹
- There was significant variability among countries in this review
Prevalence of physical prefrailty was 46% and 49% for index prefrailty⁹
Prevalence of frailty in several studies in the United States ranged from 4% to 16% in community-dwelling males and females aged 65 and older⁴⁵¹⁰¹¹
In general, the prevalence of frailty is higher in females than in males⁹
- Prevalence of physical frailty was 15% among females and 11% among males
- Prevalence of index frailty was 29% among females and 20% among males
Prevalence of frailty also increases with age⁹
- In the Cardiovascular Health Study, prevalence of frailty increased from 3.9% in the age group of 65 to 74 years to 25% in the age group older than 85 years⁴
Prevalence has also been found to be higher among people with lower income and lower education and among certain racial and ethnic groups¹⁴
- Black participants were more than twice as likely to be frail than White participants in the Cardiovascular Health Study (13% versus 6%) and the Women’s Health and Aging Studies (16% versus 10%)¹⁴
- Prevalence of frailty among older Mexican American participants in the Hispanic Established Populations for Epidemiologic Studies of the Elderly was 7.8%, similar to that of White participants¹²

Etiology and Risk Factors

Etiology

Can be classified as primary or secondary¹³
- Both result in similar phenotypes and vulnerabilities to adverse health outcomes
Primary frailty refers to frailty resulting from aging-related changes in physiologic processes and systems
- Sarcopenia (loss of skeletal muscle mass and strength) is a key component of primary frailty
Secondary frailty refers to frailty resulting from the effects various specific disorders

Primary Frailty

Figure 1. A model pathway of physical frailty that links biology and disease to physiologic changes and clinical manifestations of physical frailty.From Walston J et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc. 2006;54:991.

Primary frailty is thought to result from dysregulation of various physiologic systems (Figure 1),¹⁴ particularly those involved with the endocrine system, immune system, and pathways of energy and metabolism¹⁴
The fundamental underlying causes of this dysregulation are still unclear but are thought to involve a combination of:
- Aging-related molecular changes
- Genetic factors
- Environmental factors
- Effects of diseases
- Nutritional deficiencies (low levels of certain vitamins and carotenoids, reduced intake of protein and calories)
Physiologic abnormalities interact synergistically to increase frailty risk
- The number of abnormalities is a stronger predictor of frailty than the degree of dysfunction of any given system¹³

Secondary Frailty

Secondary frailty results from the effects of multiple disorders, which independently contribute to the development of frailty, possibly via:¹⁴
- Inflammation
- Diminished cardiopulmonary function
- Physical inactivity
Contributory disorders include:
- Immunosuppressive disorders (eg, HIV/AIDS)
- Heart failure
- COPD (chronic obstructive pulmonary disease)
- Cancer, particularly lymphoma, multiple myeloma, occult solid tumors
- Chronic kidney disease
- Metabolic syndrome
- Chronic infection (eg, tuberculosis, chronic cytomegalovirus infection, HIV)

Risk Factors

Many characteristics, comorbidities, and lifestyle factors increase the risk of frailty, including:¹⁵
- Cognitive impairment
- Depression
- Drinking
- Female sex
- Hearing impairment
- Higher education level
- History of falls
- Increasing age
- Living alone
- Low levels of exercise
- Lower BMI
- Lower vitamin D levels
- Malnutrition
- Chronic pain
- Polypharmacy
- Sleep disorders
- Smoking
The following factors can help predict loss of muscle mass and strength with aging:
- Decreased levels of anabolic factors such as testosterone, DHEA-S (dehydroepiandrosterone sulfate) and IGF-1 (insulinlike growth factor 1)
- Decreased physical activity
- Reduced caloric intake and intake of nutrients, including protein and vitamin D and other micronutrients
- Older age

Diagnosis

Approach to Diagnosis

Frailty assessment may be appropriate to:
- Identify those at risk of adverse medical or surgical outcomes and determine the severity of risk
- Identify those who may benefit from preventive or treatment measures
- Help determine prognosis
- Help guide shared decision-making about care plans and eligibility for palliative care
An international consensus conference has recommended that older adults be assessed for frailty if they have 1 or more of the following:²
- Age greater than 70 years
- Significant involuntary weight loss (greater than or equal to 5% of body weight) due to chronic illness
Numerous frailty assessment tools are available and are the basis of frailty diagnosis and screening
- Most frailty instruments are based on either the physical frailty or the deficit accumulation model
- Physical frailty is most often assessed using the physical frailty phenotype (Fried frailty tool) (Table 1)⁴⁵¹⁶
  - Assesses 5 components: weight loss, exhaustion, slowness (walking speed), strength, activity level
  - Requires active patient participation and specialized equipment for measuring grip strength and gait speed
    - Decreased gait speed alone is predictive of adverse outcomes in many settings
    - Decreased gait speed and grip strength are early manifestations of frailty and can serve as a marker in screening.
- Deficit accumulation frailty is most often assessed using the (frailty index),^78161718 which is based on the accumulation of illnesses, the presence of functional and cognitive decline, and difficulties in daily life (Table 2)
  - It requires answering 20 or more medical- and function-related questions regarding symptoms, signs, disabilities, and diseases
  - Different question sets can be used; Table 3 lists a representative example
  - Some indices also incorporate optional performance measures (eg, grip strength, gait speed)
  - The index is the ratio of deficits present to the total number of deficits assessed. For example, if 40 deficits are assessed and 10 are present in a given person, their frailty index is 10/40 = 0.25
  - The index also can be calculated based on information available in the medical record without requiring a patient interview or examination
    - Calculations can be done manually or digitally from certain electronic health records (electronic frailty index)
    - The electronic frailty index can identify older adults with mild, moderate, and severe frailty with robust predictive validity for such outcomes as mortality, hospitalization, and nursing home admission¹⁹
Patients identified as frail or prefrail based on these brief screening tools should have a more detailed clinical evaluation for the impact of frailty such as is done during a comprehensive geriatric assessment,²⁰ which more thoroughly evaluates physical and mental status, functioning, social circumstances, and environment
Frail patients also should have laboratory testing to identify potential stressors and underlying causes
- Complete blood count
- Comprehensive metabolic panel including liver biochemical tests and albumin
- TSH level
- Vitamin B₁₂ level
- Vitamin D level
- Inflammatory markers, C-reactive protein, and erythrocyte sedimentation rate
Imaging and other tests are used only as needed to evaluate abnormalities identified on examination or laboratory testing

Table 1. Physical frailty phenotype.*

Frailty criterion	Definition
Unintentional weight loss	Meets criteria for weight loss if: Lost > 5% body weight unintentionally in last year, or BMI < 18.5 kg/m² Equipment: scale for body weight; stadiometer for height
Exhaustion	Meets criteria for exhaustion if answer: Felt unusually tired or unusually weak “all of the time” or “most of the time,” or reported energy level was ≤ 3 using the following questions: 1.a. “In the past month, on the average, have you been feeling unusually tired during the day?” □ Yes □ No □ Refused □ Don’t know 1.b. “If yes, have you been feeling unusually tired?” □ All of the time □ Most of the time □ Some of the time □ Refused/Don’t know 2.a. “In the past month, on the average, have you felt unusually weak?” □ Yes □ No □ Refused □ Don’t know 2.b. “If yes, have you been feeling weak?” □ All of the time □ Most of the time □ Some of the time □ Refused/Don’t know 3. “Using the scale below, please rate your usual energy level on a scale from 0 to 10 where 0 is no energy and 10 is the most energy that you have ever had. Please give a number between 0 and 10 that describes your usual energy level while awake in the last month.” Energy level: ______
Slowness	Meets criteria for slow walking speed over 4 meters if:
	Males ≤ 0.65 m/s for height ≤ 173 cm (68 in) ≤ 0.76 m/s for height > 173 cm (68 in)	Females ≤ 0.65 m/s for height ≤ 159 cm (63 in) ≤ 0.76 m/s for height > 159 cm (63 in)
	Equipment: 4-meter course, a stopwatch Participant attempts to walk 4-meter length twice at their own pace. Use average of 2 trials
Low activity level	Meets criteria for low activity if:
	Males < 128 kcal of physical expenditure on activity scale per week (6 items^†)	Females < 90 kcal of physical expenditure on activity scale per week (6 items^†)
Weakness	Meets criteria for grip strength weakness if:
	Males ≤ 29 kg for BMI ≤ 24 ≤ 30 kg for BMI 24.1-26 ≤ 30 kg for BMI 26.1-28 ≤ 32 kg for BMI > 28	Females ≤ 17 kg for BMI ≤ 23 ≤ 17.3 kg for BMI ≤ 23.1-26 ≤ 18 kg for BMI ≤ 26.1-29 ≤ 21 kg for BMI > 29
	Equipment: (Jamar) hand dynamometer Participant attempts to squeeze the dynamometer maximally 3 times with the dominant hand. Use maximal score with dominant hand

Caption: *Scoring: ≥3/5 criteria met indicates frailty; 1-2/5 indicates pre- or intermediate frailty; 0/5 indicates nonfrail.

†Physical activity is based on modified Minnesota Leisure Time Activities Questionnaire, asking about walking (w = 3.5), strenuous household chores (w = 4.5), strenuous outdoor chores (w = 4.5), dancing (w = 5.5), bowling (w = 3.0), and exercise (w = 4.5). To compute kcals expended per week, use the formula: kcals (kilocalories/week) = w × frequency (sessions per week) × duration per session (minutes) × body weight (kg)/60, where w is the task-specific MET intensity score

Data from Fried LP et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146; Bandeen-Roche K et al. Phenotype of frailty: characterization in the women’s health and aging studies. J Gerontol A Biol Sci Med Sci. 2006;61:262; and Guidance on selecting a frailty assessment instrument. FrailtyScience.org. Johns Hopkins University. Accessed February 15, 2024. https://frailtyscience.org/frailty-assessment-instruments.

Table 2. Deficit accumulation (frailty) index.*†

Frailty criterion	Definition
Deficits in health	At least 30-40 deficits—defined as symptoms, signs, disabilities, and diseases—should be selected Deficits can be included if:They are associated with health statusThe prevalence of the deficit increases with ageSaturation of the deficit does not occur too early in the life courseThe deficits cover a range of symptoms (eg, deficits are not solely related to cognitionThe same deficits are included when used serially on the same peopleDeficit variables are scored as binary (0 or 1) or can be graded (eg, 0, 0.5, 1) The score is expressed as the ratio of deficits present over the total number of deficits included. For example, if the person has 10 deficits present out of 40 deficits total, the index score would equal 10/40 or 0.25 Examples of deficits include: ‡Restricted activityDisability in Activities of Daily Living and Instrumental ADLImpairments in general cognition and physical performance (eg, impaired grip strength, impaired walking)ComorbiditySelf-rated healthDepression/mood

Frailty criterion

Definition

Deficits in health

At least 30-40 deficits—defined as symptoms, signs, disabilities, and diseases—should be selected

Deficits can be included if:They are associated with health statusThe prevalence of the deficit increases with ageSaturation of the deficit does not occur too early in the life courseThe deficits cover a range of symptoms (eg, deficits are not solely related to cognitionThe same deficits are included when used serially on the same peopleDeficit variables are scored as binary (0 or 1) or can be graded (eg, 0, 0.5, 1)

The score is expressed as the ratio of deficits present over the total number of deficits included. For example, if the person has 10 deficits present out of 40 deficits total, the index score would equal 10/40 or 0.25

Examples of deficits include: ‡Restricted activityDisability in Activities of Daily Living and Instrumental ADLImpairments in general cognition and physical performance (eg, impaired grip strength, impaired walking)ComorbiditySelf-rated healthDepression/mood

Caption: *The deficit accumulation index approach may vary in the type and number of deficits included.

†Scoring: frailty index score of 0.2 or greater recognizes a person as approaching a frail state.

‡See Table 3 for a full list of 40 deficits and their proposed scoring.

Data from Searle SD et al. A standard procedure for creating a frailty index. BMC Geriatr. 2008;8:24; and Guidance on selecting a frailty assessment instrument. FrailtyScience.org. Johns Hopkins University. Accessed February 15, 2024. https://frailtyscience.org/frailty-assessment-instruments.

Table 3. An example of the frailty index.

Variable	Scoring
Help dressing	Yes = 1 No = 0
Help getting in/out of chair	Yes = 1 No = 0
Help walking around house	Yes = 1 No = 0
Help eating	Yes = 1 No = 0
Help grooming	Yes = 1 No = 0
Help using toilet	Yes = 1 No = 0
Help up/down stairs	Yes = 1 No = 0
Help lifting 10 lbs	Yes = 1 No = 0
Help shopping	Yes = 1 No = 0
Help with housework	Yes = 1 No = 0
Help with meal preparations	Yes = 1 No = 0
Help taking medication	Yes = 1 No = 0
Help with finances	Yes = 1 No = 0
Lost more than 10 lbs in last year	Yes = 1 No = 0
Self-rating of health	Poor = 1 Fair = 0.75 Good = 0.5 Very Good = 0.25 Excellent = 0
How health has changed in last year	Worse = 1 Better/Same = 0
Stayed in bed at least half the day due to health (in last month)	Yes = 1 No = 0
Cut down on usual activity (in last month)	Yes = 1 No = 0
Walk outside (in last month)	<3 days = 1 ≥3 days = 0
Feel everything is an effort	Most of time = 1 Sometimes = 0.5 Rarely = 0
Feel depressed	Most of time = 1 Sometimes = 0.5 Rarely = 0
Feel happy	Most of time = 0 Sometimes = 0.5 Rarely = 1
Feel lonely	Most of time = 1 Sometimes = 0.5 Rarely = 0
Have trouble getting going	Most of time = 1 Sometimes = 0.5 Rarely = 0
High blood pressure	Yes = 1 Suspect = 0.5 No = 0
Heart attack	Yes = 1 Suspect = 0.5 No = 0
Congestive heart failure	Yes = 1 Suspect = 0.5 No = 0
Stroke	Yes = 1 Suspect = 0.5 No = 0
Cancer	Yes = 1 Suspect = 0.5 No = 0
Diabetes	Yes = 1 Suspect = 0.5 No = 0
Arthritis	Yes = 1 Suspect = 0.5 No = 0
Chronic lung disease	Yes = 1 Suspect = 0.5 No = 0
Mini-Mental Status Examination	<10 = 1 11-17 = 0.75 18-20 = 0.5 20-24 = 0.25 >24 = 0
Peak flow (liters per minute)	Male: ≤340 = 1; Female: ≤310 = 1
Shoulder strength (kg)	Male: ≤12 = 1; Female: ≤9 = 1
BMI	<18.5 or ≥30 = 1 25-<30 = 0.5
Grip strength (GS) in kg	Male: BMI ≤24, GS ≤29 = 1 BMI 24.1-28, GS ≤30 = 1 BMI >28, GS ≤32 = 1 Female: BMI ≤23, GS ≤17 = 1 BMI 23.1-26, GS ≤17.3 = 1 BMI 26.1-29, GS ≤18 = 1 BMI >29, GS ≤21 = 1
20-foot walk at usual pace (seconds)	>16 seconds = 1
20-foot walk at rapid pace (seconds)	>10 seconds = 1

Caption: *The FI (frailty index) is the total point score divided by the number of items assessed; this corrects for unavailable information. Thus if a person’s score is 15 and 40 items are assessed, their FI is 15/40 = 0.375. A person with an FI of 0.2 or greater is approaching a frail state.

From Searle SD et al. A standard procedure for creating a frailty index. BMC Geriatr. 2008;8:24; Table 1.

Diagnostic Criteria

Although no gold standard for diagnosing frailty exists, scores on the frailty phenotype (Fried frailty tool) (see Table 1)⁴⁵¹⁶ or a frailty index tool (see Table 3)¹⁷ are widely used
The Fried frailty tool is based on the following 5 criteria:⁴⁵¹⁶
- Unintentional weight loss greater than or equal to 5% of body weight or greater than 10 lbs during past year
- Exhaustion: self-report regarding effort required to engage in routine activity during the past week)
- Slow walking speed (gait speed): time to walk 15 feet greater than 6 to 7 seconds. Exact cutoff depends on sex and height
- Low physical activity level (kilocalories spent per week): males expending less than 383 kcals and females less than 270 kcal (calculated from activity scale incorporating household chores, yard work, walking, and so on)
- Weakness: decreased grip strength measured with a hand dynamometer; cutoff depends on sex and BMI
- Frailty is defined as meeting 3 or more criteria
- Prefrailty is defined as meeting 1 to 2 criteria
Criteria when using the electronic frailty index are:¹⁹
- From 0 to 0.12: fit
- From greater than 0.12 to 0.24: mild frailty
- From greater than 0.24 to 0.36: moderate frailty
- Greater than 0.36: severe frailty
Different criteria are used for various frailty index calculations
- Severe frailty is defined as greater than 0.4 on non-electronic frailty indexes but greater than 0.36 on the electronic frailty index¹⁹

Workup

History and physical examination are the core of evaluation. Laboratory tests and imaging studies are supportive

History

History often shows evidence of frailty and its causes and complications
- Family members and/or caretakers may need to be questioned
Symptoms suggesting physical frailty phenotype:
- Weight loss greater than 10 lbs unintentionally in last year
- Fatigue: low energy levels and excessive fatigue
- Inactivity
  - Reduced physical activity based on activity scale (see Table 1. Physical frailty phenotype)
  - Reported difficulty or inability to do activities of daily living or previously done recreational activities
- Feeling of weakness
- Decreased food intake
Symptoms of important causes of frailty include:
- Recurrent fever, which may suggest chronic infection
- Diarrhea, which may suggest chronic infection, thyroid disease, cancer
- Weight loss and other symptoms that may be associated with specific cancers
- Dyspnea on exertion, which may suggest heart failure or COPD
Known disorders particularly associated with frailty that should be assessed on past medical history include:
- COPD
- Immunosuppressive disorders (eg, HIV/AIDS)
- Heart failure
- Cancer, particularly lymphoma, multiple myeloma, occult solid tumors
- Chronic kidney disease
- Metabolic syndrome
- Chronic infection
Complications of frailty are suggested by history of:
- Falls
- Progressive functional decline
- Surgical complications
- Disability
- Repeated hospitalizations
Potential stressors that may trigger complications in frail patients that should be sought include:
- Recent acute infection
- Recent acute exacerbation of chronic illness
- Acute injury
- Recent surgical or medical interventions

Physical Examination

May elicit findings of frailty and of its causes and complications
Examination findings suggestive of physical frailty include:
- Sarcopenia (decreased muscle mass, muscle strength, and function), which may be noted directly or based on anthropometric measurements²⁰²¹²²²³²⁴²⁵
  - Directly noted by observing muscle wasting in the face, shoulders, upper arms, and hands
  - BMI less than 18.5
  - Calf and mid-upper arm circumference and skinfold thickness¹
    - Mid-upper arm and calf circumferences have been shown to correlate with overall muscle mass and health and nutritional status and to also predict performance and survival in older people²²²³²⁴
      - Circumference values suggesting frailty include mid-upper arm less than 22.5 cm and calf less than 31 cm²¹
      - Skinfold values associated with frailty vary with age and sex
    - However, with increasing age, changes in the distribution of fat and loss of skin elasticity make circumference and skinfold measurements less reliable estimates of sarcopenia in older people²⁴²⁵
- Decreased muscle strength as indicated by:²¹
  - Handgrip strength on dynamometer
    - Depends on gender and BMI (see Table 3)
  - Lower limb muscle strength assessed by repeated chair stand test
    - Time needed to rise 5 times from a chair to standing more than 15 seconds²¹
- Balance and gait abnormalities ²¹
  - 4-stage balance test of 4 standing positions:²⁶
    - Stand with feet side-by-side
    - Stand with the instep of 1 foot touching the big toe of the other foot
    - Tandem stance: place 1 foot in front of the other with heel touching toes
    - Stand on 1 foot
  - Short Physical Performance Battery test²¹
    - Includes gait speed for 4 m plus the above balance test and repeated chair stand test
- Deconditioning:⁴⁵²¹
  - Gait speed (see Table 1)
  - Timed Get Up and Go test
    - Rise from seated, walk 3 m and back and return to seated position in less than 20 seconds
  - Timed stair climb test (varies with age)
  - Short Physical Performance Battery test²¹
  - Optional tests for more active people include:
    - 6-minute walk test²⁷
    - 400-meter walk test²⁸²⁹
Physical findings suggestive of underlying causes of frailty include:
- Dyspnea, wheezes, rhonchi: suggestive of COPD
- Weight loss, lymphadenopathy: suggestive of immunosuppressive disorders (eg, HIV/AIDS)
- Peripheral edema, jugular venous distention, abnormal heart sounds, heart murmur: suggestive of heart failure
- Weight loss, lymphadenopathy, hepatomegaly, splenomegaly, palpable tumor: suggestive of cancer, particularly lymphoma, multiple myeloma, occult solid tumors
- Ascites, peripheral edema, jaundice, spider angiomas, splenomegaly, asterixis: suggestive of chronic liver disease
- Dry skin, changes in mental status, peripheral edema: may suggest chronic kidney disease and/or vitamin deficiency

Laboratory Tests

Laboratory testing to identify potential stressors and rule out treatable conditions includes:
- Complete blood count
- Comprehensive metabolic panel including liver biochemical tests and albumin
- TSH level
- Vitamin B₁₂ level
- Vitamin D level
- Cultures, serology, and other testing for potential infectious illnesses if indicated by findings on history and examination

Imaging Studies

Imaging studies should be done as needed to confirm underlying disorders suspected based on history and examination
Imaging studies also can assess muscle mass when done for other clinical reasons (or for research purposes)
- DXA³⁰
- CT or MRI³¹³²

Other Diagnostic Tools

A very large number of frailty assessment tools have been developed and are in use
The most widely used tools include:
- Frailty phenotype (or Fried frailty tool, see Table 1)⁴⁵¹⁶
- Frailty index (see Table 3)^78161718
- Frailty index is considered a more sensitive predictor of adverse health outcomes than the Fried frailty tool⁸
Other rapid screening/assessment tests have been developed for ease of use in clinical settings:
- Interview-based FRAIL scale³³
- Study of Osteoporotic Fractures tool³⁴
- Edmonton Frailty Scale³⁵
- Clinical Frailty Scale³⁶
- Modified Frailty Index³⁷³⁸

Differential Diagnosis

Several disorders cause manifestations similar to those of frailty. These disorders are often known by history but may be undiagnosed

Table 4. Differential Diagnosis: Frailty.

Condition	Description	Differentiated by
Cardiovascular disease: heart failure	Patients with heart failure, particularly at the end stage, may present with symptoms of frailty such as weakness, fatigue, and/or weight loss (other than weight gain from volume overload during acute exacerbations)	May be differentiated by other accompanying symptoms such as shortness of breath, orthopnea, dependent edema, laboratory and imaging findings
COPD	Patients with end-stage COPD may present with symptoms of frailty such as weakness, fatigue, and/or weight loss	May be differentiated by other accompanying symptoms such as shortness of breath on exertion and at rest, wheezing, typical physical examination findings, imaging findings and pulmonary function tests
Depression	Depression may be associated with feelings of weakness, limited physical activity, and poor food intake	May be differentiated by a positive depression screen and absence of objective features of physical frailty (eg, decreased muscle mass, weakness on strength testing, impaired balance and gait)
Drug adverse effects, particularly from polypharmacy	Older adult patients are more susceptible to drug adverse effects and often have prescriptions for similar drugs from multiple providers, often resulting in symptoms of frailty such as weakness, fatigue, balance and gait disturbances, and decreased physical activity	May be identified by medication reconciliation and frequent drug review (eg, using Beers criteria³⁹) and absence of objective features of physical frailty (eg, decreased muscle mass, weakness on strength testing, impaired balance and gait) May require a trial of withdrawal from therapy
Endocrinologic disease, particularly hyper- or hypothyroidism, diabetes mellitus	Patients with these endocrinologic diseases may present with symptoms of frailty such as weakness, fatigue, and/or weight loss	Thyroid disorders may be differentiated by presence of symptoms such as weight gain, tremors, myxedema, or proptosis. Endocrine disorders also lack objective features of physical frailty (eg, decreased muscle mass, weakness on strength testing, balance and gait abnormalities) Laboratory tests such as TSH, blood sugar, and HbA1C are diagnostic
Hematologic disease, particularly myelodysplasia, iron deficiency, and vitamin B₁₂ deficiency anemia	Patients with hematologic disorders may present with symptoms of frailty such as weakness and fatigue	May be differentiated by absence of objective features of the physical frailty syndrome (eg, decreased muscle mass, weakness on strength testing, balance and gait abnormalities) Laboratory tests including blood tests and bone marrow biopsy also help diagnose these disorders
Malignancy, particularly lymphoma, multiple myeloma, occult solid tumors	Patients with malignancies often present with symptoms of frailty either from the malignancy itself or as a result of treatment, including weakness, exhaustion, and/or weight loss	May be differentiated by accompanying symptoms, physical features, and laboratory and imaging findings suggestive of malignancy
Neurologic disease, particularly Parkinson disease, vascular dementia	Patients with neurologic disorders may present with features of frailty such as weakness, fatigue, and/or balance and gait abnormality	May be differentiated by accompanying symptoms, physical features such as tremor, focal rather than generalized weakness, extrapyramidal manifestations, and/or cognitive impairment May also be differentiated by absence of some objective features of the physical frailty syndrome (eg, decreased muscle mass, weakness on strength testing, weight loss)
Renal disease: renal insufficiency	Patients with renal failure, particularly at the end stage, may present with symptoms of frailty such as weakness, fatigue, and/or weight loss	May be differentiated by laboratory and imaging findings
Rheumatologic disease, particularly polymyalgia rheumatica, vasculitis	Patients with rheumatologic diseases may present with symptoms of frailty such as weakness, fatigue, and/or weight loss	May be differentiated by other accompanying symptoms such as joint pains, predominantly proximal muscle weakness, vasculitic skin rash, elevated ESR and CRP

Caption: COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HbA1C, glycated hemoglobin A1C.

Treatment

Approach to Treatment

No specific treatments for frailty exist
- The task force of the ICFSR (International Conference on Frailty and Sarcopenia Research) has clinical practice guidelines for the identification and management of frailty (Table 5)⁴⁰
The focus of care for frail patients should be to:⁴⁰⁴¹⁴²
- Treat any modifiable precipitating causes of frailty
- Establish goals of care with the patient and family
- Improve the clinical manifestations of frailty, especially to:
  - Increase physical activity and strength
  - Improve exercise tolerance
  - Improve nutrition
- Minimize the effects of stressors such as acute illness or injury
A team-based, multidisciplinary approach including a geriatric care specialist, physical therapist, occupational therapist, pharmacist, and nutritionist can help optimize outcome and preserve independence⁴³
- Multidisciplinary approach has a positive impact on:⁴³
  - Avoiding polypharmacy
  - Preventing falls
  - Improving functional status
  - Decreasing need for nursing-home admission
  - Reducing mortality
Goals of care and treatment plans are guided by frailty scales and scores
- Goals of care should be based on shared decision-making between patients and health care providers, taking into account each patient’s goals as well as their life expectancy
- Goals should be reviewed periodically, especially when there is a change in frailty status, so that management options continue to reflect life expectancy and patient preferences
Palliative care or hospice may be appropriate for patients with severe frailty, depending on their preferences
- An interdisciplinary team approach is particularly important to ensure all components of palliation are provided, including easing symptoms, supporting psychosocial and spiritual needs, and improving quality of life⁴⁴⁴⁵

Table 5. International Conference on Frailty and Sarcopenia Research recommendations for frailty screening, assessment and management.

Recommendation		Grade	Certainty of evidence
Frailty screening
1	All adults aged 65 years and over should be offered screening for frailty using a validated rapid frailty instrument suitable to the specific setting or context	Strong	Low
Frailty assessment
2	Clinical assessment of frailty should be performed for all older adults screening as positive for frailty or prefrailty	Strong	Low
Development of a comprehensive management plan
3	A comprehensive care plan for frailty should systematically address polypharmacy, the management of sarcopenia, treatable causes of weight loss, and the causes of fatigue (depression, anemia, hypotension, hypothyroidism, and vitamin B₁₂ deficiency)	Strong	Very Low
4	Where appropriate, persons with advanced (severe) frailty should be referred to a geriatrician	CBR	No data†
Physical activity/exercise
5	Older people with frailty should be offered a multicomponent physical activity program (or those with prefrailty as a preventative component)	Strong	Moderate
6	Health practitioners are strongly encouraged to refer older people with frailty to physical activity programs with a progressive, resistance-training component	Strong	Moderate
Nutrition and oral health
7	Protein/caloric supplementation can be considered for persons with frailty when weight loss or undernutrition has been diagnosed	Conditional	Very Low
8	Health practitioners may offer nutritional/protein supplementation paired with physical activity prescription	Conditional	Low
9	Advise older adults with frailty about the importance of oral health	CBR	No data†
Pharmacological intervention
10	Pharmacologic treatment as presently available is not recommended therapy for the treatment of frailty	CBR	Very Low
Additional therapies and treatments
11	Vitamin D supplementation is not recommended for the treatment of frailty unless vitamin D deficiency is present	CBR	Very low
12	Cognitive or problem-solving therapy is not systematically recommended for the treatment of frailty	CBR	Very low
13	Hormone therapy is not recommended for the treatment of frailty	CBR	Very low
14	All persons with frailty may be offered social support as needed to address unmet needs and encourage adherence to the Comprehensive Management Plan	Strong	Very low
15	Persons with frailty can be referred to home-based training	Conditional	Low

Caption: CBR, consensus-based recommendation.

From Dent E et al. Physical frailty: ICFSR international clinical practice guidelines for identification and management. J Nutr Health Aging. 2019;23:771-787, Table 1.

Nondrug and Supportive Care

Figure 2. Potential interventions along the spectrum of frailty in older adults.ACE, acute care for elders unit; GEM, geriatric evaluation and management; PACE, program for all-inclusive care of the elderly. Walston J et al. Frailty screening and interventions: considerations for clinical practice. Clin Geriatr Med. 2018;34(1):25-38, Figure 1.

Interventions vary depending on where patients fall along the continuum of frailty (Figure 2)⁴⁶
A systematic review of the effectiveness of interventions to prevent progression of prefrailty and frailty in older adults summarized 21 randomized trials with a total of 5275 older adults and 33 interventions⁴³
- Exercise and nutrition interventions were among the most successful interventions
- Group exercise sessions were more successful than one-to-one training sessions
Exercise
- A progressive exercise program beginning with flexibility and balance training and followed by resistance and endurance training has been shown to be effective in improving physical function⁴³
  - For frail, sedentary people with safety concerns or those with difficulty adhering to a program, a gradual increase of exercise intensity is important
  - For this population, the American College of Sports Medicine guidelines recommend that resistance and/or balance training should precede aerobic training⁴⁷
- Resistance (strengthening) exercise is a key component of frailty treatment and prevention⁴⁰⁴⁸⁴⁹⁵⁰⁵¹
  - Can be done alone or as part of a multicomponent exercise program
  - Has been found to increase strength and function with few adverse health outcomes
- Walking is recommended for aerobic exercise and training balance
- Optimal frequency, intensity, and time of exercise is not yet known
Nutritional support, particularly protein-calorie supplementation,⁴⁰⁴³ is beneficial particularly when combined with exercise
- Manal et al summarized 4 types of nutritional intervention:⁵²
  - Specific nutritional supplements
  - Daily food fortification with protein supplement
  - Nutritional education and counseling
  - Supplementation of micronutrients including vitamin D, ω-3 fatty acids, and multivitamins
The person’s residential environment and support services should be evaluated to ensure they can live there safely and comfortably
- Social support services should be engaged as needed, including meal delivery services, and home aides to provide personal care⁴⁰
- Alternative living arrangements (eg, assisted-living facilities, living with a family member) may need to be considered for people whose living situation is incompatible with their degree of frailty
Regarding palliative care, models such as PATH (Palliative and Therapeutic Harmonization) are standardized systems for frail patients that provide a structured approach to medical and surgical decision-making in older adults and improve patient/family experience and resource utilization in frailty⁵³

Drug Therapy

Current medications should be reviewed to identify polypharmacy and contributors to weight loss and exhaustion⁴⁰
- Specific drugs of particular concern as causes of weight loss include metformin, acarbose, miglitol, pramlintide, liraglutide, exenatide, zonisamide, topiramate, bupropion, and fluoxetine⁵⁴
- Drug classes that may cause feelings of fatigue and exhaustion include tricyclic antidepressants, first generation antihistamines, benzodiazepines, β-blockers, muscle relaxants, opioid analgesics, antiepileptics, and chemotherapeutic agents
- The Beers criteria³⁹ are a helpful guide to evaluating medication use in older adults
No pharmacologic therapy is currently helpful in treatment of frailty⁴⁰
Despite findings that low serum levels of 25-hydroxyvitamin D (less than 20.0 ng/mL) were associated with a higher prevalence of frailty,⁵⁵ no large-scale study has demonstrated that vitamin D supplementation has a significant effect on frailty
- Several meta-analyses of randomized trials do show a reduction in falls with vitamin D supplementation,⁵⁶⁵⁷⁵⁸⁵⁹⁶⁰ along with improvement in balance and preservation of muscle strength⁶¹
Similarly, replacing deficiencies of any one hormone or repleting defects in other systems as a sole intervention have not demonstrated a significant treatment effect on frailty
- However, a multicomponent intervention that involves hormone replacement in a deficiency state such as hypothyroidism in addition to other measures such as nutrition and exercise would be helpful⁴⁰⁴²
- Androgen supplementation with atamestane (an aromatase inhibitor that increases testosterone secretion in males) and/or DHEA (a testosterone precursor) has not demonstrated a significant treatment effect on males with frailty⁶²

Admission Criteria

Hospital admission is not necessary for frailty itself although treatment of causes of frailty may require hospitalization
The ability of frail patients to reside at home or whether they require assisted living or nursing home care depends on:
- Their functional status
- The availability of family members and/or other caregivers to provide the necessary support and assistance
  - Patients with even moderate to severe functional decline may reside at home if family and/or other caregivers are available and capable of providing support
  - Other patients, particularly those with significant functional decline and dependency on others for basic activities of daily living, may require an assisted-living facility or nursing home

Follow-Up

Monitoring

Patients with prefrailty or who are identified as frail should have a comprehensive geriatric assessment and management combined with ongoing expert geriatric care and periodic reevaluation⁴⁶⁶³⁶⁴
- Individually tailored interventions based on impairments identified by the comprehensive geriatric assessment may be beneficial in reducing functional decline⁴⁶⁶⁵
- Goals of care should be reviewed periodically, especially when there is a change in frailty status and/or life expectancy, to ensure patients and family clearly understand their management options

Complications

Patients with frailty are at increased risk of procedural complications, falls, institutionalization, disability, and death
As frailty progresses, other geriatric syndromes, including cognitive impairment, delirium, falls, incontinence, pressure injury, and functional decline, may also become apparent

Prognosis

Frailty is associated with progressive functional decline and increasing dependency at the end of life
Frailty is associated with increased mortality
- Mortality was increased in those with baseline frailty (HR [hazard ratio] 1.71; 95% CI 1.48-1.97) In the longitudinal Women’s Health Initiative Observational Study¹⁰
- Mortality was twice as high for frail males, compared with robust males in another study on males (HR 2.05; 95% CI 1.55-2.72)¹¹
Severe frailty, with 4 or 5 syndrome characteristics in the frailty phenotype, and metabolic abnormalities of low cholesterol and albumin predict high short-term mortality rates in frail older adults⁶⁶
- These characteristics can be considered a predeath phase in severely frail adults who responded poorly to treatment
- A palliative approach may be appropriate for such patients if it is consistent with their goals of care
Frailty index has been shown to be superior in predicting mortality compared to the frailty phenotype⁶⁷
- Frailty index is strongly correlated with the risk of death (correlation coefficient greater than 0.95)⁶⁷
- As people approach a frailty index of 0.7, their chance of survival is greatly diminished⁴⁴
- One report suggested that 100% of those who have a frailty index greater than 0.5 die within about 20 months⁶⁸⁶⁹

Referral

Patients with frailty should be referred to a physical activity program⁴⁰
Patients with advanced frailty should be referred for expert geriatric care⁴⁰

Screening and Prevention

Screening

An international consensus conference has recommended that adults be screened for frailty if they have at least 1 of the following:²
- Age older than 70 years
- Significant involuntary weight loss (greater than or equal to 5% of body weight) with chronic illness
ICFSR clinical practice guidelines recommend that all adults aged 65 years and older be offered screening for frailty (see Table 5)⁴⁰
- However, routine frailty screening has not been conclusively shown to reduce mortality and morbidity related to frailty²⁴⁰

Prevention

Minimize frailty precipitants and their associated stress by promptly identifying and treating:
- Acute infections
- Acute exacerbations of chronic illnesses such as heart failure and COPD exacerbation
- Acute injury
- Hormonal deficiencies
- Acute exacerbations of chronic pain
- Medications
Maintaining physical activity, muscle mass, and strength is a cornerstone of prevention
- Resistance, or strengthening, exercise is effective in increasing muscle mass, strength, and walking speed in frail older adults⁴³
- Other forms of exercise, including stretching, tai chi, and aerobic exercise, are also helpful to improve physical function⁴³
- Overall, exercise has proven beneficial physiologic effects on sarcopenia, inflammation, and other systems associated with frailty⁴³
Consumption of a Mediterranean diet, including supplementation of protein, calories, and micronutrients as needed, lowered the risk of becoming frail in community-dwelling adults aged 65 years and older⁴³⁷⁰⁷¹⁷²⁷³

Author Affiliations

Ugochi Ohuabunwa, MD
Department of Medicine
Geriatrics and Gerontology
Emory University

References

1.Xue QL. The frailty syndrome: definition and natural history. Clin Geriatr Med. 2011;27(1):1-15.