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The Journal of Nutrition, Health & Aging logoLink to The Journal of Nutrition, Health & Aging
. 2018 May 28;22(8):965–974. doi: 10.1007/s12603-018-1049-x

The Relationship Between Anaemia and Frailty: A Systematic Review and Meta-Analysis of Observational Studies

Katie Palmer 1,5,*, DL Vetrano 2,3,*, A Marengoni 3,*, AM Tummolo 3,*, ER Villani 3,*, N Acampora 3,*, R Bernabei 3,*, G Onder 3,4,*; WP4 of the Joint Action Advantage
PMCID: PMC12876333  PMID: 30272101

Abstract

Background

There is increasing evidence that frailty may play a role in chronic diseases, but the associations with specific chronic disorders are still unclear.

Objectives

To conduct a systematic review and meta-analysis assessing the association of anaemia and frailty in observational studies.

Methods

The review was performed according to PRISMA guidelines. We searched PubMed, Web of Science, and Embase from 01/01/2002-10/09/2017. Pooled estimates were obtained through random effect models and Mantel-Haenszel weighting. Homogeneity was assessed with the I2 statistic. Publication bias was assessed with Egger's and Begg's tests.

Results

Nineteen studies were included; two longitudinal, seventeen cross-sectional. All studies except three reported an association between anaemia and frailty. The pooled prevalence of prefrailty in individuals with anaemia was 49% (95% CI=38-59%; I2=89.96%) and 24% (95% CI=17-31%; I2= 94.78%) for frailty. Persons with anaemia had more than a twofold odds of frailty (pooled OR=2.24 95% CI=1.53-3.30; I2=91.8%). Only two studies longitudinally examined the association between anaemia and frailty, producing conflicting results.

Conclusions

Frailty and prefrailty are common in anaemic persons. Older persons with anaemia have more than a two-fold increased odds of frailty. These results may have clinical implications, as they identify the need to assess frailty in anaemic people and investigate any potential negative effects associated with the co-occurrence of both conditions. Longitudinal research that examines temporal changes in anaemia and effect of treatment are needed to further clarify the relationship between anaemia and frailty.

Key words: Frail, hemoglobin, chronic diseases, vulnerable, ageing, anemic

Introduction

Frailty is considered to be a clinical state in which affected persons have an increased vulnerability to stressors, and an increased risk of developing adverse outcomes such as physical dependency and mortality (1, 2, 3), as well as high healthcare costs (4). Specific operationalizations of frailty differ depending on the criteria used (5). Some focus on physical components such as weight loss and weak grip strength (1), while others include more multidimensional features, including social, psychological and physical elements (6). The most commonly used definition of frailty is Fried et al‘s Cardiovascular Health Study criteria (1), which includes five components: unintentional weight loss, exhaustion, weakness, slow walking speed, and low physical activity. Frailty is common in older persons, with a prevalence of 8% to 16% in community-dwelling older adults (7, 8).

It is becoming increasingly evident that frailty may play predispose persons to the development of certain chronic diseases (9), and conversely that chronic diseases may increase the risk of frailty in older individuals. At the same time, frailty may change the prognosis and the therapeutic approach of several conditions.

Anaemia occurs frequently in the elderly, and is the most common haematological abnormality in this age group (10). Anaemia is associated with many chronic conditions, as well as negative outcomes such as mortality and dependency (11) and high healthcare costs (12). It is associated with various factors that are also implicated in the frailty process including functioning, cognition, and mood (13).

Emerging evidence suggests a link between frailty and anaemia, but until now no systematic review of the evidence is available. It is unclear what role anaemia plays in the development of frailty, and vice versa. The overall objective of the current systematic review and meta-analysis is to examine the relationship between anaemia and frailty in adults. The specific aims are: first, to identify the prevalence of frailty in persons with anaemia; second, to assess whether frailty is more common in persons with anaemia compared to persons without; and third, to examine whether persons with anaemia have a higher risk of developing incident frailty than those without anaemia, and vice versa.

Methods

We included studies providing information on the association between frailty and anaemia in adult persons. The protocol was registered in the international prospective register of systematic reviews PROSPERO (registration number 58295) The review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (14).

Search terms

We searched three databases for relevant articles published from 1st January 2002 to 10th September 2017: 1) PubMed electronic database of the National Library of Medicine, 2) Web of Science and; 3) Embase. MeSH terms and free words referring to frailty and anaemia were used as keywords. (including: anaemia, anaemic, anaemia, anaemic, low haemoglobin, frail elderly, frail, frailty). The keywords were chosen by two physicians, and by examining keywords from other reviews and articles on similar topics. References from the selected papers and from other relevant articles were also screened for potential studies. The inclusion criteria were: 1) Articles in English or another European language; 2) Study design: cross-sectional, case-control, or cohort studies; 3) Adults only. We excluded letters to the editor, abstracts, conference proceedings, reviews, and editorials.

Study selection and data extraction

Two assessors independently screened the titles and abstracts of the selected studies. Studies that reported information on any of the five aims reported above were included. Cross-sectional and longitudinal measures of association between frailty and anaemia were selected, as well as case-control studies. Articles were excluded if they 1) did not investigate the aims of the review; 2) included persons younger than 18 years; 3) was not an original article (e.g., editorial, review, or congress abstract); 4) did not provide an explicit definition of frailty and; 5) if frailty was assessed only with a single symptom/measure (e.g. only gait speed or grip strength): 6) was a duplicate; 7) was not in English or another European language. The full text of the articles selected by one or more of the assessors were retrieved for full evaluated. Two assessors read the full texts and independently extracted the information from the selected studies. A third assessor reviewed the data extraction, and any disagreement was resolved through consensus. Articles that were written in another European language than English were sent for translation by a native speaker who conducted the data extraction. The numbers of abstracts screened, and studies assessed for eligibility and included in the review, with reasons for exclusions at each stage, are presented in Figure 1.

Figure 1.

Figure 1

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Prisma flow chart for selection of papers for systematic review

Many articles used data from a longitudinal study but the data relevant to our aims were only cross-sectional; in such cases the studies are reported as cross-sectional. We also included studies on clinical samples of patients, for example heart failure patients, in order to also examine the relationship between anaemia and frailty in specific sub-populations.

Assessment of risk of bias: The quality of the studies was evaluated with the Newcastle Ottawa Scale (NOS) (15). Two assessors independently rated each study, and consensus discussion was used to resolve any disagreement. Score>7 was considered a low risk, 5–7 a moderate risk, and <5 a high risk of bias.

Statistical analysis

We performed a meta-analysis on studies using the same definition of frailty and a dichotomous definition of anaemia (rather than continuous Hb values, available only in few studies). Due to the observational design of the studies, and the methodological differences that may have contributed to a significant share of the variance within the measures of interest, the pooled estimates were obtained through random effect models and Mantel-Haenszel weighting. Homogeneity within the pooled studies was assessed through the I2 statistics (significant if ≥50%). We also ran analyses selecting studies without a high risk of bias (NOS≥5), and studies with large sample sizes (≥ 500 participants). Publication bias was assessed with the Egger's and the Begg's tests. All statistical analyses were performed with STATA version 14 (StataCorp, TX, USA), with P value <0.05 considered statistically significant.

Results

General description of included studies

Figure 1 shows the PRISMA flow chart, including the key words used in the search strategies, the number of papers identified on PubMed, Web of Science, and Embase, and the number and reasons for excluding papers at each stage. Of the 418 abstracts identified during the search, 45 were selected for full text reading. After reading the full text, 19 studies were selected for the review. Of these, 12 were included in the meta analysis. A further study (16) was not included in the review, as it was a letter to the editor with preliminary findings and therefore did not have enough information, for example, to conduct a NOS rating.

There were two longitudinal studies (Table 2), thirteen with cross-sectional data (Table 1), and four cross-sectional studies on specific clinical samples of patients (Table 3), including inpatient samples, older persons with intellectual disabilities, and patients with advanced heart failure. Some of the crosssectional studies were longitudinal but the data relevant to the current review were cross-sectional, and therefore we classify them as such.

Table 2.

Characteristics of the longitudinal studies on anaemia and frailty

Author (year) Country, Study name, Population type N Mean age ± SD Women % Anaemia Diagnosis/ definition % prevalence Frailty criteria and overall prevalence Odds ratios, risks and other results NOS
Hirani (2015) (29) Australia, Concord Health and Aging in Men Project (CHAMP), Community 1666 77 ± 5.5 Range 70-97 0 WHO criteria. 14.6% Fried criteria. Overall frail=9.%, prefrail=% 2-5 year follow-up. Baseline association between anaemia and frailty: OR=2.9 (1.9-4.5) p<.0001. Multivaraite GEE analysus for anaemia status at a previous time point with frailty (excluding men who were frail at baseline) OR=1.8 (1.1-2.9) p=.01. ADJ: Age, income, BMI, eGRF, health conditions, self-rated health, white cell count, albumin, cancer, diabetes, CHF 8
Trevisan (2017) (30) Italy, Progetto Veneto Anziani, Community 2925 74.4 ± 7.3 Range ≥65 59.7 Personal interview, medical interview and clinical examination including blood tests. Anaemia was defined with WHO criteria. Prevalence not reported Fried criteria. Overall frail=6.6%, pre-frail=49.3% Percentage of anaemic persons who were robust=6.4%, frail=25.5%. 4.4 year follow-up, progressing from nonfrail to prefrail/ frail: 0.83 (0.72–0.96) p<.05. Progressing from prefrail to frail: 0.84 (0.72-0.99)p<.05. ADJ: Age, sex, BMI, marital status, educational level, smoking, monthly income, drinking habits, living situation, diabetes mellitus, anaemia, CVD, cancer, osteoarthritis, hearing, vision, serum 25[OH]D, serum uric acid, Short Physical Performance Battery score, ADL, IADL, and daily medications 9
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ADJ=adjustment variables; ADL=activities of daily living; AF=atrial fibrillation; ECG=electrocardiogram; EHRA =European Heart Rhythm Association; IADL=instrumental activities of daily living; ICD=International Classification of Diseases; OR=odd ratios. *All numbers have been rounded up to one decimal point

Table 1.

Characteristics of the cross-sectional studies on anaemia and frailty

% with anaemia in each frailty group
Author (year) Country, Study name, Population type N Mean age ±SD Women % Anaemia Diagnosis/definition % prevalence Frailty criteria and overall prevalence Robust Prefrail Frail P Odds ratios, risks and other results NOS
Chang (2010) (22) USA, Women’s Health and Aging Studies I and II, Community 620 74.2 ± 2.8 100 WHO criteria. 13.3% Fried criteria. Overall frail =11.3% 11.3 5 .001 Odds of Being Frail vs Nonfrail by Anaemia OR= 2.5 (1.2–4.9) 5
Chaves (2005)(23) USA, Women’s Health and Aging Studies I and II, Community 670 74.3 ± 2.9 100 WHO criteria. Mean Hb 13.2 (1.1), prevalence not reported Fried criteria. Overall frail=14% Compared to an Hb concentration equal to 13.5 g/dL, the adjusted odds of being frail were 1.9 (1.1–3.4) and 1.5 (1.0–2.1) Hb concentrations equal to 11.5 g/dL and 12 g/dL, respectively. 5
Corona (2015) (24) Brazil, SABE Cohort Study (Health, Well-being and Aging, Community 1256 70 60.9 WHO criteria. 7.7% Fried criteria. Overall frail=3.8% 3.8 24.2 0.05 Mean Hb concentration among non-frail 14.3g/dL vs frail 13.3g/dL. Adjusted OR for frailty and anaemia: OR=3.3 (1.9-5.7); p< 0.01. Anaemia was associated with three specific frailty criterion – low physical activity level: OR= 2.7 (1.8-4.4); Weakness: OR=1.91 (1.2-3.1); Slowness: OR=1.98 (1.2-3.2), but was not associated with weight loss OR=1.24 (0.56-2.78) or exhaustion OR=1.59 (CI=0.92-2.76). The increased odds of frailty in persons with anaemia was present both for men and women in sex stratified analyses. Hb concentration was significantly associated with low physical activity, Weakness, Slowness, and Exhaustion in women but not men. fHb was associated with weight loss in men (OR=0.69, 95% CI=0.48-0.99) but not women. 6
Fried (2009)(28) USA, Women’s Health and Aging Studies I and II, Community 704 Range 70-79 100 WHO criteria 13.3% Fried criteria. Overall frail=10%, prefrail=45% 10.1 13.3 27 OR anaemia and frail vs nonfrail 1.5(0.7-3.4). ADJ: Age, education, race, and number of adjudicated chronic diseases. 5
Juarez-Cedillo (2014)(25) Mexico, Study on Aging and Dementia in Mexico (SADEM), Community 1933 Range ≥60 57,8 WHO criteria. 8.3% Fried criteria. Overall frail=15.9%, pre-frail=32.1% Ro- bust=5.2 Pre- frail=8.5 Frail=17.9 Adjusted multivariate logistic model frailty vs anaemia: HR (95% CI)–2.95 (2.82-3.10), p <0.05. ADJ: Age, sex, cognitive impairment, comorbidity, BMI, smoking, and alcohol. 7
Leng (2002)(18) USA, Community, Case control 30 Frail 84.9 ± 6.7; Non frail 81.3 ± 4.1 76.6 Hb analysed as continuous variable. Hb in frail Fried criteria Frail persons had significantly lower haemoglobin than nonfrail controls (12.1 ± 1.1 vs 13.9 ± 1.0 g/dL, p<.001). 4
Liotta (2017) (17) Italy, Community 1331 76.3 + 7.1 54.2 Not specified Multidimensional evaluation of physical, mental, and functional status, socio/economic resources, environment. Final score ranged from -108 points to +101. Subjects were classified as robust > ([0-9]+), frail = 10-50, and very frail-<10. Overall frail=7.6%, prefrail=13.9% Persons with vs without anaemia who were robust=58.6 vs 73.9&, prefrail=19 vs 13.7%. frail=22.4 vs 4.9%. Multivariative regression logistic model (frail and very frail vs robust) for anaemia OR=3.1 (1.3-7.4, p=0.012). ADJ: Cohabitation, education age, presence of neurological disorders, cancer, anaemia and disability in performing BADL/ IADL. 7
Llibre Jde (2014) (26) Cuba, Community 2339 Range ≥65 64.3 WHO criteria. 15.6% Four of Fried’s criteria (exhaustion, weight loss, slowed walking speed, and low physical status) + cognitive deterioration Frailty=3+ 15.1 24.9 Prevalence of frailty in anaemia group 24.9% (20.3-28.1); in group without anaemia: 15.1% (13.2-17.6), Prevalence ratio: 1.6 (1.2-2.2). ADJ: Age, sex and education 6
Ng (2014) (45) Singapore, SLAS – Singapore Longitudinal Ageing Studies I and II, Community 1685 66.7 ± 7.76 64 WHO criteria. 38.1% Fried criteria. Overall frail=5% 34.9 41.0 47.8 .002 5
Nadruz (2017) (46) USA, Atherosclerosis Risk in Communities Study, Community 3991 75.6±5.0 59 WHO criteria. 19.1% Fried criteria. Overall frail=5.3% 18 33 .001 OR for anaemia in frail vs nonfrail = 1.39 (1.01-1.93) ADJ: Demographics, diabetes, hypertension, and measures of other organ system function 7
Lahousse (2014) (27) The Netherlands, Rotterdam study, Community 2833 Median 74 Range ≥55 55.9 WHO criteria. Prevalence not reported Fried criteria. Overall frail=6%, prefrail=51% 3.8 8.9 19.9 .001 5
Serra-Prat (2016) (19) Spain, Community 324 80.1 ±3.5 47.5 Not specified. Prevalence not reported Fried criteria. Overall frail=14.2%, prefrail=53.7% 7.7 16.2 28.9 0.004 Crude OR=2.7 (1.3-5.7). In final multiadjusted model anaemia was not associated with frailty (data not given). ADJ: Age, sex, educational level, anorexia, osteoarthritis, stroke, dyspepsia. Number of medications, anaemia, CRP, % of muscle mass and creatinine 6
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ADJ=adjustment variables; ADL=activities of daily living; AF=atrial fibrillation; ECG=electrocardiogram; EHRA=European Heart Rhythm Association; IADL=instrumental activities of daily living; ICD=International Classification of Diseases; OR=odd ratios. *All numbers have been rounded up to one decimal point

Table 3.

Characteristics of the cross-sectional studies on anaemia and frailty

% with anaemia in each frailty group
Author (year) Country, Study name, Population type N Mean age ± SD Women % Anaemia Diagnosis/definition% prevalence Frailty criteria andoverall prevalence Robust Prefrail Frail p Odds ratios, risks and other results NOS
Jha (2016)(32) Australia, Clinical; consecutive patients with advanced heart failure waiting for heart transplantation 120 53 ± 12 30.8 Markers of heart failure severity were obtained as part of the patient’s pre-transplantation workup, including blood Hb level. 37% Modified Fried criteria. Overall frail=32.5% 29 56 0.01 5
Khandelwal India, Clinical (hospitalized patients) 250 66.43 ± 6.27 38.4 WHO criteria. 76% Fried criteria. Overall frail=33.2% 72.5 83.1 0.08 4
Schoufour (2016)(20) Netherlands, Healthy Aging & Intellectual Disabilities study, Older people with Intellectual Disabilities 757 61.7 ± 8.0 48 Generally according to WHO criteria. Prevalence not reported Frailty index: 51 deficits. Number of present deficits divided by the total number of measurements (score range 0-1) (high= higher frailty) Regression coefficient for the predictive value frailty in case of anaemia: B=-3.66(-4.69–2.63) p < 0.1. 5
Zilinski (2014) (21) Germany, Clinical (inpatients from an emergency department and medical ward) 100 77.8 ± 5.7 55 WHO criteria. 60% Multidimesional Lost of Function (MLF) defined as presence of abnormal results at least 3 out of 6 tests: Barthel Index, MMSE, clock drawing test, Esslinger Transfer scale, Daniels test to detect dysphagia. Overall frail=61% 75% of anaemia persons were frail vs 40% of robust people- Multivariate logistic regression for anaemia on multidimensional lost of function: OR=4.3 (1.1-16.3), p=.034. ADJ: Age, renal insufficiency, dementia, Diabetes mellitus, and hyperlipidemia. 5
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ADJ=adjustment variables; ADL=activities of daily living; AF=atrial fibrillation; ECG=electrocardiogram; EHRA =European Heart Rhythm Association; IADL=instrumental activities of daily living; ICD=International Classification of Diseases; OR=odd ratios. *All numbers have been rounded up to one decimal point

Most of the studies defined anaemia according to WHO criteria (Hb level of less than 13 g/dL in men and less than 12 g/dL in women). Both longitudinal studies used Fried et al ‘s Cardiovascular Health Study criteria (1), and WHO criteria for anaemia. In the cross-sectional studies most of the studies used Fried et al‘s (1) (n=12) but one measured with a multidimensional index (17), and 9 used WHO criteria for anaemia, while one (18) used continuous Hb levels, and two did not specify the anaemia definition (17, 19). In the four studies on specific types of patients, all used WHO criteria for anaemia, two used Fried et al‘s (1) frailty criteria, one used a Frailty Index (20), and one a multidimensional loss of function index (21).

Assessment of bias

The quality of studies differed, with only some conducting extensive multivariate analyses to account for potential confounders. In the tables, we report these study results in detail to highlight how any associations between frailty and anaemia changed in significance between crude and adjusted analyses. The NOS scores are show in Table 1, Table 2, Table 3. Three studies had a low risk of bias, two a high risk of bias, but the majority (n=14) had a moderate risk. The main reasons for bias were samples only on one sex, and selection bias or missing data. All the studies scored highly for ascertainment of exposure and outcome as they all used direct blood samples to assess Hb and frailty assessment was through structured interview with validated criteria. No strong evidence of publication bias was detected in our meta-analyses (Egger's test p=0.057; Begg's test p=0.213).

Cross-sectional association between anaemia and frailty

Table 1 summarizes the thirteen studies that provided crosssectional data on the association between frailty and anaemia. All 6 studies investigating a cross-sectional association between anaemia and frailty reported significant results. Eight studies reported an increased odds of frailty in persons with anaemia (17, 22, 23, 24, 25, 26, 27) but 2 studies did not (19, 28).

The study by Corona et al (24), additionally provided specific results concerning the relationship between anaemia and the specific frailty criterion. There was a significantly higher odds of anaemia for low physical activity level, weakness, and slowness (Table 1), but not for weight loss or exhaustion. Additionally, when stratifying for sex, the increased odds of frailty in persons with anaemia was present both for men and women. However, Hb concentration was differentially associated with the five components in men and women. Specifically all four components were associated with frailty in women except weight loss (OR=1.10, 95% CI=0.83-1.47), but in contrast weight loss was the only component associated with Hb concentration in men (OR=0.69, 95% CI=0.48-0.99).

Longitudinal association between anaemia and frailty

Table 2 summarizes the characteristic and main results of the two longitudinal studies. Both studies made multiple adjustments for clinical characteristics, including diseases that may cause anaemia. Hirani et al [29] reported a significant 80% increased risk of incident frailty over 2–5 years in men with baseline anaemia. In contrast, Trevisan et al [30] found that persons with anaemia had a lower odds of progressing from robust to prefrail/frail: 0.83 (0.72–0.96), or progressing from prefrail to frail: 0.84 (0.72-0.99) over 4.4 year followup. However, in the multivariate model they did not find a significant association between anaemia and improvement from prefrailty or frailty.

Association between anaemia and frailty in specific populations

In Table 3 four studies that looked at specific populations cross-sectionally are summarized. In the two studies on inpatients (21, 31) frailty was high in persons with anaemia, with an increased odds of frailty in inpatients with anaemia (OR=4.3) after adjusting for chronic diseases. Schoufour et al (20) reported an increased odds of frailty in older adjust with intellectual disabilities who had anaemia. Finally, in Jha et al's (32) study patients with advanced heart failure were significantly more likely to have anaemia if they were frail (56%) compared to robust patients (29%).

Meta-analyses

Studies were included in the meta-analysis if they defined frailty according to Fried et al ‘s Cardiovascular Health Study criteria (1) and anaemia according to WHO criteria.

The pooled prevalence of prefrailty in individuals with anaemia was 0.49 (95% CI=0.38-0.59; I2=89.96%), see Figure 2, and the pooled prevalence of anaemia in prefrail individuals was 0.17 (95% CI=0.17-0.28; I2=98.57%) as shown in Figure 3.

Figure 2.

Figure 2

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Proportion of anaemia participants with prefrailty

Figure 3.

Figure 3

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Proportion of prefrail persons with anaemia

The pooled prevalence of frailty in individuals with anaemia was 0.24 (95% CI=0.17-0.31; I2=94.78%) as shown in Figure 4. The pooled prevalence of anaemia in frail individuals was 0.36 (95% CI=0.24-0.48; I2=95.88%), see Figure 5. Figure 6 shows the pooled estimate for the association of frailty and anaemia. Persons with anaemia more than a twofold odds of frailty (pooled OR=2.24 95% CI=1.53-3.30; I2=91.8%) see Figure 6. These results were confirmed when only studies with NOS≥5 and large sample sizes (≥ 500 participants) were analyzed (pooled OR=2.19 95% CI=1.44-3.33; I2=93.4%), Figure 7.

Figure 4.

Figure 4

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Proportion of anaemia participants with frailty

Figure 5.

Figure 5

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Proportion of frail persons with anaemia

Figure 6.

Figure 6

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Meta-analysis: odds ratios of frailty and anaemia

Figure 7.

Figure 7

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Meta-analysis: odds ratios of frailty and anaemia in studies with large samples and moderate to low risk of bias

Discussion

Summary of main results

The results of this systematic review and meta-analysis found a two-fold increased odds of frailty in persons with anaemia compared to persons without anaemia. More than a third of frail persons have anaemia. When considering also prefrailty status, our results highlight that the majority of anaemia persons have a concurrent form of frail status, with almost half being prefrail and a quarter frail. This suggests that very few older persons with anaemia are robust. These associations appear to be independent of other chronic diseases that may be associated both with anaemia and frailty. However, no conclusions can be made concerning the longitudinal risk, as only two studies were available.

Discussion of results

The longitudinal data was unable to provide any firm conclusions. Although one study (29) found an increased risk of incident frailty in men, Trevisan et al (30) reported that the risk over four years of progressing from non-frail to prefrail/frail or from progressing from prefrail to frail was actually lower in persons with baseline anaemia. However, they did not take into account whether persons still had anaemia at followup, so it is possible that this finding could be due to changes in anaemia status over time; perhaps prefrail persons with anaemia at baseline had an improvement in Hb levels over follow-up and therefore did not progress to a full frail status. It is worth noting that they did not find an association between improvement in frailty status over time according to baseline anaemic status. These interesting, contrasting results highlight the need for more longitudinally studies to establish the long-term effect that anaemia has on frailty status, with specific need to account for treatment and changes in anaemia status over time. An important research questions is whether anaemic persons with frailty experience a change in frailty status over time following anaemia treatment.

The studies of Zilinski et al (21) and Jha et al (33) also highlight the relevance of examining anaemia and frailty within specific patient populations. Patients with advanced heart failure were significantly more likely to have anaemia if they were frail than robust, and inpatients in an emergency department had an increase odds of frailty due to anaemia. As anaemia is associated with several chronic diseases, this emphasizes the need to evaluate anaemia and frailty within specific patient populations due to the associated risk. Anaemia can be caused by chronic disease such as kidney disease, rheumatoid arthritis, HIV/AIDs, inflammatory diseases, and certain cancers, and therefore in some cases the frailty associated with anaemia may be due to specific chronic diseases. However, many of the studies in this review adjusted for chronic disease and found that the risk of frailty in persons with anaemia was still significant, suggesting a specific role of anaemia in frailty.

Symptoms of anaemia include fatigue and weakness, and therefore it can be hypothesized that there is a correlation between frailty and anaemia because some of the symptoms are correlated, such as exhaustion. However, the results of Corona et al (24) showed that anaemia was significantly associated with the specific frailty criterion for low physical activity level, weakness, and slowness, but not for weight loss or exhaustion in women.

Oxygen-carrying capacity is reduced in anaemia, and this can lead to tissue hypoxia, which can cause problems such as muscle wasting, and reduced aerobic capacity. Therefore, the association between anaemia and frailty may be via this pathway, manifesting in specific components of frailty such as low physical activity and slow walking speed. A recent review (34) found evidence of an association between frailty, anaemia, and inflammation in older persons, but due to the fact that underlying mechanisms still remain unclear, the authors concluded that further research was needed on this topic.

Low-grade inflammation is associated both with the development of anaemia (35) and frailty (36) in older adults, and therefore this may be one of the potential pathways underlying the association between anaemia and frailty. Inflammatory markers have been linked to anaemia in several chronic diseases such as cancer (37) and rheumatoid arthritis (38). Further, Leng et al (18) found an inverse correlation between serum IL-6 level and haemoglobin in frail persons but not in robust persons. In addition, Chang et al (22) reported that the risk of frailty was synergistically increased in persons with anaemia and inflammatory diseases such as depression and pulmonary disease compared to persons without either disease. Together, these findings support the hypothesis that inflammation may be one relevant mechanism by which anaemia can cause frailty.

Strengths and limitations

Our systematic review has several strengths. First, we included an extensive literature search with three medical databases, and all abstract screening and data extraction was conducted independently by two researchers. Further, the inclusion of articles in any European language is a major strength. All the studies used a direct, objective measurement of anaemia from blood testing, thus reducing the chance of measurement bias. Another strength is that we were able to conduct a meta-analysis on prefrailty as well as frailty. Finally, most studies used Fried et al's frailty criteria, making results easily comparable.

A major limitation was that there was a lack of longitudinal data. Only two studies longitudinally examined the role of anaemia on incident frailty, and no studies examined whether frailty increases the risk of anaemia. It would be clinically useful to determine whether frailty is a cause of chronic disease or vice versa. However, unless more high-quality longitudinal studies are conducted to calculate incidence, no firm conclusions can be made.

Relevance

Due to the high prevalence of both frailty and anaemia in older population, the fact that both increase dramatically with increasing age, and the rapid aging of the world's populations, the results of this review highlight the importance of identifying associations between these two conditions. A qualitative study showed that frailty factors in anaemia in elderly patients can be a reason that GPs decide to treat with blood transfusion (39). A recent meta-analysis (40) on iron deficiency in anaemia concluded that intensive treatment should be considered for patients with frailty, as anaemia may worsen their clinical outcomes, and also emphasized the need for clinicians to evaluate frailty status within anaemic patients. Another review discussed that older anaemic patients might exhibit different outcomes with liberal versus restrictive transfusion than younger adults because of age-related differences in anaemia risk and effect, related to older patients' decline in physiological reserve (41). Further, frail patients with anaemia have more than a twofold risk of rehospitalization (42). These findings all support the need for comprehensive, multidisciplinary assessment and treatment of older persons who present to care systems with complex care needs and common geriatric syndromes (43, 44).

Our review highlights that there is a significant role of anaemia in frailty and that more research is needed to establish the mechanisms behind these associations. More longitudinal studies are needed, both to investigate the risk of developing incident frailty in persons with anaemia, as well as the risk of incident anaemia in persons with frailty. Of particular importance, longitudinal studies need also to account for changes in Hb level over time and the effect of potential treatment of anaemia on frailty outcomes.

Future studies

Our review also highlights other evidence lacking in the literature. In future studies, the duration of anaemia should be taken into account to examine whether long-term anaemia increases risks of frailty more than short-term anaemia, and whether any specific causes of anaemia due to specific chronic diseases affect any associations. Also needed are studies that compare iron-deficient anaemia versus other causes of anaemia. A relevant question is whether anaemia exacerbates or affects the prognosis of an already present frailty syndrome. Studies examining inflammation makers such as interleukin-6 are also needed. For example, Leng et al (18) found an inverse correlation between serum IL-6 level and Hb in frail persons (r=0.46) but not in robust persons. Finally, the results of Corona et al's (24) study emphases the importance of examining sex difference in the association between anaemia and frailty, as well as study the individual frailty components to identify specific patterns. Is there a difference in the clinical pathways of frailty in persons with anaemia according to sex?

Conclusions

In conclusion, this systematic review found evidence of an association between anaemia and frailty, independent of the presence of comorbidity. A large proportion of older persons with anaemia are either prefrail or frail. As previously demonstrated, frailty can drive the decision-making process of physicians treating people with anaemia, which may be due to the strong prognostic power of frailty. In order to better endorse frailty as a relevant clinical significance in daily practice, more longitudinal research is needed to determine the causal link between the two conditions and to examine potential mechanisms underlying them.

Authors and contributors

KP designed the research objectives, conducted the abstract screening and data extraction, and wrote the paper. DLV designed the research objectives, performed the meta-analysis, and revised the paper. AM conducted the abstract screening and data extraction and revised the paper. AT conducted the abstract screening and revised the paper. ERV conducted the data extraction and revised the paper. NC conducted the abstract screening and revised the paper. RB designed the research objectives and revised the paper. GO designed the research objectives and revised the paper.

Disclosures

Katie Palmer has nothing to disclose. Davide L. Vetrano has nothing to disclose. Alessandra Marengoni has nothing to disclose. Anita Maria Tummolo has nothing to disclose. Emanuele R. Villani has nothing to disclose. Nicola Acampora has nothing to disclose. Roberto Bernabei has nothing to disclose. Graziano Onder has nothing to disclose.

Conflict of Interest

None

Funding

The work reported in this publication was co-funded by the European Commission through the 3rd Health Programme, under the grant agreement n° 724099. The European Commission support for the production of this publication does not constitute endorsements of the contents which reflects the views only of the authors, and the Commission cannot be held responsible for any use which may be made of the information contained therein.

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