The Cumulative Impact of Sarcopenia, Frailty, Malnutrition, and Cachexia on Other Geriatric Syndromes in Hospitalized Elderly

Background: Sarcopenia, frailty, malnutrition, and cachexia are overlapping conditions in hospitalized older adults; they are characterized by altered body composition and are associated with poor outcomes.
Aim: to quantify the effect of this overlap on other geriatric giants e.g., delirium, cognitive impairment, and functional disability in hospitalized older adults.
Methods: A cross sectional observational study involving 206 hospitalized older adults was conducted. Each patient was assessed using Arabic validated versions of mini mental state examination, geriatric depression scale-15, the mini nutritional assessment, activities of daily living and instrumental activities of daily living. Furthermore, Johns Hopkins fall risk assessment tool, bioelectrical impedance analysis, handgrip strength, and timed up and go test were performed. Comorbidities were measured using the age adjusted Charlson Comorbidity Index.
Results: 21.4% of the participants had only one syndrome, 13.1%, 14.1%, and 3.4% had two, three, and four coexisting syndromes, respectively. In the adjusted model for age, gender, and comorbidities, the combined effect of overlapping syndromes was significantly higher than the isolated presence of a single syndrome on the risk of delirium, cognitive impairment, community acquired infections, severe functional disability, high risk of falls, and pressure ulcers.
Conclusions: The overlap between frailty, sarcopenia, malnutrition, and cachexia, increases the risk of many other geriatric giants. The application of the comprehensive geriatric assessment at hospital admission would help clinicians identify this overlap. Moreover, the existing screening protocols for older adults should include these four conditions.


INTRODUCTION
Sarcopenia, frailty, cachexia, and malnutrition are prevalent health problems in older adults; with loss of body tissues being a major component of each syndrome [1,2]. For many years, these conditions have been extensively studied in parallel [3][4][5][6][7], with great interest paid to the distinction between them. Therefore, many operational definitions were set by different societies to describe each syndrome [8][9][10][11]. However, an extensive overlap exists between these definitions and diagnostic criteria [2]. Moreover, these syndromes share similar etiologies, so; they can coexist in the same patient affecting the outcomes and the treatment strategies [1]. Recently, the researchers started to focus on the concurrent occurrence of two or more of these syndromes. The coexistence of sarcopenia and malnutrition [12], sarcopenia, and frailty [13], frailty and malnutrition [14], were all studied in relation to poor outcomes [15]. multidisciplinary comprehensive geriatric assessment (CGA) which included the following: 1. A detailed socio-demographic data, medical history, and physical examination.
2. Cognitive assessment using Arabic mini mental state examination (A-MMSE) [18]. It tests the orientation, registration, attention and calculation, recall, language and praxis. The cutoff for diagnosing cognitive impairment was adjusted for age, gender, and education [18]. A-MMSE was validated for use in Arabic speaking elderly population [19].
3. Assessment of depression was done using Arabic geriatric depression scale-15 (GDS), with scores ≥ 5 suggested the presence of depression. This Arabic version was validated and exhibited good psychometric properties [20]. 4. Nutritional assessment was done using the Arabic Mini Nutritional Assessment (MNA) [21]. It was validated for the assessment of older adults in hospitals, nursing homes, or community. Patients are considered malnourished if MNA <17, the risk of malnutrition was diagnosed by MNA score between17 and 23.5. Good nutritional status was confirmed by MNA ≥ 24 [22]. 5. The premorbid physical function assessment was done using activities of daily living (ADL) [23], and instrumental activities of daily living (IADL) [24]. We used the Arabic versions provided by the Eastern Mediterranean Regional Office of the WHO [25]. Mild disability was diagnosed if the patient had difficulty in transfer and/or shopping or heavy housework. Moderate disability was defined by difficulty in dressing, bathing, or transfer, and/ or preparing meals, doing light housework. Severe disability was diagnosed if a patient had difficulty with eating and/or toileting but not with all ADLs, or difficulty using the telephone and/or managing money but not with all IADLs [26].
6. Comorbidities were assessed using the age adjusted Charlson Comorbidity Index (ACCI), which is a valid tool for predicting the outcome and risk of death using 19 comorbid diseases after adjusting for age [27].
7. Fall risk assessment was done using Johns Hopkins Fall Risk Assessment Tool (JH-FRAT) [28]. It assesses the effect of seven parameters to predict future fall risk [age, previous fall, fecal and urinary incontinence, certain medications, medical equipment (infusion lines, chest tubes, indwelling catheter, etc.), degree of mobility and cognitive status]. The JH-FRAT score < 6 indicates no risk, low risk 6-13, and high risk > 13.

Definitions of geriatric syndromes
Delirium was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) 5th edition [31].
Community-acquired infections included those presented on admission or within the next 48 hours of hospital admission. They included community-acquired pneumonia (CAP), urinary tract infections (UTI), acute bronchitis, and cellulitis. CAP was diagnosed by i) the presence of chest x-ray infiltrate on admission; and ii) the presence of one or more major criteria (cough, expectoration, dyspnea, core body temperature >38.0 °C); and iii) Auscultatory findings of abnormal breath sounds and rales [32].

Definitions of the four syndromes: (Appendix)
Physical frailty was defined according to the criteria proposed by Fried [8], it includes five domains: weakness, exhaustion, significant weight loss, slowness, and decreased physical activity. While, sarcopenia was defined according to the updated European Working Group on Sarcopenia in Older Persons (EWGSOP) which updated the operational definition of sarcopenia to include the presence of any of the following: low muscle strength, low muscle quantity/quality and low physical performance. Patients can be stratified as having probable, confirmed, or severe sarcopenia [9].
Cachexia was defined by the presence of significant weight loss in the presence of three of the following: decreased muscle strength, anorexia, fatigue, low fat-free mass index, and confirmatory laboratory markers [11].
Malnutrition was defined according to the ESPEN Consensus Statement [10]. Those with MNA SF score below 12 with BMI <18.5 kg/m2 or significant weight loss combined with either low fat-free mass index or BMI <20 kg/m 2 if patient's age is less than 70 or BMI <22 kg/m 2 if age is above 70 years.
Hand-grip strength (HGS) [29], the timed up and go test (TUG) [30], and Muscle mass measurement were performed according to a previously published study [34].

Ethical Consideration
The study was performed in adherence to the Declaration of Helsinki and the study methodology was approved by the Research Review Board of the Geriatrics and Gerontology Department, Faculty of Medicine, Ain Shams University. Informed consent was obtained from all the participants. However, some of the participants were illiterate and could not provide a signed consent, then verbal consent was documented in the presence of a next of kin and a nurse. The ethics committee approved using of verbal consent.

Sample Size
Sample was calculated using epiinfo7 (StatCalc) the expected frequency was set at 15-42% (prevalence of malnutrition and frailty in [1], accepted margin of error = 7%, confidence level = 95%, and 7% drop out, resulted in target total sample of 206 participants.

Statistical Analysis
The collected data were analyzed using MedCalc Statistical Software version 18.9.1 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2018). Quantitative variables are presented in the form of means and standard deviation or median and interquartile range. Qualitative variables are presented in the form of frequency tables. Comparison between quantitative variables was carried out using Student t test. Comparison between qualitative variables was carried out using Pearson's χ2 test. Mann-Whitney test was used for non-parametric data. Venn diagram was constructed to represent the overlap between tissue loss syndromes. Multivariable logistic regression analysis was used to study the association of tissue loss syndromes accumulation and other geriatric syndromes. Odds ratios (ORs) with 95% confidence intervals (CI) were presented. P-value <0.05 was considered to be statistically significant.
There was statistically significant gender difference in BMI, HGS, TUG, SMI, MMSE, GDS, JH-FRAT, ADL, and IADL. Females were more were more frail and sarcopenic compared to males. Although not reaching statistical significance, women were more at risk for malnutrition.
DM, HTN, IHD, and thyroid problems were more common among women, while pulmonary diseases were more common among males. Furthermore, cognitive impairment, urine incontinence, immobility, and ADL disability were more prevalent in women ( Table 2).
Regarding the prevalence rates of tissue loss syndromes, 21.4% of the participants had a single syndrome, 13.1%, 14.1%, and 3.4% had two, three, and four coexisting tissue loss syndromes, respectively (Figure 1). Table 3 showed that, the prevalence of cognitive impairment, delirium, pressure ulcer, community acquired infections, severe disability, and high risk of falls increased progressively with the increased number of coexisting tissue loss syndromes.
When both genders were analyzed separately, the prevalence of cognitive impairment, delirium, ADL dependency, and high risk of falls increased progressively with the increased number of coexisting tissue loss syndromes in both genders. In males, the prevalence of urinary incontinence and community acquired infections increased with  accumulation of the four conditions. In women, there was significant increase in the frequency of pressure ulcers with the increased number of coexisting tissue loss syndromes ( Table  3).
In the adjusted model for age, gender, and ACCI, the increased number of coexisting tissue loss syndromes increased the risk of delirium, cognitive impairment, community acquired infections, severe functional disability, high risk of falls, and pressure ulcer development ( Table 4).
Similarly, the presence of one, two, three or more of the tissue loss syndromes had (OR = 4.23, 95% CI 1.29 -13.88, P= Figure 1. Overlap of sarcopenia, frailty, cachexia, and malnutrition in older medical inpatients (n=206)

DISCUSSION
To our knowledge, the prevalence of concurrent occurrence of these syndromes in older inpatients were extensively studied, yet, this is the first study to address the impact of this overlap on other geriatric syndromes including delirium, cognitive impairment, incontinence, physical disability, risk of fall, depression, pressure ulcers, visual deficit, and hearing impairment.
The current work showed that at least one of the tissue loss syndromes was present in 51.9% of the studied sample. This prevalence was lower than a previous study by Gingrich and colleagues [1], who reported that 63% of the participants had at least one syndrome. This difference is mainly attributed to higher prevalence of oncological diseases in their study (31%).
In this study, 21.4% of the participants had only one syndrome, 13.1%, 14.1%, and 3.4% had two, three, and four coexisting tissue loss syndromes, respectively. According to Gingrich and colleagues [1], 32% of patients had one tissue loss syndrome, 11% had two, 12% had three and 8% had all four.
The overlap between frailty and sarcopenia was the most common overlap among the studied population. This overlap accounted for 25.3% of the cases. Sarcopenia was the most common condition followed by frailty; they accounted for 34.9% (n=72), 31.1% (n=64), respectively. Sarcopenia is primarily diagnosed by low physical performance; making sarcopenia one of the components used to define physical frailty. This indicates a considerable overlap between frailty and sarcopenia in different clinical settings. [35] Many previous studies documented their overlap [16,17,37,38].
Malnutrition co-occurred with sarcopenia and frailty in 11.7% and 9.3% of the studied sample, respectively. Malnutrition plays a key role in the pathogenesis of both frailty [39] and sarcopenia [40,41]. Thus, nutritional interventions should be an integral part of sarcopenia and frailty prevention and treatment programs.
To the best of our knowledge, this is the first study addressing the cumulative effect of these conditions on other geriatric giants.
The prevalence of cognitive impairment, delirium, pressure ulcer, community acquired infections, severe disability, and high risk of falls increased with the increased number of coexisting tissue loss syndromes in older inpatients. This effect persisted after adjustment of other cofounding variables i.e. age, gender, and medical comorbidities. However, the prevalence of depression, visual and hearing disabilities was not affected by the combined effect of tissue loss syndromes. This is probably due to the increased prevalence of these conditions even in the absence of the tissue loss syndromes.
Many studies have been conducted to evaluate the negative consequences of each tissue loss syndrome. The associations of cognitive decline and frailty [42], sarcopenia [38], and malnutrition were reported [43]. Similar data was found linking delirium to frailty [44], sarcopenia [45], and malnutrition in frail older adults [46]. Moreover, a recent study reported that the history of recurrent falls was higher among older adults having both sarcopenia and frailty compared to the robust, the sarcopenia only and the frailty only groups [47].
Our findings indicated that the four tissue loss syndromes could be considered a cluster of risk factors for many other geriatric giants. This approach of addressing the tissue loss syndromes as a cluster better suits recent trends in aging research, focusing on multi-morbidity and coexisting conditions [48,49]. Thus, the preventive and therapeutic interventions should be designed to target this overlap. There were several limitations to this study. First, the crosssectional design limits the implications of any causal reasoning between the overlapping tissue loss syndromes and other geriatric giants.
Second, the relatively small sample size and being conducted at a single-center may reduce the power of analysis, and limit generalization. However, this sample size is larger than previous studies investigating the overlap of tissue loss syndromes in hospital settings [1].
Third, the study was performed in hospital settings, thus results can't be generalized to older adults in outpatient settings.
Fourth, future longitudinal studies are required to clarify the significance of single and concurrent occurrence of these syndromes on clinical outcomes, length of hospital stay, and mortality.

CONCLUSIONS
The tissue loss syndromes (sarcopenia, frailty, cachexia, and malnutrition) were common among older medical inpatients. These syndromes overlapped and occurred concurrently. There is a substantial synergistic effect of multiple tissue loss syndromes on the risk of other geriatric giants including delirium, cognitive impairment, risk of fall, functional disability, and pressure ulcers.

CLINICAL IMPLICATIONS
• Owing to the considerable overlap between sarcopenia, frailty, cachexia, and malnutrition among hospitalized elderly, health-care providers should focus on identifying this overlap by administrating comprehensive assessment upon admission.
• Providing multimodal therapeutic intervention (nutrition and exercise) should be initiated upon diagnosing any of these conditions followed by monitoring for subsequent occurrence of other syndromes.
• Co-occurrence of any of these syndrome should alert physician to screen for other geriatric giants like cognitive impairment, risk of fall, functional limitation.
Author contributions: All authors have sufficiently contributed to the study, and agreed with the results and conclusions.

Funding:
No funding source is reported for this study.

Declaration of interest:
No conflict of interest is declared by authors.