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Prevalence and risk factors of senile pruritus: a systematic review and meta-analysis

Objectives To systematically assess the prevalence and risk factors for senile pruritus (SP) in the elderly (≥60 years of age). Design A meta-analysis was used to pool the prevalence and risk factors for SP estimated from individual studies. Four subgroup analyses were conducted to explore the prevalence for SP in different age, sex, research sites and region. Setting, participants and measures SP reduces quality of life in the elderly, yet the worldwide prevalence is unclear. Moreover, the risk factors for SP are controversial. Data from cross-sectional studies, case–control studies, longitudinal studies and cohort studies that reported the prevalence or the risk factors for SP were collected by searching nine electronic databases up to October 2020, including Web of Science, PubMed, Embase, Cochrane Library, CINAHL, CBM, CNKI, Wanfang and VIP. Two reviewers independently screened studies according to the inclusion and exclusion criteria, extracted data and assessed methodological quality. Data analysis was performed using Stata V.15.1 software. Results Seventeen studies involving 28 666 participants were included. The overall pooled prevalence of SP was 21.04% (95% CI 11.37% to 32.72%). In addition, the results showed that smoking, excessive drinking and monophagism were possible risk factors for SP, with pooled ORs of 1.26 (95% CI 1.14 to 1.40), 25.03 (95% CI 18.28 to 34.25) and 1.22 (95% CI 1.12 to 1.33), respectively. Conclusions The overall prevalence of SP was high. Smoking, excessive drinking and monophagism were possible risk factors for SP. PROSPERO registration number CRD42019143295.


INTRODUCTION
The geriatric population (≥60 years of age) has been growing steadily worldwide in recent decades. It is estimated that the geriatric population will account for 20% of the world's population by the middle of this century. [1][2][3] Ageing results in numerous adverse changes in the structure and function of multiple human organs, including the skin. 4 Senile pruritus (SP) is defined as generalised pruritus in patients without primary skin lesions. [5][6][7][8] Pruritus is the most common skin disorder in the geriatric population. 9 It can lead to an unpleasant cutaneous sensation, which provokes the desire to scratch (itchiness) and is accompanied by skin lesions, pain and infection. 10 Furthermore, it can lead to adverse consequences for patients' psychological health and quality of life, including anxiety, depression, disruption of normal sleep patterns and poor daytime concentration. 10 11 Therefore, investigating the prevalence of SP is essential for informing policymakers, clinicians, and the general population.
The prevalence of SP has been reported around the world, ranging from 41% in Thailand, 12 40.6% in America, 13 18.9% in Italy 14 and 14.2% in China. 15 However, these studies were limited by sample size and regional differences, and therefore do not represent the prevalence of SP worldwide. Furthermore, several studies conducted surveys on inpatients or outpatients to report the prevalence of SP. 1 11 16 17 Inpatients or outpatients do not represent the whole elderly population, making the results less representative of the actual prevalence of SP in the community. For these reasons, the precise prevalence and characteristics of the population are unknown worldwide. Furthermore, the risk factors for SP have been reported extensively, but with controversial conclusions. 18 19 In this study, we conducted a systematic review and metaanalysis to synthesise the prevalence of SP in different ages, sexes and regions based on the general population and to evaluate the risk factors for SP.

MATERIALS AND METHODS Protocol registration
This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 20 Search strategy Nine databases were searched in this study, including Web of Science, PubMed, Embase, Cochrane Library, CINAHL, CBM, CNKI, Wanfang and VIP. The following strategy was used in the searches: (Pruritus OR Itching) AND (Senile OR Aging OR Aged OR Geriatrics) AND (Incidence OR Epidemiology OR Prevalence OR Risk factors). Complete details of the search strategy are available in online supplemental table S1. All of the databases were searched from their inception dates to the 24 October 2020. Additional relevant literature was included following a manual search of the included studies reference lists.

Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) the study design was either cross-sectional study, case-control study, cohort study or longitudinal study; (2) participants were greater than or equal to 60 years of age; (3) exact diagnostic criteria for SP were provided and (4) prevalence or risk factors for SP were reported. The exclusion criteria were as follows: (1) the study populations were inpatients and outpatients; (2) the prevalence or risk factor effect value (mainly referred to as OR in this study) of SP was not clearly reported in the original study, and the data provided by the original study couldn't calculate the prevalence or risk factor effect value of SP; (3) republished literature and (4) or studies published in a language other than Chinese or English.
Quality of the studies Two independent reviewers assessed the quality of the included studies according to 11 criteria recommended by the American Agency for Healthcare Research and Quality. The criteria included assessment of selection bias, performance bias, attrition bias, detection bias and publication bias. An item would be scored '1' if it was answered 'YES', and if it was answered 'NO' or 'UNCLEAR', then the item scored '0', 21 providing a maximum score of 11.

Data extraction
Study selection and data extraction were independently conducted by two reviewers. Any disagreement was resolved by discussion the two reviewers or a third reviewer. The articles were first screened by the title and abstract, and then full-text documents were reviewed for inclusion if they reported the prevalence and risk factors for SP. By using a standardised and pilot-tested form, two reviewers independently extracted data from eligible studies, including the title, first author name, publication year, study location, age, sample size, diagnostic criteria, prevalence and risk factors for SP.

Data analysis
Double arcsine transformation was used to convert the prevalence of SP so that the data can follow an approximately normal distribution. 22 The ORs with their corresponding 95% CIs were selected to assess the effect size of risk factors for SP. Heterogeneity among studies was tested by Cochrane's Q and I 2 statistics. Heterogeneity was recognised as significant when I 2 >50%. A fixedeffect model (Mantel and Haenszel method) was used if I 2 ≤50%, otherwise a random-effects model (DerSimonian and Laird method) was used. 23 Forest plots were constructed for a visual display of the pooled results if necessary. Four subgroup analyses were conducted to explore the prevalence for SP in different age, sex, research sites and region. Sensitivity analysis were assessed by excluding single studies. Publication bias was assessed by using Begg's and Egger's tests. 24 Tests of publication bias and sensitivity analysis were not conducted in the risk factor analysis section due to the limited number of studies included. Statistical analyses were conducted using STATA V.15.1 (Stata).

Study description
A total of 8518 records were identified from the 9 databases, of which 647 were duplicates. After screening Open access titles and abstracts, 7740 records were excluded with reasons of age, outcome, study design. Full-text documents of 131 records were screened, and 114 studies were excluded with reasons listed as follows: participants were not ≥60 years of age (n=49), outcome was not SP (n=44), not cross-sectional, case-control, cohort or longitudinal study (n=9), non-Chinese and English study (n=5), duplicate publication (n=7). In summary, 17 studies were eligible and included in the meta-analysis finally (figure 1).

Characteristics of the included studies
The characteristics of the 17 studies are summarised in table 1. Eleven articles were written in Chinese, 18 19 25-33 and six were written in English. [34][35][36][37][38][39] Thirteen studies were conducted in Asia 18 19 25-33 35 37 and four in Europe. 34 36 38 39 Sample sizes ranged from 45 39 to 8252. 36 Four of the 17 studies reported the risk factors for SP. 18 19 26 33 Risk of bias assessment Results of the risk of bias assessment are listed in online supplemental table S2. Higher scores indicative of less bias and more quality. Article quality was assessed as follows: 0-3 indicates a low quality, 4-7 indicates a moderate quality and 8-11 indicates a high quality. 40 Study quality was found to be moderate in 11 studies and high in the other six studies.

Risk factors
Four studies, including 5619 participants, reported the risk factors for SP. 18 19 26 33 There were three studies, 18 19 33 including 4383 participants, that reported the association of smoking and SP. Meta-analyses showed smoking was associated with SP (pooled OR of 1.26 (95% CI 1.14 to 1.40), I 2 =0%). The results of two studies, 19    Open access prevalence of SP was associated with increasing age. Xerosis is related to ageing and is reported as the most common cause of SP. [41][42][43] One of the skin's most important functions is to retain water. skin surface lipids and sebum on the skin helps retain water. 44 As skin ages, there is a decrease in lipids and sebum on the skin, leading to suboptimal moisture retention. 42 It was reported that pruritus can also be secondary to diabetes, kidney disease, liver disease, etc. 44 45 Furthermore, pruritus is commonly listed as a medication complication, 46 including ACE inhibitors, salicylates, chloroquine and calcium channel blockers. 44 However, elderly people have more basic diseases and complex medication, which also contributed to the higher incidence of pruritus. Another view is that SP is probably a subclinical neuropathy, degenerative change in peripheral nerve endings may be attributable to age. This age alteration can cause pruritus without specific stimuli. 7 In addition, immunosenescence occurs with ageing and also produces a higher incidence of pruritus. 42 Moreover, decreases in androgen, oestrogen and glucocorticoid in aged people can contribute to SP. 47 48 All these factors will increase the prevalence of SP with age.
The results of subregional analyses found that individuals who were living in Turkey and China were associated with a higher prevalence of SP. Pruritus is influenced by multiple factors, such as genetic, biological, psychological, social, environmental and cultural factors. 49 Different countries vary in society, culture and environment, genetic, biological and psychological factors also differ among populations in different countries. Therefore, the different prevalence among countries is related to the above factors.
The results of subsex found that the prevalence of male is higher. Subresearch sites analyses found that the highest prevalence of SP was found in health examination centres. The reasons for these results are unclear based on the current scientific knowledge available on SP prevalence. Further studies would be helpful in further exploring these phenomena. In conclusion, the prevalence of SP varies among different populations. However, the reasons underlying the differences in prevalence observed in the current study remain unclear. It is suggested that further studies of the prevalence of SP in different populations be conducted in the future.
Meta-analyses showed that smoking, excessive drinking,and monophagism were possible risk factors for SP. It has been shown that smoking can cause nutrient and oxygen deprivation in cutaneous tissues, decreases collagen and elastin fibres in the dermis, and increases keratinocyte dysplasia. 50 These changes reduce skin lipids, sebum and moisture retention, leading to dryness and pruritus of skin. 51 52 Therefore, smoking is a potential risk factor for SP. This study also identified drinking alcohol as a potential risk factor for SP. Studies have demonstrated that alcohol consumption could reduce the concentration of carotenoids in the skin. 53 Carotenoids can neutralise free radicals, delay premature skin ageing and skin diseases caused by free radicals. [53][54][55] It could be proposed that alcohol consumption may lead to skin diseases by affecting the concentration of carotenoids. The human body cannot synthesise carotenoids in sufficient amounts without relying on a nutrient rich diet including fruit and vegetables. Therefore, monophagism could contribute to reducing the concentration of carotenoids and it could be considered a risk factors for skin diseases. Regrettably, the specific types of monophagism wasn't pointed out in the included study, which prevented further analysis and discussion. We expect that follow-up studies will explore and investigate this. In addition, point out the participants' dietary structure and specific types of monophagism.
Although this study indicated smoking, excessive drinking and monophagism were associated with an increased risk of SP, all the studies included in the meta-analysis were crosssectional. Consequently, It is not possible to infer on the causality between exposure and outcomes. Further studies are needed to confirm these findings. In addition to the three risk factors identified through the meta-analyses, the included studies also showed that the risk factors for SP also include age, xerosis, astriction, less water intake, bathing with soap, bathing too frequently, malignant tumour, chronic illness, excessive drinking, insomnia and contact with animals.
To the best of our knowledge, this study is the first to provide a systematic review of SP prevalence and risk factors. However, several limitations of this study should be noted. First, The epidemiological data on SP was only from Norway, China, Turkey, Britain and Denmark, which cannot be generalised to the worldwide population. Second, the methods of identifying SP varied among the included studies, the definitions of SP may not be uniform among investigators and researchers in different countries, the study of different countries may not be unified in assessing the prevalence of SP, making it difficult to analyse the prevalence of SP using a gold standard method. These limitations make we less confident that the final estimate is close to a 'true' estimate. Considering these limitations, further studies will be needed to better understand the prevalence and risk factors of SP worldwide.

CONCLUSION
In conclusion, this study found the prevalence of SP was 21.04%. Individuals who were older, male or living in Turkey and China were associated with a higher prevalence of SP. Additionally, among health examination centres, nursing homes and communities, the highest detection rate of SP was found in the health examination centres. Smoking, excessive drinking and monophagism were possible individual risk factors for SP.