Frailty is Associated with Susceptibility to and Severity of Pneumonia in Functionally-independent Community-dwelling Older Adults: A JAGES Multilevel Cross-sectional Study

Pneumonia is a leading cause of mortality among older adults worldwide. Recently, several studies reported that frailty was associated with mortality among older adults hospitalized due to respiratory infectious diseases, including pneumonia. However, it is unknown whether frailty is associated with susceptibility to and severity of pneumonia in functionally-independent community-dwelling older adults. In this study, we examined whether frailty increased the susceptibility to pneumonia and hospitalization in older adults. We used cross-sectional data from the Japan Gerontological Evaluation Study; the data was collected by using mail-based, self-reported questionnaires from 177,991 functionally-independent community-dwelling older adults aged ≥ 65 years. Our results showed that frailty was signi�cantly associated with both occurrence of and hospitalization due to pneumonia after adjustments with covariates; (Preference ratio {PR}1.92, 95% con�dence interval {95%CI} [1.66 − 2.22] and PR 1.80, 95%CI [1.42 − 2.28], respectively, p < 0.001 for the both). Pre-frailty was associated only with the occurrence of pneumonia. Besides, the instrumental activity of daily living, physical strength, nutrition status, oral function, homeboundness, and depression status in frail older adults were associated with either or both occurrence of and hospitalization due to pneumonia. Our results suggest that frailty in�uenced the susceptibility to and severity of pneumonia in older adults.


Introduction
Pneumonia is a major cause of mortality and morbidity among older adults worldwide 1 .Community-acquired pneumonia (CAP) is a leading cause of morbidity among community-dwelling older adults in many countries and is different from hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).The overall incidence rates of CAP have been estimates as 1,790-4,000 in Japan, 2015; 630-1,463 in the U.S., 2015, and 1,400 in Europe, 2013 per 100,000 older adults aged ≥ 65 years [2][3][4] .A recent report showed that 6.8 million episodes of clinical pneumonia, including CAP, resulted in hospital admissions of older adults globally in 2015 5 .
Frailty is a state of increased vulnerability to stressors, including infectious diseases, which develops as a consequence of age-related decline in multiple physiological and psychological systems, including the central nervous, endocrine, skeletal muscle, and immune systems 6,7 .A recent report showed that the pooled prevalence rates of frail older adults in 62 countries were 22-26%, based on the de cit accumulation model 8 .Several reports have recently shown that frailty was associated with increased severity and mortality of hospitalized older adults due to respiratory infectious diseases.He witt and colleagues showed that frailty in older adults hospitalized due to COVID-19 was associated with in-hospital mortality 9 .Lees and colleagues reported that the frailty of hospitalized older adults with in uenza and acute respiratory illness was associated with lower odds of recovery 10 .Luo and colleagues recently reported that frailty was associated with the severity of CAP and mortality among hospitalized older adults 11 .However, it was unknown whether frailty was related to the susceptibility to and severity of pneumonia among community-dwelling older adults.
Therefore, we examined whether frailty was associated with susceptibility to pneumonia and hospitalization among functionally-independent community-dwelling older adults aged ≥ 65 years.We assessed associations between each physical or psychological condition in frailty and the prevalence and severity of pneumonia.

Study sample
The present study had a cross-sectional design and uses data from the Japan Gerontological Evaluation Study (JAGES).JAGES was designed to describe the health status and social determinants of people aged 65 years and older, without disabilities, and not eligible for the long-term care insurance (LTCI) in Japan.We used the data "JAGES 2016," which was obtained from self-reported questionnaires mailed to and lled-in by communitydwelling individuals in 39 municipalities in 2016.In the JAGES 2016 wave, self-administered questionnaires were mailed to functionally independent adults aged 65 years or older who did not receive bene ts from the LTCI insurance in Japan.The survey was conducted in the municipalities between September 2016 and January 2017.The data included 180,021 individuals who answered the questionnaires with the basic items (response rate was 70.2%).Participants who did not answer questions regarding age or sex were excluded (n=2,030).The data consisted of individuals who were not eligible for LTCI on 1 st April 2016.The data consisted of a three-stage hierarchal structure.The individual data were nested into 720 communities based on elementary or junior high school districts, and these communities were further nested into 39 municipalities.

Outcome variables
The occurrence of pneumonia and hospitalization due to it in the past year from September 2016 to January 2017 were the outcome variables.The occurrence of pneumonia was assessed by asking "Did you fall sick in the past year?"and instructing the participants to select an appropriate answer from the following items: "In uenza," "Pneumonia", and "none of them."Hospitalization due to pneumonia was assessed for participants who answered "In uenza" or "pneumonia" in the previous question by asking "If the sickness was due to in uenza or pneumonia, were you hospitalized with relation to it?"and instructing the participants to select an answer from the following options: "Not hospitalized," "Hospitalized due to in uenza," "Hospitalized due to pneumonia," "Contracted in uenza while I was hospitalized for other diseases," and "Developed pneumonia while I was hospitalized for other diseases."Only participants who answered "Hospitalized due to pneumonia" were considered to be hospitalized.The participants who answered "In uenza" in the rst question and "Hospitalized due to pneumonia" in the second were included because in uenza can cause primary viral or secondary bacterial pneumonia 12 .

Frailty
Frailty was assessed using the Kihon Check List (KCL) 13 .KCL was developed by the Japanese Ministry of Health, Labor and Welfare to identify older adults requiring LTCI.KCL was included in the self-administered questionnaires of the JAGES 2016 wave.KCL consists of 25 questions classi ed into the following seven categories: instrumental activity of daily living (IADL), physical strength, nutritional status, oral function, homeboundness, cognitive function, and depressive mood (Supplemental Table 1).The scores from the KCL was well correlated with the validated assessments of physical strength, nutritional state, cognitive function, depressive mood, and the number of frailty phenotypes de ned by the Cardiovascular Health Study criteria (CHS) 13 .Frailty was categorized into three groups based on KCL scores: robust, 0-3; pre-frail, 4-7; and frail, ≥8; scores were calculated from the KCL questions, which were validated with the pre-frail and frail categories established by the CHS criteria 13 .KCL variables were generated for each of the seven categories.Each KCL variable was categorized into three groups, based on answers to questions: 0, not applicable; 1, applicable; and 2 or ≥2 applicable.

Covariates
Age was classi ed into two groups (65-74 years and ≥ 75 years).Educational attainment was categorized into ve groups: < 6 years, 6-9 years, 10-12 years, ≥ 13 years, and others.Equalized income was calculated by dividing the normalized household gross income in 2015 by the square root of the number of household members, and was categorized into ve groups: < 0.5, 0.50-0.99,1.00-1.99,2.00-3.99,and ≥ 4.00 million yen.
The household structure was assessed by asking the respondents the question, "Who do you live with?".They were asked to choose from the following options: "no one," "spouse," "son," "daughter," "spouse of child," "grandchild," "brother or sister, "father," "mother," "father-in-law," "mother-in-law," and "other."The responses were classi ed into six groups as follows: living alone, living with a spouse, living with children, living with a spouse and children, living in three-generation households (living with/without a spouse, but with one of the sons/daughters/son's or daughter's spouse and grandchildren), and the in a household structure other than the above ve categories.Marital status was assessed by asking, "What is your marital status?" and participants were instructed to select one from the following ve options: "Married," "Widowed," "Divorced," "Never married" and "Other."Smoking status was assessed by asking, "Do you smoke cigarettes?" and the participants were instructed to select appropriate answers from the following items: "Never smoked," "Quit smoking ≥5 years ago", "Quit smoking < 5 years ago," "Smoke sometimes" and "Smoke almost every day."The population density of the municipality was categorized as follows: metropolitan (density over 4,000 people per km 2 ), urban (density between 1,500 and 4,000 people per km 2 ), semi-urban (density between 1,000 and 1,499 people per km 2 ), and rural (density below 1,000 people per km 2 ) 14 .A municipality dummy variable was generated to adjust for differences in municipalities' policies in preventing frailty 15 .The diabetes, respiratory, heart, kidney/prostate gland, hematological, or immune disease status was assessed by asking participants whether they were receiving any treatment or experiencing after-effects of any of the above diseases.Pneumococcal vaccination status was assessed by asking the participants, "Did you get a pneumococcal vaccination in the last ve years?They chose from the following options: "No," "Yes, I got vaccinated using my municipality's subsidy", and "Yes, but I did not get vaccinated using my municipality's subsidy".The participants who chose the two latter options were categorized as vaccinated.

Statistical analysis
Multilevel Poisson regression analyses with random intercepts were performed to assess associations between frailty and pneumonia/hospitalization after adjusting for all the covariates.The data were structured in three levels: the individuals were nested within their elementary or junior high school districts and the districts were further nested within the municipalities.The covariates consist of all the covariates at individual-level and the municipality dummy variable used to adjust for differences in municipalities' policies in older adult's health including preventing frailty and pneumonia at municipality-level 15,16 .The individual-level covariates were: age group, sex, educational attainment, equivalized income, household structure, marital status, smoking status, municipality population density, diabetes, respiratory disease, heart disease, kidney/prostate gland disease, hematological/immune disease, and pneumococcal vaccination.The prevalence ratios (PRs) and 95% con dence intervals (95% CIs) were calculated after adjusting for all covariates.We used Stata version 14.2 (StataCorp., College Station, TX, USA) for all analyses, with a 2-tailed signi cance level set at 5%.

Ethical consideration
The process of obtaining informed consent in the present study was as follows: the questionnaire was sent by mail with the explanation of the study; the participants read the written explanation about the purpose of study and replied.Hence, we considered that informed consent was provided by those who replied and sent back the questionnaire.The JAGES protocol in 2016 was approved by the ethics committee of National Center for Geriatrics and Gerontology (No. 992) and the ethics committee of Chiba University (No. 2493).We followed the STROBE Statement to report our observational study.This study was performed in accordance with the principles of the Declaration of Helsinki.Informed consent was obtained from all participants.

Results
The relationship between prevalence rates of pneumonia and hospitalization with frailty and other characteristics of older adults Table 1 compares the prevalence rates of pneumonia in the past year with the characteristics of communitydwelling older adults.Frail and pre-frail older adults were 3-and 1.5-times, respectively, more likely to contract pneumonia than non-frail adults.Older adults, with ≥ 1 applicable question in KCL related to IADL, physical strength, nutrition status, oral function, homeboundness, cognitive function, and depression status, were likely to contract pneumonia than those with a score = 0 (none of the questions were applicable).Older adults aged ≥ 75 years, who were male, had lower education/income, who lived in three-generation households, had "other" marital status, who had quit smoking < 5 years ago, and who lived in rural or semi-urban areas were more likely to contract pneumonia than those in other categories.Older adults with diabetes, respiratory, heart, kidney/prostate gland, and hematological/immune diseases, and those who received pneumococcal vaccination were more likely to contract pneumonia more than those without any disease.Frail and pre-frail older adults were 3.3-and 1.6-times, respectively, more likely to be hospitalized than nonfrail adults.Older adults, with ≥ 1 applicable question in KCL from all the seven categories were more likely to be hospitalized than those with a score = 0 (none of the questions were applicable).Older adults aged ≥ 75, who were male, had lower education/income, who lived in three-generation households, had "other" marital status, who had quit smoking < 5 years ago, and who lived in rural areas were more likely to be hospitalized than those in other categories.Older adults with diabetes, respiratory, heart, kidney/prostate gland, and hematological/immune diseases and who received pneumococcal vaccination were more likely to be hospitalized than those without any disease.Frailty was associated with susceptibility to and severity of pneumonia among community-dwelling older adults.

Discussion
We examined whether frailty was associated with the occurrence of and hospitalization due to pneumonia compared to non-frailty in community-dwelling older adults.Our analysis showed that frailty was signi cantly associated with both occurrence of and hospitalization due to pneumonia after adjusting for all covariates (Table 3).Besides, IADL, physical strength, nutrition status, oral function, homeboundness, and depression status were associated with either or both of them (Table 4).Our results also suggested that frailty was associated with both susceptibility to and severity of pneumonia, and the six physical or psychological conditions in frailty were associated with either or both of them in community-dwelling older adults.
Several reports have recently shown that frailty was related to mortality in older adults hospitalized due to respiratory infectious diseases [9][10][11] .However, it is unknown whether frailty is associated with susceptibility to and severity of pneumonia in community-dwelling older adults.Our results showed that frailty was associated with both occurrence of and hospitalization due to pneumonia in community-dwelling older adults, suggesting that frailty was associated with susceptibility to and severity of pneumonia in these adults (Table 3).Therefore, our results indicate the possibility that frailty may be one of the risk factors related to CAP and hospitalization in community-dwelling older adults.The pneumonia cases were likely CAP because HAP and VAP were excluded by asking corresponding questions to the participants (see "Outcome variables" in Methods).Our results also suggest that frailty may be an important indicator in the prevention of pneumonia among community-dwelling older adults, not only be an indicator of the mortality in older adults hospitalized for pneumonia as recently reported 11 .
Our results showed that low IADL was negatively associated with pneumonia after adjusting for all other KCL categories and covariates (Table 4).However, a negative association between low IADL and pneumonia has not been reported so far.Several reports have shown that community-dwelling older adults with low IADL are less social than those with normal IADL [17][18][19] .Social participation was reported to be associated with in uenza among community-dwelling older adults 20 .Taken together, low IADL may present fewer opportunities for infection with respiratory infectious pathogens.However, our results showed that the lowest IADL was associated with hospitalization among older adults (Table 4).Reichard and colleagues reported that adults with low IADL delayed or forewent receiving healthcare services twice more often than those with normal IADL, even if they were insured 21 .Older adults with the lowest IADL may have done the same when compared to those with normal IADL; they might have delayed visiting the physician even if they had perceived subjective symptoms of pneumonia and hence, the symptoms may have worsened and become more severe leading to hospitalization.
The decline in immune function, so-called "immune senescence", occurs in frail older adults; this is associated with the malfunction of the cellular and humoral immune systems 6,22 .Several research groups have reported that antibodies against in uenza were more prevalent in physically active older adults than in sedentary individuals after vaccination; exercise enhanced the production of immunoglobulin A (IgA) secreted by the salivary gland in adults aged ≥ 65 [23][24][25] .IgA is important for mucosal immunity as frontline protection against infections.Our results showed that the lowest physical strength was associated with both occurrence of and hospitalization due to pneumonia (Table 4).Older adults with the lowest physical strength may be more susceptible to infections by pneumonia-causing pathogens due to decreased immunity, including the poor secretion of IgA; this may enable pathogens to invade the upper and lower respiratory tracts causing pneumonia and subsequent hospitalization.
Beard and the colleagues reported that iron de ciency was common among homebound older adults and it was associated with the impairment of cellular and innate immunities 26 .However, the relationship between older adults' homebound status and the prevalence of pneumonia has not been investigated before.Our results showed that the worst case of homeboundness was associated with hospitalization (Table 4).Impairment of immunity may increase the severity of pneumonia and subsequent hospitalization among homebound older adults.
Several reports have already shown that poor nutrition is associated with CAP and hospitalization [27][28][29] .The decline in oral function, including poor swallowing and cough re ex, causes dysphagia, which induces aspiration pneumonia in frail older adults 4,30−33 .Geriatric depression is associated with the malfunction of the immune system and increased susceptibility to infection [34][35][36] .Our results showed that the nutrition status, oral function, and depression status were associated with either or both occurrence of and hospitalization due to pneumonia (Table 4).The concordance between our results and the reported studies on the associations between poor conditions and infectious diseases, including pneumonia, suggests that frailty is associated with susceptibility to pneumonia or hospitalization.
Our study has some limitations.First, this study has a cross-sectional design.Therefore, the possibility of pneumonia causing frailty cannot be completely excluded.However, the prevalence rate of pneumonia was 3.0% among all frail older adults (Table 1).Second, the occurrence of and hospitalization due to pneumonia were selfreported by the participants and not collected from medical records from the physicians in-charge.However, it is unlikely that they arbitrarily diagnosed themselves with pneumonia or non-medical professionals did so and they trusted it because most Japanese citizens have good medical access due to the national health coverage 37 .
Third, we did not categorize the medical records based on the type of pneumonia, for example, CAP, HAP, or VAP.However, we expect most cases to be CAP because we excluded cases of nosocomial pneumonia with a question (see Methods).Besides, all the participants were functionally-independent community-dwelling older adults, not eligible for Japan's LTCI.

Conclusion
It was unknown whether frailty was associated with the susceptibility to and severity of pneumonia among community-dwelling older adults, although recent reports have shown that it is related to mortality due to respiratory infectious diseases in hospitalized older adults.We examined whether frailty was associated with the occurrence of and hospitalization due to pneumonia in functionally-independent community-dwelling older adults.Our results showed that frailty was signi cantly associated with both occurrence of and hospitalization due to pneumonia after adjusting for all covariates.Our results showed that the IADL, physical strength, nutrition status, oral function, homeboundness, and depression status in frail older adults were signi cantly associated with either or both.Our results suggested that frailty was associated with susceptibility to and severity of pneumonia, which is a leading cause of mortality and morbidity among community-dwelling older adults worldwide.This study showed frailty as a risk factor for increased susceptibility to and severity of pneumonia among community-dwelling older adults.It is necessary to assess whether frailty is also signi cantly associated with CAP diagnosed by medical doctors and the causal relationship between frailty and pneumonia should be con rmed in longitudinal studies in the future.

Table 1
Prevalence rates of pneumonia in comparison with the characteristics of older adults Numbers in IADL, physical strength, nutrition status, oral function, homebound, cognitive function, depressive mode are the numbers of the applicable KCL questions for the older adults.PR, prevalence rate; IADL, instrumental activity of daily living; KCL, Kihon checklist.Table 2 compares the prevalence rates of hospitalization due to pneumonia with the characteristics of older adults.
*Numbers in IADL, physical strength, nutrition status, oral function, homebound, cognitive function, depressive mode are the numbers of the applicable KCL questions for the older adults.PR, prevalence rate; IADL, instrumental activity of daily living; KCL, Kihon checklist.*

Table 2
Prevalence rates of hospitalization due to pneumonia in comparison with the characteristics of older adults *Numbers in IADL, physical strength, nutrition status, oral function, homebound, cognitive function, depressive mode indicate how many of the KCL questions were applicable to older adults.PR, prevalence rate; IADL, instrumental activity of daily living; KCL, Kihon checklist.*Numbers in IADL, physical strength, nutrition status, oral function, homebound, cognitive function, depressive mode indicate how many of the KCL questions were applicable to older adults.PR, prevalence rate; IADL, instrumental activity of daily living; KCL, Kihon checklist.

Table 3 shows
PR and 95% CI of the association between frailty and the occurrence of pneumonia in the past year or hospitalization due to pneumonia among the community-dwelling older adults.After adjusting with all the covariates, frailty in older adults was signi cantly associated with both occurrence of and hospitalization due to pneumonia compared to non-frailty (PR 1.92 [95% CI 1.66-2.22]and PR 1.80 [95% CI 1.42-2.28],respectively, p < 0.001 for the both).Pre-frailty was also signi cantly associated with the occurrence of pneumonia but not with hospitalization, compared to non-frailty (PR 1.30 [95% CI 1.14-1.48,p < 0.001] and PR 1.23 [95% CI 0.98-1.53],respectively).

Table 3
Prevalence ratios (PR) and 95% con dence intervals (95% CIs) between the occurrence of or hospitalization due to pneumonia and frailty among the community-dwelling older adults

Table 4
shows PRs and 95% CIs of associations between each of the KCL categories and the occurrence of or hospitalization due to pneumonia in the past year.After adjusting with all the other KCL categories and covariates, the lower and lowest IADL (≥ 1 and ≥ 2 KCL questions were applicable) were negatively associated with the occurrence of pneumonia (PR 0.90, 95% CI [0.84-0.97],p < 0.01 and PR 0.79, 95% CI [0.72-0.86],p< 0.001, respectively) and the lowest was associated with hospitalization in older adults (PR 1.24, 95% CI [1.01-1.53],p < 0.05).The lowest physical strength was associated with both occurrence of and hospitalization due to pneumonia in older adults (PR 1.12, 95% CI [1.03-1.22]and PR 1.32, 95% CI [1.07-1.64]),respectively, p < 0.01 for the both).The lower nutrition status was associated with both occurrence of and hospitalization due to pneumonia (PR 1.09, 95% CI [1.004-1.14],p < 0.05 and PR 1.54, 95% CI [1.30-1.82],p < 0.001, respectively), and the lowest was associated only with hospitalization in older adults (PR 1.71, 95% CI [1.25 − 2.34], p < 0.01).The lower and lowest oral function were associated with the occurrence of pneumonia in older adults (PR 1.

Table 4
Prevalence ratios (PR) and 95% con dence intervals (95% CIs) of associations between the occurrence of/hospitalization due to pneumonia and each of the KCL categories in community-dwelling older adults The KCL and other variables were inputs for the multilevel Poisson regression with random intercepts.Numbers in KCL scores represent how many questions were applicable to older adults.*p < 0.05, **p < 0.01, ***p < 0.001 IADL, instrumental activity of daily living; KCL, Kihon checklist.