Abstract
Background
Pneumonia is common among older adults and often recurrent. Several studies have been conducted on the risk factors for pneumonia; however, little is known about the risk factors for recurrent pneumonia. This study aimed to identify the risk factors for developing recurrent pneumonia among older adults and to investigate methods of prevention.
Methods
We analysed the data of 256 patients aged 75 years or older who were admitted for pneumonia between June 2014 and May 2017. Moreover, we reviewed the medical records for the subsequent 3 years and defined the readmission caused by pneumonia as recurrent pneumonia. Risk factors for recurrent pneumonia were analysed using multivariable logistic regression analysis. Differences in the recurrence rate based on the types and use of hypnotics were also evaluated.
Results
Of the 256 patients, 90 (35.2%) experienced recurrent pneumonia. A low body mass index (OR: 0.91; 95% CI: 0.83‒0.99), history of pneumonia (OR: 2.71; 95% CI: 1.23‒6.13), lung disease as a comorbidity (OR: 4.73; 95% CI: 2.13‒11.60), taking hypnotics (OR: 2.16; 95% CI: 1.18‒4.01) and taking histamine-1 receptor antagonist (H1RA) (OR: 2.38; 95% CI: 1.07‒5.39) were risk factors. Patients taking benzodiazepine as hypnotics were more likely to experience recurrent pneumonia than patients not taking hypnotics (OR: 2.29; 95% CI: 1.25–4.18).
Conclusion
We identified several risk factors for recurrent pneumonia. Among them, restricting the use of H1RA and hypnotics, in particular benzodiazepines, may be useful in preventing the recurrence of pneumonia in adults aged 75 years or older.
Short abstract
Methods for preventing recurrent pneumonia in older adults are limited. This study shows that avoiding the use of benzodiazepine hypnotics and histamine 1 receptor antagonists could help prevent recurrence of pneumonia in adults aged ≥75 years. https://bit.ly/403Nsuu
Introduction
In recent decades, pneumonia has been a major cause of death globally [1]. An increase in the number of patients with pneumonia is a serious issue, especially in super-aging societies such as Japan, because the morbidity of pneumonia increases with age in adults [2, 3]. Additionally, hospitalisation and treatment for pneumonia lead to a marked decline in physical function, especially in patients aged 75 years or older [4]. Admissions for pneumonia cases also lead to an increase in social welfare costs. Thus, the prevention and treatment of pneumonia in older adults is vital for improving the quality of life of people.
Pneumococcal vaccination and oral care for older adults are effective in preventing pneumonia [5–7]; however, pneumonia is still prevalent, in spite of these preventive measures. Moreover, patients that have previously developed pneumonia are likely to have a recurrence [8, 9], which increases proportionally with age [8, 10]. There have been many studies on the risk factors for the initial episode of pneumonia [10]; however, only a few studies have assessed the risk factors for recurrent pneumonia [9–11]. Moreover, to our knowledge, no reports have been published on the risk factors for recurrent pneumonia using cohorts limited to patients aged 75 years or older, which are a critical issue in clinical practice. In previous studies, recurrent pneumonia has been defined as pneumonia within a few years of the initial episode of pneumonia [10, 12]. Only a few risk factors for developing recurrent pneumonia have been identified. These include chronic lung disease, decreased swallowing function and the use of inhaled corticosteroids (ICS) [9–11]. Hypnotics and sedatives have also been reported to be associated with aspiration and the development of recurrent pneumonia [9, 11]; however, the results are inconsistent between studies. In addition, the specific types of hypnotics that are associated with recurrent pneumonia are unknown. As medication change is relatively easy for clinicians to implement among the limited preventive measures available for recurrent pneumonia in older patients, it is important to clarify the role of hypnotics in increasing the risk of recurrent pneumonia among older patients.
We hypothesised that hypnotics and histamine-1 receptor antagonists (H1RA), which also have a sedative effect, are risk factors for developing recurrent pneumonia among patients aged 75 years or older. In this study, we retrospectively reviewed the records of patients aged 75 years or older with recurrent pneumonia, and attempted to determine the risk factors for developing recurrent pneumonia, with a particular focus on these medications.
Materials and methods
Study participants
We retrieved the medical records of patients aged 75 years or older who were admitted to the Department of Respiratory Medicine of our hospital (an 819-bed acute care general hospital in Tokyo, Japan) for pneumonia, including aspiration pneumonia, from June 2014 to May 2017. Pneumonia was defined as having relevant clinical and imaging findings on admission, and diagnosis of pneumonia by an attending physician. Medical records were retrospectively reviewed by respiratory physicians who confirmed that the overall clinical course was consistent with pneumonia. A total of 275 patients were enrolled in the study; however, 19 patients died during their first inpatient stay within this period and were excluded. The remaining 256 patients were included in this study. The study was approved by the local ethics committee of the Toranomon Hospital (approval number: #1960:2020/Feb.) The requirement for informed consent was waived owing to the retrospective nature of the study. This retrospective single-centre study was conducted following the amended Declaration of Helsinki.
Study design
This retrospective single-centre study determined the risk factors for developing recurrent pneumonia in patients aged 75 years or older and the association between the use of hypnotic agents and recurrent pneumonia.
Methods
The “inclusion day” was the day from June 2014 to May 2017 on which the patient was admitted due to the first episode of pneumonia. In addition, we used the records of patient visits to our hospital to follow-up patients for 3 years from the “inclusion day” to determine the incidence of recurrent pneumonia in the cohort, defined as readmission due to a new episode of pneumonia after a previous admission for pneumonia. We evaluated the risk factors for developing recurrent pneumonia.
We collected data on physical measurements, comorbidities, medical history and blood test results on the “inclusion day”. The patients who were admitted to our hospital because of pneumonia within the 3 years prior to the “inclusion day” were defined as having a history of pneumonia. Bacterial pathogens were identified by sputum culture or a urinary antigen test. We used the A-DROP scoring system to assess the severity of pneumonia, as recommended by the Japanese Respiratory Society (JRS). A-DROP is a simple modified version of the CURB-65 scoring system, which is advocated by the British Thoracic Society (BTS) [13], and these two systems are considered to correlate with 30-day mortality in patients with community-acquired pneumonia (CAP) [14]. A-DROP is a 6-point (0–5) scoring system that assesses the following parameters: age (male ≥70 years, female ≥75 years), dehydration (blood urea nitrogen ≥210 mg·L−1), respiratory failure (oxygen saturation measured by pulse oximetry ≤90% or arterial oxygen tension ≤60 mmHg), orientation disturbance and low blood pressure (systolic blood pressure ≤90 mmHg). The number of fulfilled items was scored, and patients with scores over 3 points were considered to have severe disease.
We classified pneumonia as CAP or nursing and healthcare-associated pneumonia (NHCAP). NHCAP is a concept established by the JRS conforming to the Japanese healthcare insurance system, including the nursing-care insurance system, and the Japanese population, which has many older adults who require nursing care or suffer from many complications [15]. Patients categorised as having NHCAP include not only patients who stay at care facilities or nursing homes and immunocompromised patients, but also older or disabled adults who live at home but need nursing care.
As a primary analysis, we examined the risk factors for recurrent pneumonia using data from the inclusion day. We divided the patients into two groups: with or without readmission due to recurrent pneumonia within the subsequent 3 years, and then compared patient characteristics, blood test results, severity, causative pathogens and comorbidities among the recurrent pneumonia and non-recurrent pneumonia groups. In addition, as further exploratory analysis, we examined the differences in risks according to the type of hypnotic agent used. We categorised the patients into four groups based on the type and uses of hypnotics and compared their readmission rates and times. Group 1: patients who did not take hypnotics; Group 2: patients who took a benzodiazepine as a hypnotic; Group 3: patients who took Z-drugs (zopiclone, eszopiclone, zaleplon and zolpidem) as a hypnotic but did not take a benzodiazepine as a hypnotic; and Group 4: patients who took hypnotics other than benzodiazepines or Z-drugs.
Statistical analysis
Categorical variables were compared between the two groups using the χ2 test, and continuous variables were compared using the Wilcoxon rank-sum test. Multivariable logistic regression analysis was conducted as a primary analysis to identify risk factors for recurrent pneumonia. In addition to the risk factors reported in previous studies [9–11], the use of medications which we hypothesised to be a risk factor for recurrent pneumonia was included in this analysis. The risk factors used in this analysis were predefined before statistic comparison of these two groups according to the results of previous studies and our hypothesis that hypnotics may be a risk factor for recurrent pneumonia. The following factors were considered: age, sex, body mass index (BMI), history of pneumonia, presence or absence of complications of lung disease, administration of H1RA, hypnotics, ICS and NHCAP. As a further exploratory analysis for evaluating the types of hypnotics used, the readmission rates and readmission times for pneumonia in each group were assessed. Subsequently, univariate logistic regression analyses were conducted to determine the risk of recurrent pneumonia according to type of hypnotics used. In addition, the survival time was analysed using the Kaplan–Meier method, and the risk of recurrent pneumonia according to the use of each candidate risk medication was assessed by comparing patients who did and did not use the medication, using the log-rank test. We reported a two-tailed p-value, and p-values <0.05 were considered to be statistically significant. All statistical analyses were performed using the R software version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria) and the JMP Pro software version 16 (SAS Institute Japan, Tokyo, Japan).
Results
Of the 256 patients, 90 (35.2%) were readmitted to our hospital in the 3 years following the “inclusion day” because of recurrent pneumonia (recurrent group) and 166 were not (non-recurrent group). The median follow-up period from the “inclusion day” was 29 months (893 days; range 4–1096 days). Of all the patients, 112 (43.8%) had visited our outpatient clinic for more than 3 years, of whom 44 belonged to the recurrent group. 55 patients (28 (21.5%) in the recurrent group) died within 3 years. Patient characteristics on the day of inclusion are summarised according to group in table 1. The values of BMI and serum C-reactive protein (CRP) on the inclusion day were lower in the recurrent group than in the non-recurrent group. The prevalence of patients with a history of pneumonia prior to the inclusion day was higher in the recurrent group than in the non-recurrent group (p=0.001). With regard to the age, sex, category and severity of pneumonia, there were no significant differences between the groups.
TABLE 1.
Patient characteristics on admission
| Characteristics | All patients | Recurrent pneumonia group | Non-recurrent pneumonia group | p-value |
| Patients n | 256 | 90 | 166 | |
| Age years | 82.0 (78.0–86.0) | 82.0 (78.0–84.8) | 82.0 (78.0–86.0) | 0.988 |
| Males | 160 (62.5) | 57 (63.3) | 103 (62.0) | 0.946 |
| BMI kg·m−2 | 20.6 (17.9–22.9) | 19.6 (17.4–22.0) | 21.0 (18.2–23.5) | 0.009 |
| Pneumonia type | 0.998 | |||
| CAP | 155 (60.5) | 55 (61.1) | 100 (60.2) | |
| NHCAP | 101 (39.5) | 35 (38.9) | 66 (39.8) | |
| A-DROP (score) | 0.146 | |||
| 1 | 94 (36.7) | 40 (44.4) | 54 (32.5) | |
| 2 | 111 (43.4) | 35 (38.9) | 76 (45.8) | |
| 3 | 39 (15.2) | 14 (15.6) | 25 (15.1) | |
| 4 | 9 (3.5) | 1 (1.1) | 8 (4.8) | |
| 5 | 3 (1.2) | 0 (0.0) | 3 (1.8) | |
| History of pneumonia | 36 (14.1) | 22 (24.4) | 14 (8.4) | 0.001 |
| Smoking history | 124 (51.7) | 47 (53.4) | 77 (50.7) | 0.782 |
| Blood test | ||||
| Alb g·dL−1 | 3.40 (3.08–3.70) | 3.45 (3.10–3.70) | 3.40 (3.00–3.70) | 0.341 |
| WBC per μL | 9200 (6975–11 725) | 9250 (7000–11 675) | 9150 (6925–11 725) | 0.746 |
| CRP mg·dL−1 | 6.10 (1.85–11.50) | 4.55 (1.12–9.25) | 6.70 (3.00–13.40) | 0.003 |
Data are presented as median (interquartile range) or n (%), unless indicated otherwise. BMI: body mass index; CAP: community-acquired pneumonia; NHCAP: nursing and healthcare-associated pneumonia; Alb: albumin; WBC: white blood cell; CRP: C-reactive protein.
Complications and medications used in these patients are presented in table 2. A higher percentage of patients in the recurrent group had lung disease as a comorbidity (90.0%) compared to the non-recurrent group (64.5%) (p<0.001), although lung disease was common among both groups. Regarding medication use, the number of patients who took hypnotics was higher in the recurrent group (38.9% versus 21.7%; p=0.005). Most patients (95.8%) who used hypnotics took either a benzodiazepine or a Z-drug. The incidence of H1RA use was also higher in the recurrent group (20.0% versus 10.2%; p=0.048). There was no significant difference in the bacterial pathogens between groups (supplementary table S1).
TABLE 2.
Comorbidities and medication use in patients with recurrent and non-recurrent pneumonia
| Characteristics | All patients | Recurrent group | Non-recurrent group | p-value |
| Patients n | 256 | 90 | 166 | |
| Comorbidities | ||||
| Lung disease | 188 (73.4) | 81 (90.0) | 107 (64.5) | <0.001 |
| Surgical history | 42 (16.4) | 17 (18.9) | 25 (15.1) | 0.54 |
| Interstitial pneumonia | 54 (21.1) | 23 (25.6) | 31 (18.7) | 0.259 |
| COPD or emphysema | 54 (21.1) | 23 (25.6) | 31 (18.7) | 0.259 |
| Lung cancer | 36 (14.1) | 16 (17.8) | 20 (12.0) | 0.284 |
| Bronchial asthma | 34 (13.3) | 15 (16.7) | 19 (11.4) | 0.326 |
| NTM | 23 (9.0) | 13 (14.4) | 10 (6.0) | 0.043 |
| Tuberculosis | 26 (10.2) | 15 (16.7) | 11 (6.6) | 0.02 |
| Pulmonary aspergillosis | 4 (1.6) | 2 (2.2) | 2 (1.2) | 0.921 |
| Bronchiectasis | 19 (7.4) | 10 (11.1) | 9 (5.4) | 0.159 |
| Other than lung disease | ||||
| Parkinson's syndrome | 5 (2.0) | 3 (3.3) | 2 (1.2) | 0.483 |
| Dementia | 27 (10.5) | 10 (11.1) | 17 (10.2) | 0.997 |
| Cerebrovascular disease | 26 (10.2) | 9 (10.0) | 17 (10.2) | >0.999 |
| Gastrointestinal surgery | 48 (18.8) | 23 (25.6) | 25 (15.1) | 0.059 |
| Diabetes | 55 (21.5) | 14 (15.6) | 41 (24.7) | 0.123 |
| Dialysis | 3 (1.2) | 1 (1.1) | 2 (1.2) | >0.999 |
| Viral hepatitis | 16 (6.3) | 7 (7.8) | 9 (5.4) | 0.636 |
| Medication | ||||
| Six or more medications | 162 (63.3) | 63 (70.0) | 99 (59.6) | 0.132 |
| Inhaled steroids | 53 (20.7) | 25 (27.8) | 28 (16.9) | 0.058 |
| Antihistamine | 58 (22.7) | 29 (32.2) | 29 (17.5) | 0.011 |
| H1 receptor antagonist | 35 (13.7) | 18 (20.0) | 17 (10.2) | 0.048 |
| H2 receptor antagonist | 26 (10.2) | 13 (14.4) | 13 (7.8) | 0.145 |
| Hypnotic | 71 (27.7) | 35 (38.9) | 36 (21.7) | 0.005 |
| Benzodiazepines | 59 (23.0) | 29 (32.2) | 30 (18.1) | 0.016 |
| Z-drugs | 15 (5.9) | 6 (6.7) | 9 (5.4) | 0.9 |
| Benzodiazepines or Z-drugs# | 68 (26.6) | 34 (37.8) | 34 (20.5) | 0.004 |
Data are presented as n (%), unless otherwise indicated. H1: histamine 1; H2: histamine 2; NTM: nontuberculous mycobacteria. #: six patients used both benzodiazepine and Z-drug.
The multivariable analysis for evaluating the risk of recurrent pneumonia showed that low BMI (OR: 0.91; 95% CI: 0.83–0.99), history of pneumonia prior to the inclusion day (OR: 2.71; 95% CI: 1.23–6.13), lung disease as a comorbidity (OR: 4.73; 95% CI: 2.13–11.60), use of H1RA (OR: 2.38; 95% CI: 1.07–5.39) and hypnotics (OR: 2.16; 95% CI: 1.18–4.01) were independent risk factors for recurrent pneumonia (table 3).
TABLE 3.
Multivariable logistic regression analysis of risk factors for recurrent pneumonia
| Variables | Adjusted OR (95% CI) | p-value |
| Age years | 1.02 (0.96‒1.08) | 0.473 |
| Male | 1.05 (0.58‒1.92) | 0.874 |
| BMI | 0.91 (0.83‒0.99) | 0.025 |
| History of pneumonia | 2.71 (1.23‒6.13) | 0.014 |
| Lung disease | 4.73 (2.13‒11.60) | <0.001 |
| H1RA | 2.38 (1.07‒5.39) | 0.034 |
| Hypnotic | 2.16 (1.18‒4.01) | 0.013 |
| ICS | 1.31 (0.66‒2.61) | 0.437 |
| NHCAP | 0.87 (0.47‒1.61) | 0.658 |
BMI: body mass index; H1RA: histamine 1 receptor antagonist; ICS: inhaled corticosteroid; NHCAP: nursing and healthcare-associated pneumonia.
A stratified analysis according to the type of hypnotic used revealed a difference in the risk of recurrence pneumonia according to the type of hypnotic used (tables 4–7). Of the 256 patients analysed, 185 (72.3%) did not use any hypnotics. Of the remaining 71 patients, 59 (23.0%) took a benzodiazepine as a hypnotic (table 4). Clinical characteristics and the rate of pneumonia recurrence in each group are summarised in tables 5 and 6. The risk of recurrent pneumonia was evaluated using Group 1 (non-users) as the reference group. Patients in Group 2 (benzodiazepine users) were more likely to experience recurrent pneumonia (OR: 2.29; 95% CI: 1.25–4.18). However, the risk of recurrent pneumonia in Group 3 (Z-drug users) (OR: 2.96; 95% CI: 0.76–12.33) and Group 4 (other hypnotic users) (OR: 1.18; 95% CI: 0.054–12.58) did not differ significantly from non-hypnotic users (table 7). There was no significant difference in survival time with or without use of each medication, including H1RA, H2RA, benzodiazepines and Z-drugs (supplementary figure S1).
TABLE 4.
Grouping according to type of hypnotic
| Benzodiazepines | Z-drug | Others | n | ||
| Ramelteon | Suvorexant | ||||
| Patients n | 59 | 15 | 4 | 1 | |
| Group 2 | + | + | − | − | 6 |
| Group 2 | + | − | + | − | 1 |
| Group 2 | + | − | − | − | 52 |
| Group 3 | − | + | − | + | 1 |
| Group 3 | − | + | − | − | 8 |
| Group 4 | − | − | + | − | 3 |
Group 2: patients taking benzodiazepines as hypnotics; Group 3: patients taking Z-drugs as hypnotics but not benzodiazepines; Group 4: patients taking other types of hypnotics.
TABLE 7.
Odds ratio of recurrent pneumonia for each group
| OR (95% CI) | p-value | |
| Group 1 | Ref. | |
| Group 2 | 2.29 (1.25‒4.18) | 0.007 |
| Group 3 | 2.96 (0.76‒12.33) | 0.116 |
| Group 4 | 1.18 (0.054‒12.58) | 0.892 |
Group 1: patients not taking any hypnotics; Group 2: patients taking benzodiazepines as hypnotics; Group 3: patients taking Z-drugs as hypnotics but not benzodiazepines; Group 4: patients taking other types of hypnotics.
TABLE 5.
Characteristics of the participants in each group
| Group | ||||
| 1 | 2 | 3 | 4 | |
| Patients n | 185 | 59 | 9 | 3 |
| Age years | 82.0 (78.0–85.0) | 82.0 (78.0–85.5) | 87.0 (79.0–88.0) | 88.0 (82.0–90.0) |
| Males | 119 (64.3) | 35 (59.3) | 4 (44.4) | 2 (66.7) |
| BMI kg·m−2 | 20.7 (17.9–23.0) | 20.0 (17.7–23.0) | 18.8 (18.4–21.5) | 18.7 (18.6–20.3) |
| CAP | 112 (60.5) | 38 (64.4) | 5 (55.6) | 0 (0.0) |
| NHCAP | 73 (39.5) | 21 (35.6) | 4 (44.4) | 3 (100.0) |
| Comorbidity | ||||
| Lung disease | 130 (70.3) | 49 (83.1) | 7 (77.8) | 2 (66.7) |
| Parkinson's syndrome | 2 (1.1) | 3 (5.1) | 0 (0.0) | 0 (0.0) |
| Dementia | 21 (11.4) | 3 (5.1) | 1 (11.1) | 2 (66.7) |
| Cerebrovascular disease | 18 (9.7) | 7 (11.9) | 1 (11.1) | 0 (0.0) |
| Gastrointestinal surgery | 35 (18.9) | 11 (18.6) | 1 (11.1) | 1 (33.3) |
| Diabetes | 40 (21.6) | 12 (20.3) | 2 (22.2) | 1 (33.3) |
| Dialysis | 2 (1.1) | 1 (1.7) | 0 (0.0) | 0 (0.0) |
| Viral hepatitis | 13 (7.0) | 3 (5.1) | 0 (0.0) | 0 (0.0) |
| Blood test | ||||
| Alb g·dL−1 | 3.40 (3.10–3.70) | 3.60 (3.15–3.80) | 3.20 (3.10–3.80) | 2.80 (2.75–2.90) |
| WBC per μL | 9300 (6900–11 600) | 8700 (6850–11 700) | 8800 (8100–14 700) | 7700 (6800–13 600) |
| CRP mg·dL−1 | 6.30 (1.80–12.65) | 4.50 (1.85–10.30) | 2.60 (1.90–6.20) | 5.70 (5.35–8.75) |
Data are presented as n (%) or median (interquartile range), unless otherwise indicated. Group 1: patients not taking any hypnotics; Group 2: patients taking benzodiazepines as hypnotics; Group 3: patients taking Z-drugs as hypnotics but not benzodiazepines; Group 4: patients taking other types of hypnotics. BMI: body mass index; CAP: community-acquired pneumonia; NHCAP: nursing and healthcare-associated pneumonia; Alb: albumin; WBC: white blood cell; CRP: C-reactive protein.
TABLE 6.
Number of pneumonia admissions for each group during the 3-year follow-up period
| Group | ||||
| 1 | 2 | 3 | 4 | |
| Patients n | 185 | 59 | 9 | 3 |
| Recurrent | 55 (29.7) | 29 (49.2) | 5 (55.5) | 1 (33.3) |
| Number of pneumonia admissions | ||||
| 1 | 130 (70.3) | 30 (50.8) | 4 (44.4) | 2 (66.7) |
| 2 | 36 (19.5) | 16 (27.1) | 3 (33.3) | 1 (33.3) |
| 3 | 9 (4.9) | 5 (8.5) | 1 (11.1) | 0 (0.0) |
| 4 | 5 (2.7) | 3 (5.1) | 1 (11.1) | 0 (0.0) |
| 5 | 1 (0.5) | 2 (3.4) | 0 (0.0) | 0 (0.0) |
| 6 | 2 (1.1) | 1 (1.7) | 0 (0.0) | 0 (0.0) |
| 7 | 0 (0.0) | 1 (1.7) | 0 (0.0) | 0 (0.0) |
| 9 | 0 (0.0) | 1 (1.7) | 0 (0.0) | 0 (0.0) |
| 10 | 1 (0.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| 14 | 1 (0.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Data are presented as n (%), unless otherwise indicated. Group 1: patients not taking any hypnotics; Group 2: patients taking benzodiazepines as hypnotics; Group 3: patients taking Z-drugs as hypnotics but not benzodiazepines; Group 4: patients taking other types of hypnotics.
Discussion
In this study, 35.2% (90 patients) of the 256 patients had recurrent pneumonia within 3 years after the inclusion day. In recent studies, the rates of recurrent pneumonia among patients with CAP within 3–5 years have been estimated to be 9–12% [10]. In a previous study of the Japanese population, 16% of patients had a pneumonia recurrence within 1‒2 years [9]. In contrast to these other studies, this study was specific to older adults that were admitted to the respiratory department of our hospital. A cohort selection restricted to older patients might be representative of the real-world clinical setting in a super-aging society and might show a higher recurrence rate of pneumonia than previous reports.
Low BMI was an independent risk factor for recurrent pneumonia in our study. Low BMI is associated with the development of pneumonia, recurrence of pneumonia, prolonged hospital stay and mortality in patients with pneumonia [9, 16–18]. Low BMI is also associated with undernutrition, frailty and sarcopenia; therefore, it is important to pay attention not only to treating pneumonia, but also to improving nutritional status and increasing respiratory and swallowing muscle mass, especially among older patients.
Furthermore, lung disease was a risk factor in our study. Previous studies have reported that chronic lung disease is a risk factor for pneumonia [19–21], which is consistent with this study. Some patients in the recurrent group might have been hospitalised due to mild pneumonia owing to a decline in their general status, because this group had a significant higher prevalence of underlying lung disease. Therefore, this might explain the lower CRP level in the recurrent group than in the non-recurrent group.
Older adults often have comorbidities and tend to use many medications. Moreover, adverse drug events are common in older adults because of their decreased physiological function [22]. Medications therefore should be kept to a minimum as necessary. Benzodiazepines are considered potentially inappropriate medications (PIMs) for older people in many studies based on criteria of PIMs [23]. According to the American Geriatrics Society Beers Criteria 2019, benzodiazepines are identified as PIMs because of the increasing risk of adverse effects such as cognitive impairment, delirium, falls and fractures [24]. In addition, benzodiazepines reduce muscle tone during sleep. The criteria also state that Z-drugs should be avoided in older adults with delirium. In this study, we examined the relationship between the use of these medications and recurrent pneumonia among older adults. Our findings revealed that use of benzodiazepines as hypnotics was associated with a significantly greater risk of pneumonia recurrence. Insomnia is common in older people. Benzodiazepines, which produce a hypnotic effect by binding to the γ-aminobutyric acid (GABA) type A receptor, have been commonly prescribed for patients with insomnia; however, there are many concerns about some of their side-effects such as cognitive decline, dependence, withdrawal symptoms and falls [25–27]. Z-drugs (zopiclone, eszopiclone, zaleplon and zolpidem), which bind to GABA type A receptors but are non-benzodiazepines, were launched on the market in the 1990s and are considered safer than benzodiazepines. Since then, the use of Z-drugs has rapidly increased compared to the use of benzodiazepines in patients with insomnia in the USA [28, 29]. In Japan, the use of hypnotics, including Z-drugs, is very high, especially in older adults [30, 31].
Most studies reported that the use of benzodiazepines is a risk factor for pneumonia [32–35]. Z-drugs have also been reported to be a risk factor for pneumonia, especially among older adults [34, 35]; however, some studies have not found an association between Z-drug use and pneumonia [33, 36]. Differences in the study design, inclusion criteria (such as only patients with Alzheimer's disease) [33] and Z-drugs studies (some studies have included only zopiclone as a Z-drug) [36] may have resulted in the disparity between results. A study that showed Z-drugs to be a significant risk factor for pneumonia also showed that the risk of pneumonia is lower with Z-drugs than with benzodiazepines [35]. Our study showed that benzodiazepine use is an important risk factor for recurrent pneumonia, but survival after pneumonia did not differ significantly between patients who used benzodiazepines and those who did not. Further studies are needed to examine the differences in the effects of the benzodiazepines and Z-drugs on pneumonia and recurrent pneumonia. New types of hypnotics, including melatonin receptor agonists and orexin receptor antagonists, have recently been launched to the market. The use of these drugs is increasing, and the possibility of them being a risk factor for developing pneumonia is unknown. In this study, only a few patients used melatonin receptor agonists or orexin receptor antagonists. Thus, we were unable to evaluate the risk of recurrent pneumonia associated with this type of medication.
In many studies, antihistamines are considered PIMs [23]. In this study, only H1RA were related to recurrent pneumonia. H2RA is used to suppress gastric juice development. Previous studies have shown that proton pump inhibitors are associated with pneumonia due to alterations in the gut flora; however, H2RA do not significantly increase the risk of pneumonia [37, 38]. H1RA are used for their anti-allergic effects; however, it has not been established whether H1RA use is associated with an increased risk of pneumonia. H1RA causes drowsiness by influencing the central histamine neurons and causes dryness of the oral cavity [39, 40], which may lead to pneumonia, especially in older adults.
Our study had some limitations. First, this study was a retrospective, single-centre study. Hence, patients with pneumonia who were treated in an outpatient setting or at other facilities were not included in the analysis. Second, since many of the patients who were admitted to our department had underlying lung diseases as comorbidities, these results may not be representative of pneumonia patients in adults aged 75 years or older in the general population. Owing to the retrospective nature of this study, it was not possible to obtain information regarding vaccination status, swallowing function, dysphagia or the frailty index on the “inclusion day”. However, as mentioned in the Methods section, the NHCAP category contained the frail individuals with declined physical status receiving home-based care. Further investigations are required to address these limitations.
In conclusion, this study is valuable in that it evaluated the risks of developing recurrent pneumonia in adults aged 75 years or older. Whilst there are limited ways to prevent recurrent pneumonia in older patients, our study suggests that restricting the use of medications such as hypnotics, particularly benzodiazepines, and H1RA, in addition to interventions for undernutrition and low body weight, may help to reduce the risk of recurrent pneumonia.
Supplementary material
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Footnotes
Provenance: Submitted article, peer reviewed.
Conflict of interest: Authors have no conflict of interest to declare.
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