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Risk of developing pneumonia associated with clinically diagnosed hypothyroidism: a nationwide population-based cohort study

Risk of developing pneumonia associated with clinically diagnosed hypothyroidism: a nationwide... Abstract Background Hypothyroidism has a detrimental effect on the immune system, which may predispose patients to infection. However, evidence about the risk of developing either community- or hospital-acquired pneumonia in patients with hypothyroidism is scarce. Objective To evaluate the association between hypothyroidism and the risk of developing pneumonia. Methods This was a retrospective population-based cohort study from Taiwan’s National Health Insurance Research Database. After 1:1 propensity score matching, 9749 patients (age ≥20 years) newly diagnosed with hypothyroidism between 2001 and 2014 and 9749 patients without hypothyroidism or other thyroid diseases were included in the hypothyroidism and non-hypothyroidism cohorts, respectively, and followed up until 2015. The development of pneumonia was defined as the primary outcome. Cox proportional hazards regression models were used to calculate the hazard ratios (HRs) of developing pneumonia between hypothyroidism and non-hypothyroidism cohorts after adjusting for age, sex and baseline comorbidities. To evaluate whether thyroxine replacement therapy (TRT) modified the risk for pneumonia, we divided patients with hypothyroidism into subgroups: patients who received TRT and those who did not. Results Hypothyroidism was associated with a higher risk of pneumonia [adjusted HR (aHR) 1.38, 95% confidence interval (CI) 1.29–1.49, P < 0.001]. Patients with hypothyroidism who received TRT had a lower risk of pneumonia than patients who did not (aHR 0.85, 95% CI 0.76–0.93, P = 0.001). Similar results were obtained in the age- and sex-stratified analyses. Conclusions Clinically diagnosed hypothyroidism was independently associated with the risk of pneumonia. In patients with hypothyroidism, TRT was associated with a lower risk of pneumonia. Lay Summary Hypothyroidism has a detrimental effect on the immune system, which may predispose patients to infection. The risk factors for pneumonia include older age, chronic lung diseases and, most importantly, a decreased immune response against respiratory pathogens. However, evidence of the risk for pneumonia in patients with hypothyroidism is scarce. The high prevalence of hypothyroidism, high annual incidence rate of pneumonia and their interrelationship through the immune system emphasize the importance of understanding the association between the two diseases. This study aimed to determine whether patients diagnosed with hypothyroidism conferred a predisposition to the development of pneumonia. In this 15-year population-based retrospective cohort study, we found that patients clinically diagnosed with hypothyroidism might be at increased risk for the future development of pneumonia. Moreover, in patients with hypothyroidism, the risk of pneumonia may be reduced by thyroxine replacement treatment. Additional prospective cohort studies, which include thyroid function tests and a more accurate clinical diagnosis of pneumonia based on radiological findings, are needed to confirm the effects of hypothyroidism on the risk of developing pneumonia. Cohort studies, hypothyroidism, pneumonia, respiratory tract diseases, thyroid diseases, thyroxine Key Messages Hypothyroidism has a detrimental effect on the immune system. The association between hypothyroidism and pneumonia remains undetermined. Clinically diagnosed hypothyroidism was related to a higher risk of pneumonia. Thyroxine treatment attenuated the increased risk of pneumonia in hypothyroidism. Introduction Hypothyroidism is a common endocrine disorder that mainly affects the thyroid gland and decreases thyroid function (1). In adults, the aetiology of hypothyroidism is either a thyroid disease (primary hypothyroidism) or a hypothalamic–pituitary disease (central hypothyroidism). The commonest cause of clinically diagnosed hypothyroidism is autoimmune thyroiditis (2). The deficiency of the thyroid hormone can affect multiple body systems including the heart, blood vessels, bones and central nervous system, which may contribute to mortality in older adults (3–6). Moreover, hypothyroidism may have a detrimental effect on the immune system and subsequently make patients vulnerable to infection (7,8). Pneumonia is one of the most prevalent and fatal infectious diseases worldwide (9). Based on the site of infection acquisition, pneumonia is classified as either community-acquired pneumonia or hospital-acquired pneumonia (10). The risk factors for pneumonia include older age, chronic lung diseases and, most importantly, a decreased immune response against respiratory pathogens (11,12). The high prevalence of hypothyroidism (5% of the general population) and high annual incidence rate of pneumonia (2.6–13.4 per 1000 person-years) and their interrelationship through the immune system emphasize the importance of understanding the association between the two diseases (1,9). Few previous studies have assessed the association between thyroid status and pneumonia, and most of them were about low triiodothyronine (T3) syndrome. A low T3 level was a significant predictor for 30-day mortality in patients with community-acquired pneumonia (13). Patients with severe community-acquired pneumonia who required intensive care unit admission had lower free T3 levels (14); however, it may reflect early changes in thyroid function during severe illnesses, which limits the ability to draw causal inferences. Therefore, longitudinal research to evaluate whether clinically diagnosed hypothyroidism is a determining factor for the emergence of pneumonia might better capture the effect of this clinical disease on the susceptibility to pneumonia. To evaluate the association between hypothyroidism and the risk of developing pneumonia, we conducted a nationwide, population-based, retrospective cohort study to determine whether patients diagnosed with hypothyroidism conferred a predisposition to the development of pneumonia. Methods Data sources This nationwide population-based cohort study was conducted by using the data from the Longitudinal Health Insurance Database (LHID), a subdatabase of Taiwan’s National Health Insurance Research Database (NHIRD). The LHID contains the medical information of two million patients by using stratified random sampling from the entire population of Taiwan. First, persons whose personal data with repetitions, unknown sex, unknown date of birth, illogical age and unspecified region were removed before sampling. Second, the entire sampling population was categorized according to sex, age and region. Lastly, the number of samples was drawn proportionally from each category to reach the target number of two million people. Taiwan’s National Health Insurance (NHI) program was launched in 1995. The NHI covers more than 99% of the population of Taiwan (~23 million people) and has contracts with 97% of the hospitals and clinics in Taiwan (15). The LHID contains all medical claims records of the outpatient, inpatient and emergency department services. The diagnostic codes used in the LHID follow the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. We retrieved information on patient characteristics and medical details from the reimbursement claims data during 2000–15 in the LHID. To protect patient privacy and data security, the personal identifiers were encrypted before providing access to researchers by the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan. The need for informed consent was waived, as the study used anonymized data. This study was conducted in accordance with the World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. The study protocol was approved by the Institutional Review Board of Hualien Tzu Chi Hospital (IRB 108-126-C). Study populations and exposure The study population included a hypothyroidism cohort (exposed cohort) and a non-hypothyroidism cohort (comparison cohort). All adult individuals aged 20 years and older diagnosed with hypothyroidism between 2001 and 2014, based on the records in the LHID, were identified as the hypothyroidism cohort. The patients with hypothyroidism were defined as those who were clinically diagnosed with hypothyroidism (ICD-9-CM code: 244 and 245.2) on at least three separate occasions, regardless of inpatients or outpatient services, during the study period. Based on this definition, we included cases of clinically diagnosed hypothyroidism (including Hashimoto’s disease). Patients with low T3 syndrome could present euthyroid sick syndrome (ICD-9-CM code: 790.94) instead of hypothyroidism, and such cases were excluded in our analyses. Individuals with any diagnoses of thyroid disease (ICD-9-CM code: 193, 240–246) in 2000 were also excluded to increase the likelihood for the identification of newly diagnosed hypothyroidism. In addition, we excluded patients who were diagnosed with hyperthyroidism before the index date. The index date in the hypothyroidism cohort was defined as the date of the first hypothyroidism diagnosis. Similarly, the non-hypothyroidism cohort (comparison cohort) was selected from the LHID by conducting 1:1 propensity score matching. Before matching the non-hypothyroidism cohort, we excluded patients with diagnoses of hypothyroidism or any other thyroid disease (ICD-9-CM code: 193, 240–246) during the entire period that the database was in use (2000–15) to obtain an unexposed cohort without any clinically diagnosed thyroid diseases. In the non-hypothyroidism cohort, the index date of each individual was assigned as the same index date for each matched hypothyroidism case. Any patients with a diagnosis of pneumonia, which was the primary outcome of this study, before the index date were excluded. All patients began their follow-up from their respective index dates. To evaluate how thyroxine replacement therapy (TRT) influenced the pneumonia risk in patients with hypothyroidism, we subdivided the hypothyroidism cohort into the TRT and non-TRT groups. The patients in the TRT group were defined as those had received TRT for at least 30 days after a diagnosis of hypothyroidism during the follow-up period; therefore, patients who did not receive or received TRT for <30 days were included in the non-TRT group. Outcome measures and covariates The primary outcome was defined as the occurrence of pneumonia (including lung abscess or empyema; using ICD-9-CM code: 480–486, 510 and 513) during the follow-up period. The accuracy of the ICD-9-CM codes for diagnosing pneumonia has been validated previously in Taiwan by clinical investigators who independently reviewed the clinical information and imaging records for the selected study sample (16). All study subjects were followed from the index date until the occurrence of pneumonia, death or until 31 December 2015 (the last date in the research database). A pre-existing comorbidity was defined as a disease that was diagnosed by at least one inpatient or two outpatient services in the year prior to the index date. The baseline comorbidities and possible confounding factors (Table 1) were identified in accordance with their respective ICD-9-CM codes: diabetes mellitus (250), hypertension (401–405), hyperlipidaemia (272.0–272.4), coronary artery disease (410–414 and 429.2), congestive heart failure (428), cerebrovascular disease (430–438), dementia (290 and 331), epilepsy (345), Parkinson’s disease (332), chronic kidney disease (582–583, 585–586 and 588), chronic liver disease (571, 456.0–456.2 and 572.2–572.8), gastroesophageal reflux disease (530.11 and 530.81), malignancy (140–208 and 209.0–209.3), chronic obstructive pulmonary disease (490–496), asthma (493), pulmonary tuberculosis (011), upper respiratory tract infection (465.9). Table 1. Baseline characteristics of patients diagnosed with and without hypothyroidism after 1:1 propensity score matching (2001–14) Characteristics . Propensity score matching (1:1) . . . . Hypothyroidism . . . . Yes (n = 9749) . No (n = 9749) . SMD . Age, years (mean ± SD) 50.6 ± 15.5 51.7 ± 16.0 −0.07 Sex, female 7627 (78.2%) 7733 (79.3%) −0.03 Comorbidities  Diabetes mellitus 1209 (12.4%) 1299 (13.3%) −0.03  Hypertension 2332 (23.9%) 2516 (25.8%) −0.04  Hyperlipidaemia 1445 (14.8%) 1549 (15.9%) −0.03  CAD 839 (8.6%) 888 (9.1%) −0.02  CHF 238 (2.4%) 219 (2.2%) 0.01  CVD 492 (5.0%) 517 (5.3%) −0.01  Dementia 160 (1.6%) 199 (2.0%) −0.03  Epilepsy 79 (0.8%) 56 (0.6%) 0.03  PD 80 (0.8%) 79 (0.8%) 0.00  CKD 408 (4.2%) 385 (3.9%) 0.01  Chronic liver disease 701 (7.2%) 734 (7.5%) −0.01  GERD 341 (3.5%) 359 (3.7%) −0.01  Malignancy 928 (9.5%) 884 (9.1%) 0.02  COPD 556 (5.7%) 566 (5.8%) 0.00  Asthma 229 (2.3%) 217 (2.2%) 0.01  Pulmonary TB 21 (0.2%) 21 (0.2%) 0.00  Upper respiratory tract infection 2678 (27.5%) 2748 (28.2%) −0.02 Characteristics . Propensity score matching (1:1) . . . . Hypothyroidism . . . . Yes (n = 9749) . No (n = 9749) . SMD . Age, years (mean ± SD) 50.6 ± 15.5 51.7 ± 16.0 −0.07 Sex, female 7627 (78.2%) 7733 (79.3%) −0.03 Comorbidities  Diabetes mellitus 1209 (12.4%) 1299 (13.3%) −0.03  Hypertension 2332 (23.9%) 2516 (25.8%) −0.04  Hyperlipidaemia 1445 (14.8%) 1549 (15.9%) −0.03  CAD 839 (8.6%) 888 (9.1%) −0.02  CHF 238 (2.4%) 219 (2.2%) 0.01  CVD 492 (5.0%) 517 (5.3%) −0.01  Dementia 160 (1.6%) 199 (2.0%) −0.03  Epilepsy 79 (0.8%) 56 (0.6%) 0.03  PD 80 (0.8%) 79 (0.8%) 0.00  CKD 408 (4.2%) 385 (3.9%) 0.01  Chronic liver disease 701 (7.2%) 734 (7.5%) −0.01  GERD 341 (3.5%) 359 (3.7%) −0.01  Malignancy 928 (9.5%) 884 (9.1%) 0.02  COPD 556 (5.7%) 566 (5.8%) 0.00  Asthma 229 (2.3%) 217 (2.2%) 0.01  Pulmonary TB 21 (0.2%) 21 (0.2%) 0.00  Upper respiratory tract infection 2678 (27.5%) 2748 (28.2%) −0.02 Data are presented as mean ± SD or number (%). CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. Open in new tab Table 1. Baseline characteristics of patients diagnosed with and without hypothyroidism after 1:1 propensity score matching (2001–14) Characteristics . Propensity score matching (1:1) . . . . Hypothyroidism . . . . Yes (n = 9749) . No (n = 9749) . SMD . Age, years (mean ± SD) 50.6 ± 15.5 51.7 ± 16.0 −0.07 Sex, female 7627 (78.2%) 7733 (79.3%) −0.03 Comorbidities  Diabetes mellitus 1209 (12.4%) 1299 (13.3%) −0.03  Hypertension 2332 (23.9%) 2516 (25.8%) −0.04  Hyperlipidaemia 1445 (14.8%) 1549 (15.9%) −0.03  CAD 839 (8.6%) 888 (9.1%) −0.02  CHF 238 (2.4%) 219 (2.2%) 0.01  CVD 492 (5.0%) 517 (5.3%) −0.01  Dementia 160 (1.6%) 199 (2.0%) −0.03  Epilepsy 79 (0.8%) 56 (0.6%) 0.03  PD 80 (0.8%) 79 (0.8%) 0.00  CKD 408 (4.2%) 385 (3.9%) 0.01  Chronic liver disease 701 (7.2%) 734 (7.5%) −0.01  GERD 341 (3.5%) 359 (3.7%) −0.01  Malignancy 928 (9.5%) 884 (9.1%) 0.02  COPD 556 (5.7%) 566 (5.8%) 0.00  Asthma 229 (2.3%) 217 (2.2%) 0.01  Pulmonary TB 21 (0.2%) 21 (0.2%) 0.00  Upper respiratory tract infection 2678 (27.5%) 2748 (28.2%) −0.02 Characteristics . Propensity score matching (1:1) . . . . Hypothyroidism . . . . Yes (n = 9749) . No (n = 9749) . SMD . Age, years (mean ± SD) 50.6 ± 15.5 51.7 ± 16.0 −0.07 Sex, female 7627 (78.2%) 7733 (79.3%) −0.03 Comorbidities  Diabetes mellitus 1209 (12.4%) 1299 (13.3%) −0.03  Hypertension 2332 (23.9%) 2516 (25.8%) −0.04  Hyperlipidaemia 1445 (14.8%) 1549 (15.9%) −0.03  CAD 839 (8.6%) 888 (9.1%) −0.02  CHF 238 (2.4%) 219 (2.2%) 0.01  CVD 492 (5.0%) 517 (5.3%) −0.01  Dementia 160 (1.6%) 199 (2.0%) −0.03  Epilepsy 79 (0.8%) 56 (0.6%) 0.03  PD 80 (0.8%) 79 (0.8%) 0.00  CKD 408 (4.2%) 385 (3.9%) 0.01  Chronic liver disease 701 (7.2%) 734 (7.5%) −0.01  GERD 341 (3.5%) 359 (3.7%) −0.01  Malignancy 928 (9.5%) 884 (9.1%) 0.02  COPD 556 (5.7%) 566 (5.8%) 0.00  Asthma 229 (2.3%) 217 (2.2%) 0.01  Pulmonary TB 21 (0.2%) 21 (0.2%) 0.00  Upper respiratory tract infection 2678 (27.5%) 2748 (28.2%) −0.02 Data are presented as mean ± SD or number (%). CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. Open in new tab Propensity score matching We performed 1:1 propensity score matching to minimize the possibility of selection bias that was caused by differences in the baseline characteristics between the exposed and comparison cohorts. The propensity scores, which estimated the probability of a patient being diagnosed with hypothyroidism, were calculated by using logistic regression analyses adjusted for age, sex and baseline comorbidities. The propensity score matching was based on the nearest-neighbour matching method without replacement, with a caliper width equal to 0.2 of the standard deviation of the logit of the propensity score. Statistical analysis For sample-size calculation, with a relative hazard of 1.4 (the ratio of exposed/comparison cohort incidence rates) in 1:1 propensity score matching, a two-sided significance of 0.05, and a power of 0.8, a total of 277 events was required. Assuming a planned average 6-year follow-up duration with a baseline event rate of 0.03 for the comparison cohort and a censoring rate of 0.13 for both cohorts, a minimum of 2030 patients were required (17). We used the standardized mean difference (SMD) to measure the difference in baseline characteristics between the two cohorts (18), with a value <0.1 considered negligible. To evaluate the risk of pneumonia in patients with and without hypothyroidism, the cumulative incidence curves were estimated by Kaplan–Meier methods, and the differences between the curves were compared by using log-rank tests. We used univariable and multivariable Cox proportional hazards regression models to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of developing pneumonia. The multivariable regression models adjusted for age, sex and individually baseline comorbidities listed in Table 1. To evaluate whether the TRT and non-TRT groups in the hypothyroidism cohort had different risks for developing pneumonia compared with the non-hypothyroidism cohort, we performed an analysis to calculate the HRs for the TRT and non-TRT groups with the non-hypothyroidism cohort as the comparison group. Furthermore, we performed an analysis to evaluate whether the TRT and non-TRT groups in the hypothyroidism cohort had different risks for developing pneumonia. To test whether the duration of follow-up period influenced the result, we conducted a sensitivity analysis that included study population from 2001 to 2011 and used a standardized 4-year follow-up period to detect the pneumonia events. Furthermore, we analysed patient data stratified for age, sex and the years before and after the introduction of the pneumococcal polysaccharide vaccine (2001–07 and 2008–14) and checked interaction to determine whether patients with different characteristics altered outcomes. A two-sided probability value of <0.05 was considered statistically significant. Statistical analyses were performed using SAS 9.4 software (SAS Institute, Inc., Cary, NC). Results Demographics In the analyses that were conducted after 1:1 propensity score matching, a total of 19 498 patients were enrolled; 9749 patients with hypothyroidism (hypothyroidism cohort) were matched to 9749 controls without hypothyroidism (non-hypothyroidism cohort). All baseline characteristics were balanced well after propensity score matching, including age, sex and comorbidities (SMD <0.1) (Table 1). Risk of pneumonia in patients with and without hypothyroidism There were more pneumonia events in the hypothyroidism cohort than in the non-hypothyroidism cohorts [1775 (18.2%) versus 1329 (13.6%)]. Incidence rates in the hypothyroidism and non-hypothyroidism cohorts were 29.2 (1775 events with 60 735 person-years) and 21.3 (1329 events with 62 483 person-years) per 1000 person-years, respectively. In the comparisons that were undertaken after propensity score matching, the cumulative incidence curves showed that the incidence of pneumonia was higher in the hypothyroidism cohort than that in the non-hypothyroidism cohort (log-rank test, P < 0.001; Fig. 1a). The Cox proportional hazards regression models showed that hypothyroidism was significantly associated with a higher risk of developing pneumonia in both the univariable and multivariable regression models [crude HR 1.30, 95% CI 1.21–1.40, P < 0.001; adjusted HR (aHR) 1.38, 95% CI 1.29–1.49, P < 0.001; Table 2]. Table 2. Results of multivariable Cox proportional hazards regression models estimating the risk of incident pneumonia in patients diagnosed with and without hypothyroidism (2001–15) Factors . aHR (95% CI)a . P value . Hypothyroidism 1.38 (1.29–1.49) <0.001 Age, years  ≥65, compared with <65 2.36 (2.16–2.57) <0.001 Male, compared with female 1.29 (1.19–1.41) <0.001 Comorbidities  Diabetes mellitus 1.36 (1.23–1.50) <0.001  Hypertension 1.15 (1.05–1.26) 0.002  Hyperlipidaemia 0.93 (0.84–1.03) 0.15  CAD 1.21 (1.09–1.35) <0.001  CHF 1.42 (1.20–1.69) <0.001  CVD 1.53 (1.35–1.74) <0.001  Dementia 1.83 (1.53–2.19) <0.001  Epilepsy 1.60 (1.14–2.26) 0.007  PD 1.65 (1.27–2.14) <0.001  CKD 1.84 (1.60–2.10) <0.001  Chronic liver disease 1.01 (0.89–1.15) 0.85  GERD 1.13 (0.92–1.38) 0.24  Malignancy 1.67 (1.50–1.86) <0.001  COPD 1.59 (1.39–1.83) <0.001  Asthma 1.02 (0.82–1.26) 0.88  Pulmonary TB 1.59 (0.98–2.58) 0.06  Upper respiratory tract infection 1.16 (1.07–1.25) <0.001 Factors . aHR (95% CI)a . P value . Hypothyroidism 1.38 (1.29–1.49) <0.001 Age, years  ≥65, compared with <65 2.36 (2.16–2.57) <0.001 Male, compared with female 1.29 (1.19–1.41) <0.001 Comorbidities  Diabetes mellitus 1.36 (1.23–1.50) <0.001  Hypertension 1.15 (1.05–1.26) 0.002  Hyperlipidaemia 0.93 (0.84–1.03) 0.15  CAD 1.21 (1.09–1.35) <0.001  CHF 1.42 (1.20–1.69) <0.001  CVD 1.53 (1.35–1.74) <0.001  Dementia 1.83 (1.53–2.19) <0.001  Epilepsy 1.60 (1.14–2.26) 0.007  PD 1.65 (1.27–2.14) <0.001  CKD 1.84 (1.60–2.10) <0.001  Chronic liver disease 1.01 (0.89–1.15) 0.85  GERD 1.13 (0.92–1.38) 0.24  Malignancy 1.67 (1.50–1.86) <0.001  COPD 1.59 (1.39–1.83) <0.001  Asthma 1.02 (0.82–1.26) 0.88  Pulmonary TB 1.59 (0.98–2.58) 0.06  Upper respiratory tract infection 1.16 (1.07–1.25) <0.001 CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Table 2. Results of multivariable Cox proportional hazards regression models estimating the risk of incident pneumonia in patients diagnosed with and without hypothyroidism (2001–15) Factors . aHR (95% CI)a . P value . Hypothyroidism 1.38 (1.29–1.49) <0.001 Age, years  ≥65, compared with <65 2.36 (2.16–2.57) <0.001 Male, compared with female 1.29 (1.19–1.41) <0.001 Comorbidities  Diabetes mellitus 1.36 (1.23–1.50) <0.001  Hypertension 1.15 (1.05–1.26) 0.002  Hyperlipidaemia 0.93 (0.84–1.03) 0.15  CAD 1.21 (1.09–1.35) <0.001  CHF 1.42 (1.20–1.69) <0.001  CVD 1.53 (1.35–1.74) <0.001  Dementia 1.83 (1.53–2.19) <0.001  Epilepsy 1.60 (1.14–2.26) 0.007  PD 1.65 (1.27–2.14) <0.001  CKD 1.84 (1.60–2.10) <0.001  Chronic liver disease 1.01 (0.89–1.15) 0.85  GERD 1.13 (0.92–1.38) 0.24  Malignancy 1.67 (1.50–1.86) <0.001  COPD 1.59 (1.39–1.83) <0.001  Asthma 1.02 (0.82–1.26) 0.88  Pulmonary TB 1.59 (0.98–2.58) 0.06  Upper respiratory tract infection 1.16 (1.07–1.25) <0.001 Factors . aHR (95% CI)a . P value . Hypothyroidism 1.38 (1.29–1.49) <0.001 Age, years  ≥65, compared with <65 2.36 (2.16–2.57) <0.001 Male, compared with female 1.29 (1.19–1.41) <0.001 Comorbidities  Diabetes mellitus 1.36 (1.23–1.50) <0.001  Hypertension 1.15 (1.05–1.26) 0.002  Hyperlipidaemia 0.93 (0.84–1.03) 0.15  CAD 1.21 (1.09–1.35) <0.001  CHF 1.42 (1.20–1.69) <0.001  CVD 1.53 (1.35–1.74) <0.001  Dementia 1.83 (1.53–2.19) <0.001  Epilepsy 1.60 (1.14–2.26) 0.007  PD 1.65 (1.27–2.14) <0.001  CKD 1.84 (1.60–2.10) <0.001  Chronic liver disease 1.01 (0.89–1.15) 0.85  GERD 1.13 (0.92–1.38) 0.24  Malignancy 1.67 (1.50–1.86) <0.001  COPD 1.59 (1.39–1.83) <0.001  Asthma 1.02 (0.82–1.26) 0.88  Pulmonary TB 1.59 (0.98–2.58) 0.06  Upper respiratory tract infection 1.16 (1.07–1.25) <0.001 CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Figure 1. Open in new tabDownload slide Cumulative incidence curves of pneumonia in (a) patients with hypothyroidism versus patients without hypothyroidism and (b) patients with hypothyroidism who received TRT versus those who did not. Figure 1. Open in new tabDownload slide Cumulative incidence curves of pneumonia in (a) patients with hypothyroidism versus patients without hypothyroidism and (b) patients with hypothyroidism who received TRT versus those who did not. Sensitivity analysis using a standardized 4-year follow-up period revealed similar results. Patients with hypothyroidism had a significantly higher risk of pneumonia compared with those without hypothyroidism (crude HR 1.32, 95% CI 1.18–1.48, P < 0.001; aHR 1.41, 95% CI 1.26–1.58, P < 0.001; Supplementary Table 1). Risk of pneumonia in hypothyroidism with and without TRT Incidence rates in the TRT and non-TRT groups were 28.1 and 31.2 persons per 1000 person-years, respectively. Compared with the non-hypothyroidism cohort, we found an increased risk for pneumonia in the patients with hypothyroidism who were administered TRT (aHR 1.30, 95% CI 1.20–1.42, P < 0.001) and in those who did not receive TRT (aHR 1.54, 95% CI 1.40–1.69, P < 0.001) in multivariable analyses. The cumulative incidence curves showed that the incidence of pneumonia was higher in the non-TRT group than that in the TRT group (log-rank test, P < 0.001; Fig. 1b). The use of TRT was associated with a lower risk of pneumonia compared with no TRT (aHR 0.85, 95% CI 0.76–0.93, P = 0.001; Table 3). Table 3. Results of multivariable Cox proportional hazards regression models estimating the risk of incident pneumonia in patients diagnosed with hypothyroidism who did or did not receive TRT (2001–15) Factors . aHR (95% CI)a . P value . TRT, compared with non-TRT 0.85 (0.76–0.93) 0.001 Age, years  ≥65, compared with <65 2.42 (2.15–2.72) <0.001 Male, compared with female 1.30 (1.17–1.46) <0.001 Comorbidities  Diabetes mellitus 1.30 (1.13–1.49) <0.001  Hypertension 1.21 (1.08–1.36) 0.001  Hyperlipidaemia 0.89 (0.78–1.03) 0.11  CAD 1.20 (1.03–1.39) 0.02  CHF 1.46 (1.16–1.84) 0.001  CVD 1.56 (1.31–1.85) <0.001  Dementia 1.80 (1.39–2.33) <0.001  Epilepsy 2.04 (1.34–3.10) 0.001  PD 1.49 (1.01–2.19) 0.05  CKD 1.99 (1.66–2.37) <0.001  Chronic liver disease 1.15 (0.97–1.35) 0.11  GERD 1.06 (0.79–1.41) 0.71  Malignancy 1.70 (1.46–1.97) <0.001  COPD 1.38 (1.13–1.69) 0.002  Asthma 1.02 (0.75–1.39) 0.90  Pulmonary TB 2.20 (1.04–4.66) 0.04  Upper respiratory tract infection 1.16 (1.05–1.29) 0.004 Factors . aHR (95% CI)a . P value . TRT, compared with non-TRT 0.85 (0.76–0.93) 0.001 Age, years  ≥65, compared with <65 2.42 (2.15–2.72) <0.001 Male, compared with female 1.30 (1.17–1.46) <0.001 Comorbidities  Diabetes mellitus 1.30 (1.13–1.49) <0.001  Hypertension 1.21 (1.08–1.36) 0.001  Hyperlipidaemia 0.89 (0.78–1.03) 0.11  CAD 1.20 (1.03–1.39) 0.02  CHF 1.46 (1.16–1.84) 0.001  CVD 1.56 (1.31–1.85) <0.001  Dementia 1.80 (1.39–2.33) <0.001  Epilepsy 2.04 (1.34–3.10) 0.001  PD 1.49 (1.01–2.19) 0.05  CKD 1.99 (1.66–2.37) <0.001  Chronic liver disease 1.15 (0.97–1.35) 0.11  GERD 1.06 (0.79–1.41) 0.71  Malignancy 1.70 (1.46–1.97) <0.001  COPD 1.38 (1.13–1.69) 0.002  Asthma 1.02 (0.75–1.39) 0.90  Pulmonary TB 2.20 (1.04–4.66) 0.04  Upper respiratory tract infection 1.16 (1.05–1.29) 0.004 CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Table 3. Results of multivariable Cox proportional hazards regression models estimating the risk of incident pneumonia in patients diagnosed with hypothyroidism who did or did not receive TRT (2001–15) Factors . aHR (95% CI)a . P value . TRT, compared with non-TRT 0.85 (0.76–0.93) 0.001 Age, years  ≥65, compared with <65 2.42 (2.15–2.72) <0.001 Male, compared with female 1.30 (1.17–1.46) <0.001 Comorbidities  Diabetes mellitus 1.30 (1.13–1.49) <0.001  Hypertension 1.21 (1.08–1.36) 0.001  Hyperlipidaemia 0.89 (0.78–1.03) 0.11  CAD 1.20 (1.03–1.39) 0.02  CHF 1.46 (1.16–1.84) 0.001  CVD 1.56 (1.31–1.85) <0.001  Dementia 1.80 (1.39–2.33) <0.001  Epilepsy 2.04 (1.34–3.10) 0.001  PD 1.49 (1.01–2.19) 0.05  CKD 1.99 (1.66–2.37) <0.001  Chronic liver disease 1.15 (0.97–1.35) 0.11  GERD 1.06 (0.79–1.41) 0.71  Malignancy 1.70 (1.46–1.97) <0.001  COPD 1.38 (1.13–1.69) 0.002  Asthma 1.02 (0.75–1.39) 0.90  Pulmonary TB 2.20 (1.04–4.66) 0.04  Upper respiratory tract infection 1.16 (1.05–1.29) 0.004 Factors . aHR (95% CI)a . P value . TRT, compared with non-TRT 0.85 (0.76–0.93) 0.001 Age, years  ≥65, compared with <65 2.42 (2.15–2.72) <0.001 Male, compared with female 1.30 (1.17–1.46) <0.001 Comorbidities  Diabetes mellitus 1.30 (1.13–1.49) <0.001  Hypertension 1.21 (1.08–1.36) 0.001  Hyperlipidaemia 0.89 (0.78–1.03) 0.11  CAD 1.20 (1.03–1.39) 0.02  CHF 1.46 (1.16–1.84) 0.001  CVD 1.56 (1.31–1.85) <0.001  Dementia 1.80 (1.39–2.33) <0.001  Epilepsy 2.04 (1.34–3.10) 0.001  PD 1.49 (1.01–2.19) 0.05  CKD 1.99 (1.66–2.37) <0.001  Chronic liver disease 1.15 (0.97–1.35) 0.11  GERD 1.06 (0.79–1.41) 0.71  Malignancy 1.70 (1.46–1.97) <0.001  COPD 1.38 (1.13–1.69) 0.002  Asthma 1.02 (0.75–1.39) 0.90  Pulmonary TB 2.20 (1.04–4.66) 0.04  Upper respiratory tract infection 1.16 (1.05–1.29) 0.004 CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Sensitivity analysis using a standardized 4-year follow-up period revealed similar results. Among the patients with hypothyroidism, the TRT group had a significantly lower risk of pneumonia compared with those without TRT (aHR 0.81, 95% CI 0.69–0.94, P = 0.007; Supplementary Table 2). Analyses stratified by age, sex and the years before and after the introduction of pneumococcal polysaccharide vaccine In the age-stratified analyses, hypothyroidism was significantly associated with a higher risk of pneumonia in both the strata of younger and older patients (<65 years: aHR 1.34, 95% CI 1.22–1.48, P < 0.001; ≥65 years: aHR 1.39, 95% CI 1.24–1.55, P < 0.001). In sex-stratified analyses, patients with hypothyroidism had a significantly higher risk of pneumonia than the non-hypothyroidism cohort, regardless of their sex (male: aHR 1.46, 95% CI 1.27–1.67, P < 0.001; female: aHR 1.36, 95% CI 1.25–1.48, P < 0.001; Table 4). The stratified analysis using a shorter sampling period (2001–07 and 2008–14) before and after the introduction of the pneumococcal polysaccharide vaccine revealed similar results (2001–07: aHR 1.40, 95% CI 1.27–1.53, P < 0.001; 2008–14: aHR 1.37, 95% CI 1.21–1.54, P < 0.001; Table 4). All the P value for interactions showed no significant interactions. Table 4. Results of multivariable Cox proportional hazards regression models stratified by age, sex and the year before and after the introduction of the pneumococcal polysaccharide vaccine to estimate the risk of incident pneumonia in patients diagnosed with and without hypothyroidism (2001–15) Factors . Propensity score matching (1:1) . . P for interaction . . aHRa (95% CI) . P value . . Age, years 0.53  20–64 1.34 (1.22–1.48) <0.001  ≥65 1.39 (1.24–1.55) <0.001 Sex 0.53  Male 1.46 (1.27–1.67) <0.001  Female 1.36 (1.25–1.48) <0.001 Year 0.78  2001–07 1.40 (1.27–1.53) <0.001  2008–14 1.37 (1.21–1.54) <0.001 Factors . Propensity score matching (1:1) . . P for interaction . . aHRa (95% CI) . P value . . Age, years 0.53  20–64 1.34 (1.22–1.48) <0.001  ≥65 1.39 (1.24–1.55) <0.001 Sex 0.53  Male 1.46 (1.27–1.67) <0.001  Female 1.36 (1.25–1.48) <0.001 Year 0.78  2001–07 1.40 (1.27–1.53) <0.001  2008–14 1.37 (1.21–1.54) <0.001 aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Table 4. Results of multivariable Cox proportional hazards regression models stratified by age, sex and the year before and after the introduction of the pneumococcal polysaccharide vaccine to estimate the risk of incident pneumonia in patients diagnosed with and without hypothyroidism (2001–15) Factors . Propensity score matching (1:1) . . P for interaction . . aHRa (95% CI) . P value . . Age, years 0.53  20–64 1.34 (1.22–1.48) <0.001  ≥65 1.39 (1.24–1.55) <0.001 Sex 0.53  Male 1.46 (1.27–1.67) <0.001  Female 1.36 (1.25–1.48) <0.001 Year 0.78  2001–07 1.40 (1.27–1.53) <0.001  2008–14 1.37 (1.21–1.54) <0.001 Factors . Propensity score matching (1:1) . . P for interaction . . aHRa (95% CI) . P value . . Age, years 0.53  20–64 1.34 (1.22–1.48) <0.001  ≥65 1.39 (1.24–1.55) <0.001 Sex 0.53  Male 1.46 (1.27–1.67) <0.001  Female 1.36 (1.25–1.48) <0.001 Year 0.78  2001–07 1.40 (1.27–1.53) <0.001  2008–14 1.37 (1.21–1.54) <0.001 aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Discussion In this population-based retrospective cohort study, we found that hypothyroidism was an independent risk factor for developing pneumonia. Thyroxine treatment attenuated the increased risk of pneumonia associated with hypothyroidism. Thus, TRT may result in better physiological control of thyroid levels in the body, which conferred improved immune status (19). This study is the first to use a longitudinal approach to evaluate whether hypothyroidism is a determining factor for the emergence of pneumonia, and we confirmed that clinically diagnosed hypothyroidism is a significant factor that contributes to the development of pneumonia. The association between the low T3 syndrome and pneumonia has been assessed previously (13,14), but there are only a few studies that have examined the association between hypothyroidism and pneumonia. In a study among patients with primary total knee arthroplasty, hypothyroidism was associated with a significantly higher risk of postoperative pneumonia than that in the matched controls (20). Another cohort study, which evaluated the risk of heart failure after community-acquired pneumonia, showed that patients with pneumonia had a higher prevalence of baseline hypothyroidism that those without pneumonia (21). Both of the above-mentioned studies mainly explored the relationship between other diseases and pneumonia, wherein the association between pneumonia and thyroid function was incidentally identified. Therefore, the association between hypothyroidism and pneumonia risk can be more accurately explored through well-designed research. The underlying mechanism that leads to pneumonia in hypothyroidism may be the impaired immune function. Thyroid hormones have shown an immunomodulatory property in response to environmental changes or stress (19). Patients with hypothyroidism may have abnormal lymphocyte function and decreased natural killer cell activity (7), which possibly makes it more difficult for them to eradicate pathogens and confers susceptibility to infection. The use of TRT may improve lymphocyte function by restoring the patients with hypothyroidism to a euthyroid status (22). Moreover, thyroxine supplementation of thyroxine has been shown to enhance bacterial clearance and promote survival (23). There were several possible reasons why TRT only partially attenuated the increased risk of pneumonia: first, hypothyroidism required long-term treatment; second, a previous study reported that even if patients received thyroxine treatment to restore normal thyroid function, they may manifest some symptoms of organ damage (24); finally, although the patients were treated with thyroxine, we could not confirm whether the patients with hypothyroidism were treated to regain an appropriate level of thyroid function. Over- and under-treatment of hypothyroidism may lead to a poor prognosis (25). Therefore, TRT may be used to restore thyroid function to decrease the pneumonia risk with close monitoring of the thyroid level. The strengths of this study included its nationwide, population-based study design, which could trace nearly all cases of hypothyroidism and subsequent pneumonia in Taiwan because the national insurance system covers all clinical practice establishments for endocrine and infectious diseases. However, this study had some limitations. First, the diagnoses of hypothyroidism and pneumonia that rely on the ICD-9-CM may be less accurate than diagnoses in a clinical, prospective study. The primary outcome included community- and hospital-acquired pneumonia, but we could not distinguish between them from the ICD-9-CM codes. Potential information biases might have been introduced because of misclassifications based on the ICD-9-CM diagnosis codes in the LHID. Due to the anonymization of patient data, we could not obtain information on laboratory examination (e.g. thyroid function) or imaging data for pneumonia from the LHID; thus, we could not confirm the exact thyroid status, distinguish the overt and subclinical hypothyroidism or confirm the pneumonia diagnosis by radiological evidence. However, we have attempted to mitigate this limitation by restricting our definition of hypothyroidism to diagnoses on at least three separate occasions, regardless of inpatient or outpatient services. In addition, a previous study reported that a diagnosis of pneumonia based on the ICD-9-CM codes in the LHID has high accuracy and validity (16). Second, there was no information on the physiological thyroid function between those who were treated and those who were not treated to determine whether a reduced risk was associated with physiological control of hypothyroidism. Lastly, we could not obtain information from the LHID on potential confounding factors (e.g. body mass index and lifestyle factors such as smoking history), whereby a bias related to unknown or unmeasured confounders might exist. Nonetheless, some health consequences would, at least in part, be reflected and adjusted in the presentation of the baseline comorbidities (e.g. smoking and chronic obstructive pulmonary disease; high body mass index and diabetes). Conclusions In summary, this population-based retrospective cohort study revealed that patients clinically diagnosed with hypothyroidism might be at increased risk for the future development of pneumonia. Moreover, in patients with hypothyroidism, the risk of pneumonia may be reduced by thyroxine replacement treatment. Additional prospective cohort studies, which include thyroid function tests and a more accurate clinical diagnosis of pneumonia based on radiological findings, are needed to confirm the effects of hypothyroidism and TRT on the risk of developing pneumonia. Acknowledgements The authors would like to thank the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan, for maintaining and processing the database, and the Health and Welfare Data Science Center of Tzu Chi University for providing administrative, technical and funding support. Declaration Funding: this work was supported by the Hualien Tzu Chi Hospital (TCRD-108-05) and the Health and Welfare Data Science Center of Tzu Chi University. The study sponsors were not involved in the design, conduct, analysis or reporting of this work. Ethical approval: the study protocol was approved by the Institutional Review Board of Hualien Tzu Chi Hospital (IRB 108-126-C). Conflict of interest: there are no conflicts of interest to declare. Data availability The data underlying this article were provided by Health and Welfare Data Science Center by permission. Data will be shared on request to the corresponding author with permission of Health and Welfare Data Science Center. References 1. Chiovato L , Magri F, Carlé A. Hypothyroidism in context: where we’ve been and where we’re going . Adv Ther 2019 ; 36 ( suppl 2 ): 47 – 58 . Google Scholar Crossref Search ADS PubMed WorldCat 2. Kostoglou-Athanassiou I , Ntalles K. Hypothyroidism—new aspects of an old disease . Hippokratia 2010 ; 14 ( 2 ): 82 – 7 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 3. Deegan RJ , Furman WR. Cardiovascular manifestations of endocrine dysfunction . J Cardiothorac Vasc Anesth 2011 ; 25 ( 4 ): 705 – 20 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Tuchendler D , Bolanowski M. The influence of thyroid dysfunction on bone metabolism . 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Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2021. Published by Oxford University Press. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Family Practice Oxford University Press

Risk of developing pneumonia associated with clinically diagnosed hypothyroidism: a nationwide population-based cohort study

Huang, Huei-Kai; Wang, Jen-Hung; Kao, Sheng-Lun
Family Practice , Volume Advance Article – Apr 27, 2021
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Oxford University Press
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Copyright © 2021 Oxford University Press
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0263-2136
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DOI
10.1093/fampra/cmab027
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Abstract

Abstract Background Hypothyroidism has a detrimental effect on the immune system, which may predispose patients to infection. However, evidence about the risk of developing either community- or hospital-acquired pneumonia in patients with hypothyroidism is scarce. Objective To evaluate the association between hypothyroidism and the risk of developing pneumonia. Methods This was a retrospective population-based cohort study from Taiwan’s National Health Insurance Research Database. After 1:1 propensity score matching, 9749 patients (age ≥20 years) newly diagnosed with hypothyroidism between 2001 and 2014 and 9749 patients without hypothyroidism or other thyroid diseases were included in the hypothyroidism and non-hypothyroidism cohorts, respectively, and followed up until 2015. The development of pneumonia was defined as the primary outcome. Cox proportional hazards regression models were used to calculate the hazard ratios (HRs) of developing pneumonia between hypothyroidism and non-hypothyroidism cohorts after adjusting for age, sex and baseline comorbidities. To evaluate whether thyroxine replacement therapy (TRT) modified the risk for pneumonia, we divided patients with hypothyroidism into subgroups: patients who received TRT and those who did not. Results Hypothyroidism was associated with a higher risk of pneumonia [adjusted HR (aHR) 1.38, 95% confidence interval (CI) 1.29–1.49, P < 0.001]. Patients with hypothyroidism who received TRT had a lower risk of pneumonia than patients who did not (aHR 0.85, 95% CI 0.76–0.93, P = 0.001). Similar results were obtained in the age- and sex-stratified analyses. Conclusions Clinically diagnosed hypothyroidism was independently associated with the risk of pneumonia. In patients with hypothyroidism, TRT was associated with a lower risk of pneumonia. Lay Summary Hypothyroidism has a detrimental effect on the immune system, which may predispose patients to infection. The risk factors for pneumonia include older age, chronic lung diseases and, most importantly, a decreased immune response against respiratory pathogens. However, evidence of the risk for pneumonia in patients with hypothyroidism is scarce. The high prevalence of hypothyroidism, high annual incidence rate of pneumonia and their interrelationship through the immune system emphasize the importance of understanding the association between the two diseases. This study aimed to determine whether patients diagnosed with hypothyroidism conferred a predisposition to the development of pneumonia. In this 15-year population-based retrospective cohort study, we found that patients clinically diagnosed with hypothyroidism might be at increased risk for the future development of pneumonia. Moreover, in patients with hypothyroidism, the risk of pneumonia may be reduced by thyroxine replacement treatment. Additional prospective cohort studies, which include thyroid function tests and a more accurate clinical diagnosis of pneumonia based on radiological findings, are needed to confirm the effects of hypothyroidism on the risk of developing pneumonia. Cohort studies, hypothyroidism, pneumonia, respiratory tract diseases, thyroid diseases, thyroxine Key Messages Hypothyroidism has a detrimental effect on the immune system. The association between hypothyroidism and pneumonia remains undetermined. Clinically diagnosed hypothyroidism was related to a higher risk of pneumonia. Thyroxine treatment attenuated the increased risk of pneumonia in hypothyroidism. Introduction Hypothyroidism is a common endocrine disorder that mainly affects the thyroid gland and decreases thyroid function (1). In adults, the aetiology of hypothyroidism is either a thyroid disease (primary hypothyroidism) or a hypothalamic–pituitary disease (central hypothyroidism). The commonest cause of clinically diagnosed hypothyroidism is autoimmune thyroiditis (2). The deficiency of the thyroid hormone can affect multiple body systems including the heart, blood vessels, bones and central nervous system, which may contribute to mortality in older adults (3–6). Moreover, hypothyroidism may have a detrimental effect on the immune system and subsequently make patients vulnerable to infection (7,8). Pneumonia is one of the most prevalent and fatal infectious diseases worldwide (9). Based on the site of infection acquisition, pneumonia is classified as either community-acquired pneumonia or hospital-acquired pneumonia (10). The risk factors for pneumonia include older age, chronic lung diseases and, most importantly, a decreased immune response against respiratory pathogens (11,12). The high prevalence of hypothyroidism (5% of the general population) and high annual incidence rate of pneumonia (2.6–13.4 per 1000 person-years) and their interrelationship through the immune system emphasize the importance of understanding the association between the two diseases (1,9). Few previous studies have assessed the association between thyroid status and pneumonia, and most of them were about low triiodothyronine (T3) syndrome. A low T3 level was a significant predictor for 30-day mortality in patients with community-acquired pneumonia (13). Patients with severe community-acquired pneumonia who required intensive care unit admission had lower free T3 levels (14); however, it may reflect early changes in thyroid function during severe illnesses, which limits the ability to draw causal inferences. Therefore, longitudinal research to evaluate whether clinically diagnosed hypothyroidism is a determining factor for the emergence of pneumonia might better capture the effect of this clinical disease on the susceptibility to pneumonia. To evaluate the association between hypothyroidism and the risk of developing pneumonia, we conducted a nationwide, population-based, retrospective cohort study to determine whether patients diagnosed with hypothyroidism conferred a predisposition to the development of pneumonia. Methods Data sources This nationwide population-based cohort study was conducted by using the data from the Longitudinal Health Insurance Database (LHID), a subdatabase of Taiwan’s National Health Insurance Research Database (NHIRD). The LHID contains the medical information of two million patients by using stratified random sampling from the entire population of Taiwan. First, persons whose personal data with repetitions, unknown sex, unknown date of birth, illogical age and unspecified region were removed before sampling. Second, the entire sampling population was categorized according to sex, age and region. Lastly, the number of samples was drawn proportionally from each category to reach the target number of two million people. Taiwan’s National Health Insurance (NHI) program was launched in 1995. The NHI covers more than 99% of the population of Taiwan (~23 million people) and has contracts with 97% of the hospitals and clinics in Taiwan (15). The LHID contains all medical claims records of the outpatient, inpatient and emergency department services. The diagnostic codes used in the LHID follow the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. We retrieved information on patient characteristics and medical details from the reimbursement claims data during 2000–15 in the LHID. To protect patient privacy and data security, the personal identifiers were encrypted before providing access to researchers by the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan. The need for informed consent was waived, as the study used anonymized data. This study was conducted in accordance with the World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. The study protocol was approved by the Institutional Review Board of Hualien Tzu Chi Hospital (IRB 108-126-C). Study populations and exposure The study population included a hypothyroidism cohort (exposed cohort) and a non-hypothyroidism cohort (comparison cohort). All adult individuals aged 20 years and older diagnosed with hypothyroidism between 2001 and 2014, based on the records in the LHID, were identified as the hypothyroidism cohort. The patients with hypothyroidism were defined as those who were clinically diagnosed with hypothyroidism (ICD-9-CM code: 244 and 245.2) on at least three separate occasions, regardless of inpatients or outpatient services, during the study period. Based on this definition, we included cases of clinically diagnosed hypothyroidism (including Hashimoto’s disease). Patients with low T3 syndrome could present euthyroid sick syndrome (ICD-9-CM code: 790.94) instead of hypothyroidism, and such cases were excluded in our analyses. Individuals with any diagnoses of thyroid disease (ICD-9-CM code: 193, 240–246) in 2000 were also excluded to increase the likelihood for the identification of newly diagnosed hypothyroidism. In addition, we excluded patients who were diagnosed with hyperthyroidism before the index date. The index date in the hypothyroidism cohort was defined as the date of the first hypothyroidism diagnosis. Similarly, the non-hypothyroidism cohort (comparison cohort) was selected from the LHID by conducting 1:1 propensity score matching. Before matching the non-hypothyroidism cohort, we excluded patients with diagnoses of hypothyroidism or any other thyroid disease (ICD-9-CM code: 193, 240–246) during the entire period that the database was in use (2000–15) to obtain an unexposed cohort without any clinically diagnosed thyroid diseases. In the non-hypothyroidism cohort, the index date of each individual was assigned as the same index date for each matched hypothyroidism case. Any patients with a diagnosis of pneumonia, which was the primary outcome of this study, before the index date were excluded. All patients began their follow-up from their respective index dates. To evaluate how thyroxine replacement therapy (TRT) influenced the pneumonia risk in patients with hypothyroidism, we subdivided the hypothyroidism cohort into the TRT and non-TRT groups. The patients in the TRT group were defined as those had received TRT for at least 30 days after a diagnosis of hypothyroidism during the follow-up period; therefore, patients who did not receive or received TRT for <30 days were included in the non-TRT group. Outcome measures and covariates The primary outcome was defined as the occurrence of pneumonia (including lung abscess or empyema; using ICD-9-CM code: 480–486, 510 and 513) during the follow-up period. The accuracy of the ICD-9-CM codes for diagnosing pneumonia has been validated previously in Taiwan by clinical investigators who independently reviewed the clinical information and imaging records for the selected study sample (16). All study subjects were followed from the index date until the occurrence of pneumonia, death or until 31 December 2015 (the last date in the research database). A pre-existing comorbidity was defined as a disease that was diagnosed by at least one inpatient or two outpatient services in the year prior to the index date. The baseline comorbidities and possible confounding factors (Table 1) were identified in accordance with their respective ICD-9-CM codes: diabetes mellitus (250), hypertension (401–405), hyperlipidaemia (272.0–272.4), coronary artery disease (410–414 and 429.2), congestive heart failure (428), cerebrovascular disease (430–438), dementia (290 and 331), epilepsy (345), Parkinson’s disease (332), chronic kidney disease (582–583, 585–586 and 588), chronic liver disease (571, 456.0–456.2 and 572.2–572.8), gastroesophageal reflux disease (530.11 and 530.81), malignancy (140–208 and 209.0–209.3), chronic obstructive pulmonary disease (490–496), asthma (493), pulmonary tuberculosis (011), upper respiratory tract infection (465.9). Table 1. Baseline characteristics of patients diagnosed with and without hypothyroidism after 1:1 propensity score matching (2001–14) Characteristics . Propensity score matching (1:1) . . . . Hypothyroidism . . . . Yes (n = 9749) . No (n = 9749) . SMD . Age, years (mean ± SD) 50.6 ± 15.5 51.7 ± 16.0 −0.07 Sex, female 7627 (78.2%) 7733 (79.3%) −0.03 Comorbidities  Diabetes mellitus 1209 (12.4%) 1299 (13.3%) −0.03  Hypertension 2332 (23.9%) 2516 (25.8%) −0.04  Hyperlipidaemia 1445 (14.8%) 1549 (15.9%) −0.03  CAD 839 (8.6%) 888 (9.1%) −0.02  CHF 238 (2.4%) 219 (2.2%) 0.01  CVD 492 (5.0%) 517 (5.3%) −0.01  Dementia 160 (1.6%) 199 (2.0%) −0.03  Epilepsy 79 (0.8%) 56 (0.6%) 0.03  PD 80 (0.8%) 79 (0.8%) 0.00  CKD 408 (4.2%) 385 (3.9%) 0.01  Chronic liver disease 701 (7.2%) 734 (7.5%) −0.01  GERD 341 (3.5%) 359 (3.7%) −0.01  Malignancy 928 (9.5%) 884 (9.1%) 0.02  COPD 556 (5.7%) 566 (5.8%) 0.00  Asthma 229 (2.3%) 217 (2.2%) 0.01  Pulmonary TB 21 (0.2%) 21 (0.2%) 0.00  Upper respiratory tract infection 2678 (27.5%) 2748 (28.2%) −0.02 Characteristics . Propensity score matching (1:1) . . . . Hypothyroidism . . . . Yes (n = 9749) . No (n = 9749) . SMD . Age, years (mean ± SD) 50.6 ± 15.5 51.7 ± 16.0 −0.07 Sex, female 7627 (78.2%) 7733 (79.3%) −0.03 Comorbidities  Diabetes mellitus 1209 (12.4%) 1299 (13.3%) −0.03  Hypertension 2332 (23.9%) 2516 (25.8%) −0.04  Hyperlipidaemia 1445 (14.8%) 1549 (15.9%) −0.03  CAD 839 (8.6%) 888 (9.1%) −0.02  CHF 238 (2.4%) 219 (2.2%) 0.01  CVD 492 (5.0%) 517 (5.3%) −0.01  Dementia 160 (1.6%) 199 (2.0%) −0.03  Epilepsy 79 (0.8%) 56 (0.6%) 0.03  PD 80 (0.8%) 79 (0.8%) 0.00  CKD 408 (4.2%) 385 (3.9%) 0.01  Chronic liver disease 701 (7.2%) 734 (7.5%) −0.01  GERD 341 (3.5%) 359 (3.7%) −0.01  Malignancy 928 (9.5%) 884 (9.1%) 0.02  COPD 556 (5.7%) 566 (5.8%) 0.00  Asthma 229 (2.3%) 217 (2.2%) 0.01  Pulmonary TB 21 (0.2%) 21 (0.2%) 0.00  Upper respiratory tract infection 2678 (27.5%) 2748 (28.2%) −0.02 Data are presented as mean ± SD or number (%). CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. Open in new tab Table 1. Baseline characteristics of patients diagnosed with and without hypothyroidism after 1:1 propensity score matching (2001–14) Characteristics . Propensity score matching (1:1) . . . . Hypothyroidism . . . . Yes (n = 9749) . No (n = 9749) . SMD . Age, years (mean ± SD) 50.6 ± 15.5 51.7 ± 16.0 −0.07 Sex, female 7627 (78.2%) 7733 (79.3%) −0.03 Comorbidities  Diabetes mellitus 1209 (12.4%) 1299 (13.3%) −0.03  Hypertension 2332 (23.9%) 2516 (25.8%) −0.04  Hyperlipidaemia 1445 (14.8%) 1549 (15.9%) −0.03  CAD 839 (8.6%) 888 (9.1%) −0.02  CHF 238 (2.4%) 219 (2.2%) 0.01  CVD 492 (5.0%) 517 (5.3%) −0.01  Dementia 160 (1.6%) 199 (2.0%) −0.03  Epilepsy 79 (0.8%) 56 (0.6%) 0.03  PD 80 (0.8%) 79 (0.8%) 0.00  CKD 408 (4.2%) 385 (3.9%) 0.01  Chronic liver disease 701 (7.2%) 734 (7.5%) −0.01  GERD 341 (3.5%) 359 (3.7%) −0.01  Malignancy 928 (9.5%) 884 (9.1%) 0.02  COPD 556 (5.7%) 566 (5.8%) 0.00  Asthma 229 (2.3%) 217 (2.2%) 0.01  Pulmonary TB 21 (0.2%) 21 (0.2%) 0.00  Upper respiratory tract infection 2678 (27.5%) 2748 (28.2%) −0.02 Characteristics . Propensity score matching (1:1) . . . . Hypothyroidism . . . . Yes (n = 9749) . No (n = 9749) . SMD . Age, years (mean ± SD) 50.6 ± 15.5 51.7 ± 16.0 −0.07 Sex, female 7627 (78.2%) 7733 (79.3%) −0.03 Comorbidities  Diabetes mellitus 1209 (12.4%) 1299 (13.3%) −0.03  Hypertension 2332 (23.9%) 2516 (25.8%) −0.04  Hyperlipidaemia 1445 (14.8%) 1549 (15.9%) −0.03  CAD 839 (8.6%) 888 (9.1%) −0.02  CHF 238 (2.4%) 219 (2.2%) 0.01  CVD 492 (5.0%) 517 (5.3%) −0.01  Dementia 160 (1.6%) 199 (2.0%) −0.03  Epilepsy 79 (0.8%) 56 (0.6%) 0.03  PD 80 (0.8%) 79 (0.8%) 0.00  CKD 408 (4.2%) 385 (3.9%) 0.01  Chronic liver disease 701 (7.2%) 734 (7.5%) −0.01  GERD 341 (3.5%) 359 (3.7%) −0.01  Malignancy 928 (9.5%) 884 (9.1%) 0.02  COPD 556 (5.7%) 566 (5.8%) 0.00  Asthma 229 (2.3%) 217 (2.2%) 0.01  Pulmonary TB 21 (0.2%) 21 (0.2%) 0.00  Upper respiratory tract infection 2678 (27.5%) 2748 (28.2%) −0.02 Data are presented as mean ± SD or number (%). CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. Open in new tab Propensity score matching We performed 1:1 propensity score matching to minimize the possibility of selection bias that was caused by differences in the baseline characteristics between the exposed and comparison cohorts. The propensity scores, which estimated the probability of a patient being diagnosed with hypothyroidism, were calculated by using logistic regression analyses adjusted for age, sex and baseline comorbidities. The propensity score matching was based on the nearest-neighbour matching method without replacement, with a caliper width equal to 0.2 of the standard deviation of the logit of the propensity score. Statistical analysis For sample-size calculation, with a relative hazard of 1.4 (the ratio of exposed/comparison cohort incidence rates) in 1:1 propensity score matching, a two-sided significance of 0.05, and a power of 0.8, a total of 277 events was required. Assuming a planned average 6-year follow-up duration with a baseline event rate of 0.03 for the comparison cohort and a censoring rate of 0.13 for both cohorts, a minimum of 2030 patients were required (17). We used the standardized mean difference (SMD) to measure the difference in baseline characteristics between the two cohorts (18), with a value <0.1 considered negligible. To evaluate the risk of pneumonia in patients with and without hypothyroidism, the cumulative incidence curves were estimated by Kaplan–Meier methods, and the differences between the curves were compared by using log-rank tests. We used univariable and multivariable Cox proportional hazards regression models to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of developing pneumonia. The multivariable regression models adjusted for age, sex and individually baseline comorbidities listed in Table 1. To evaluate whether the TRT and non-TRT groups in the hypothyroidism cohort had different risks for developing pneumonia compared with the non-hypothyroidism cohort, we performed an analysis to calculate the HRs for the TRT and non-TRT groups with the non-hypothyroidism cohort as the comparison group. Furthermore, we performed an analysis to evaluate whether the TRT and non-TRT groups in the hypothyroidism cohort had different risks for developing pneumonia. To test whether the duration of follow-up period influenced the result, we conducted a sensitivity analysis that included study population from 2001 to 2011 and used a standardized 4-year follow-up period to detect the pneumonia events. Furthermore, we analysed patient data stratified for age, sex and the years before and after the introduction of the pneumococcal polysaccharide vaccine (2001–07 and 2008–14) and checked interaction to determine whether patients with different characteristics altered outcomes. A two-sided probability value of <0.05 was considered statistically significant. Statistical analyses were performed using SAS 9.4 software (SAS Institute, Inc., Cary, NC). Results Demographics In the analyses that were conducted after 1:1 propensity score matching, a total of 19 498 patients were enrolled; 9749 patients with hypothyroidism (hypothyroidism cohort) were matched to 9749 controls without hypothyroidism (non-hypothyroidism cohort). All baseline characteristics were balanced well after propensity score matching, including age, sex and comorbidities (SMD <0.1) (Table 1). Risk of pneumonia in patients with and without hypothyroidism There were more pneumonia events in the hypothyroidism cohort than in the non-hypothyroidism cohorts [1775 (18.2%) versus 1329 (13.6%)]. Incidence rates in the hypothyroidism and non-hypothyroidism cohorts were 29.2 (1775 events with 60 735 person-years) and 21.3 (1329 events with 62 483 person-years) per 1000 person-years, respectively. In the comparisons that were undertaken after propensity score matching, the cumulative incidence curves showed that the incidence of pneumonia was higher in the hypothyroidism cohort than that in the non-hypothyroidism cohort (log-rank test, P < 0.001; Fig. 1a). The Cox proportional hazards regression models showed that hypothyroidism was significantly associated with a higher risk of developing pneumonia in both the univariable and multivariable regression models [crude HR 1.30, 95% CI 1.21–1.40, P < 0.001; adjusted HR (aHR) 1.38, 95% CI 1.29–1.49, P < 0.001; Table 2]. Table 2. Results of multivariable Cox proportional hazards regression models estimating the risk of incident pneumonia in patients diagnosed with and without hypothyroidism (2001–15) Factors . aHR (95% CI)a . P value . Hypothyroidism 1.38 (1.29–1.49) <0.001 Age, years  ≥65, compared with <65 2.36 (2.16–2.57) <0.001 Male, compared with female 1.29 (1.19–1.41) <0.001 Comorbidities  Diabetes mellitus 1.36 (1.23–1.50) <0.001  Hypertension 1.15 (1.05–1.26) 0.002  Hyperlipidaemia 0.93 (0.84–1.03) 0.15  CAD 1.21 (1.09–1.35) <0.001  CHF 1.42 (1.20–1.69) <0.001  CVD 1.53 (1.35–1.74) <0.001  Dementia 1.83 (1.53–2.19) <0.001  Epilepsy 1.60 (1.14–2.26) 0.007  PD 1.65 (1.27–2.14) <0.001  CKD 1.84 (1.60–2.10) <0.001  Chronic liver disease 1.01 (0.89–1.15) 0.85  GERD 1.13 (0.92–1.38) 0.24  Malignancy 1.67 (1.50–1.86) <0.001  COPD 1.59 (1.39–1.83) <0.001  Asthma 1.02 (0.82–1.26) 0.88  Pulmonary TB 1.59 (0.98–2.58) 0.06  Upper respiratory tract infection 1.16 (1.07–1.25) <0.001 Factors . aHR (95% CI)a . P value . Hypothyroidism 1.38 (1.29–1.49) <0.001 Age, years  ≥65, compared with <65 2.36 (2.16–2.57) <0.001 Male, compared with female 1.29 (1.19–1.41) <0.001 Comorbidities  Diabetes mellitus 1.36 (1.23–1.50) <0.001  Hypertension 1.15 (1.05–1.26) 0.002  Hyperlipidaemia 0.93 (0.84–1.03) 0.15  CAD 1.21 (1.09–1.35) <0.001  CHF 1.42 (1.20–1.69) <0.001  CVD 1.53 (1.35–1.74) <0.001  Dementia 1.83 (1.53–2.19) <0.001  Epilepsy 1.60 (1.14–2.26) 0.007  PD 1.65 (1.27–2.14) <0.001  CKD 1.84 (1.60–2.10) <0.001  Chronic liver disease 1.01 (0.89–1.15) 0.85  GERD 1.13 (0.92–1.38) 0.24  Malignancy 1.67 (1.50–1.86) <0.001  COPD 1.59 (1.39–1.83) <0.001  Asthma 1.02 (0.82–1.26) 0.88  Pulmonary TB 1.59 (0.98–2.58) 0.06  Upper respiratory tract infection 1.16 (1.07–1.25) <0.001 CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Table 2. Results of multivariable Cox proportional hazards regression models estimating the risk of incident pneumonia in patients diagnosed with and without hypothyroidism (2001–15) Factors . aHR (95% CI)a . P value . Hypothyroidism 1.38 (1.29–1.49) <0.001 Age, years  ≥65, compared with <65 2.36 (2.16–2.57) <0.001 Male, compared with female 1.29 (1.19–1.41) <0.001 Comorbidities  Diabetes mellitus 1.36 (1.23–1.50) <0.001  Hypertension 1.15 (1.05–1.26) 0.002  Hyperlipidaemia 0.93 (0.84–1.03) 0.15  CAD 1.21 (1.09–1.35) <0.001  CHF 1.42 (1.20–1.69) <0.001  CVD 1.53 (1.35–1.74) <0.001  Dementia 1.83 (1.53–2.19) <0.001  Epilepsy 1.60 (1.14–2.26) 0.007  PD 1.65 (1.27–2.14) <0.001  CKD 1.84 (1.60–2.10) <0.001  Chronic liver disease 1.01 (0.89–1.15) 0.85  GERD 1.13 (0.92–1.38) 0.24  Malignancy 1.67 (1.50–1.86) <0.001  COPD 1.59 (1.39–1.83) <0.001  Asthma 1.02 (0.82–1.26) 0.88  Pulmonary TB 1.59 (0.98–2.58) 0.06  Upper respiratory tract infection 1.16 (1.07–1.25) <0.001 Factors . aHR (95% CI)a . P value . Hypothyroidism 1.38 (1.29–1.49) <0.001 Age, years  ≥65, compared with <65 2.36 (2.16–2.57) <0.001 Male, compared with female 1.29 (1.19–1.41) <0.001 Comorbidities  Diabetes mellitus 1.36 (1.23–1.50) <0.001  Hypertension 1.15 (1.05–1.26) 0.002  Hyperlipidaemia 0.93 (0.84–1.03) 0.15  CAD 1.21 (1.09–1.35) <0.001  CHF 1.42 (1.20–1.69) <0.001  CVD 1.53 (1.35–1.74) <0.001  Dementia 1.83 (1.53–2.19) <0.001  Epilepsy 1.60 (1.14–2.26) 0.007  PD 1.65 (1.27–2.14) <0.001  CKD 1.84 (1.60–2.10) <0.001  Chronic liver disease 1.01 (0.89–1.15) 0.85  GERD 1.13 (0.92–1.38) 0.24  Malignancy 1.67 (1.50–1.86) <0.001  COPD 1.59 (1.39–1.83) <0.001  Asthma 1.02 (0.82–1.26) 0.88  Pulmonary TB 1.59 (0.98–2.58) 0.06  Upper respiratory tract infection 1.16 (1.07–1.25) <0.001 CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Figure 1. Open in new tabDownload slide Cumulative incidence curves of pneumonia in (a) patients with hypothyroidism versus patients without hypothyroidism and (b) patients with hypothyroidism who received TRT versus those who did not. Figure 1. Open in new tabDownload slide Cumulative incidence curves of pneumonia in (a) patients with hypothyroidism versus patients without hypothyroidism and (b) patients with hypothyroidism who received TRT versus those who did not. Sensitivity analysis using a standardized 4-year follow-up period revealed similar results. Patients with hypothyroidism had a significantly higher risk of pneumonia compared with those without hypothyroidism (crude HR 1.32, 95% CI 1.18–1.48, P < 0.001; aHR 1.41, 95% CI 1.26–1.58, P < 0.001; Supplementary Table 1). Risk of pneumonia in hypothyroidism with and without TRT Incidence rates in the TRT and non-TRT groups were 28.1 and 31.2 persons per 1000 person-years, respectively. Compared with the non-hypothyroidism cohort, we found an increased risk for pneumonia in the patients with hypothyroidism who were administered TRT (aHR 1.30, 95% CI 1.20–1.42, P < 0.001) and in those who did not receive TRT (aHR 1.54, 95% CI 1.40–1.69, P < 0.001) in multivariable analyses. The cumulative incidence curves showed that the incidence of pneumonia was higher in the non-TRT group than that in the TRT group (log-rank test, P < 0.001; Fig. 1b). The use of TRT was associated with a lower risk of pneumonia compared with no TRT (aHR 0.85, 95% CI 0.76–0.93, P = 0.001; Table 3). Table 3. Results of multivariable Cox proportional hazards regression models estimating the risk of incident pneumonia in patients diagnosed with hypothyroidism who did or did not receive TRT (2001–15) Factors . aHR (95% CI)a . P value . TRT, compared with non-TRT 0.85 (0.76–0.93) 0.001 Age, years  ≥65, compared with <65 2.42 (2.15–2.72) <0.001 Male, compared with female 1.30 (1.17–1.46) <0.001 Comorbidities  Diabetes mellitus 1.30 (1.13–1.49) <0.001  Hypertension 1.21 (1.08–1.36) 0.001  Hyperlipidaemia 0.89 (0.78–1.03) 0.11  CAD 1.20 (1.03–1.39) 0.02  CHF 1.46 (1.16–1.84) 0.001  CVD 1.56 (1.31–1.85) <0.001  Dementia 1.80 (1.39–2.33) <0.001  Epilepsy 2.04 (1.34–3.10) 0.001  PD 1.49 (1.01–2.19) 0.05  CKD 1.99 (1.66–2.37) <0.001  Chronic liver disease 1.15 (0.97–1.35) 0.11  GERD 1.06 (0.79–1.41) 0.71  Malignancy 1.70 (1.46–1.97) <0.001  COPD 1.38 (1.13–1.69) 0.002  Asthma 1.02 (0.75–1.39) 0.90  Pulmonary TB 2.20 (1.04–4.66) 0.04  Upper respiratory tract infection 1.16 (1.05–1.29) 0.004 Factors . aHR (95% CI)a . P value . TRT, compared with non-TRT 0.85 (0.76–0.93) 0.001 Age, years  ≥65, compared with <65 2.42 (2.15–2.72) <0.001 Male, compared with female 1.30 (1.17–1.46) <0.001 Comorbidities  Diabetes mellitus 1.30 (1.13–1.49) <0.001  Hypertension 1.21 (1.08–1.36) 0.001  Hyperlipidaemia 0.89 (0.78–1.03) 0.11  CAD 1.20 (1.03–1.39) 0.02  CHF 1.46 (1.16–1.84) 0.001  CVD 1.56 (1.31–1.85) <0.001  Dementia 1.80 (1.39–2.33) <0.001  Epilepsy 2.04 (1.34–3.10) 0.001  PD 1.49 (1.01–2.19) 0.05  CKD 1.99 (1.66–2.37) <0.001  Chronic liver disease 1.15 (0.97–1.35) 0.11  GERD 1.06 (0.79–1.41) 0.71  Malignancy 1.70 (1.46–1.97) <0.001  COPD 1.38 (1.13–1.69) 0.002  Asthma 1.02 (0.75–1.39) 0.90  Pulmonary TB 2.20 (1.04–4.66) 0.04  Upper respiratory tract infection 1.16 (1.05–1.29) 0.004 CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Table 3. Results of multivariable Cox proportional hazards regression models estimating the risk of incident pneumonia in patients diagnosed with hypothyroidism who did or did not receive TRT (2001–15) Factors . aHR (95% CI)a . P value . TRT, compared with non-TRT 0.85 (0.76–0.93) 0.001 Age, years  ≥65, compared with <65 2.42 (2.15–2.72) <0.001 Male, compared with female 1.30 (1.17–1.46) <0.001 Comorbidities  Diabetes mellitus 1.30 (1.13–1.49) <0.001  Hypertension 1.21 (1.08–1.36) 0.001  Hyperlipidaemia 0.89 (0.78–1.03) 0.11  CAD 1.20 (1.03–1.39) 0.02  CHF 1.46 (1.16–1.84) 0.001  CVD 1.56 (1.31–1.85) <0.001  Dementia 1.80 (1.39–2.33) <0.001  Epilepsy 2.04 (1.34–3.10) 0.001  PD 1.49 (1.01–2.19) 0.05  CKD 1.99 (1.66–2.37) <0.001  Chronic liver disease 1.15 (0.97–1.35) 0.11  GERD 1.06 (0.79–1.41) 0.71  Malignancy 1.70 (1.46–1.97) <0.001  COPD 1.38 (1.13–1.69) 0.002  Asthma 1.02 (0.75–1.39) 0.90  Pulmonary TB 2.20 (1.04–4.66) 0.04  Upper respiratory tract infection 1.16 (1.05–1.29) 0.004 Factors . aHR (95% CI)a . P value . TRT, compared with non-TRT 0.85 (0.76–0.93) 0.001 Age, years  ≥65, compared with <65 2.42 (2.15–2.72) <0.001 Male, compared with female 1.30 (1.17–1.46) <0.001 Comorbidities  Diabetes mellitus 1.30 (1.13–1.49) <0.001  Hypertension 1.21 (1.08–1.36) 0.001  Hyperlipidaemia 0.89 (0.78–1.03) 0.11  CAD 1.20 (1.03–1.39) 0.02  CHF 1.46 (1.16–1.84) 0.001  CVD 1.56 (1.31–1.85) <0.001  Dementia 1.80 (1.39–2.33) <0.001  Epilepsy 2.04 (1.34–3.10) 0.001  PD 1.49 (1.01–2.19) 0.05  CKD 1.99 (1.66–2.37) <0.001  Chronic liver disease 1.15 (0.97–1.35) 0.11  GERD 1.06 (0.79–1.41) 0.71  Malignancy 1.70 (1.46–1.97) <0.001  COPD 1.38 (1.13–1.69) 0.002  Asthma 1.02 (0.75–1.39) 0.90  Pulmonary TB 2.20 (1.04–4.66) 0.04  Upper respiratory tract infection 1.16 (1.05–1.29) 0.004 CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GERD, gastroesophageal reflux disease; PD, Parkinson’s disease; TB, tuberculosis. aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Sensitivity analysis using a standardized 4-year follow-up period revealed similar results. Among the patients with hypothyroidism, the TRT group had a significantly lower risk of pneumonia compared with those without TRT (aHR 0.81, 95% CI 0.69–0.94, P = 0.007; Supplementary Table 2). Analyses stratified by age, sex and the years before and after the introduction of pneumococcal polysaccharide vaccine In the age-stratified analyses, hypothyroidism was significantly associated with a higher risk of pneumonia in both the strata of younger and older patients (<65 years: aHR 1.34, 95% CI 1.22–1.48, P < 0.001; ≥65 years: aHR 1.39, 95% CI 1.24–1.55, P < 0.001). In sex-stratified analyses, patients with hypothyroidism had a significantly higher risk of pneumonia than the non-hypothyroidism cohort, regardless of their sex (male: aHR 1.46, 95% CI 1.27–1.67, P < 0.001; female: aHR 1.36, 95% CI 1.25–1.48, P < 0.001; Table 4). The stratified analysis using a shorter sampling period (2001–07 and 2008–14) before and after the introduction of the pneumococcal polysaccharide vaccine revealed similar results (2001–07: aHR 1.40, 95% CI 1.27–1.53, P < 0.001; 2008–14: aHR 1.37, 95% CI 1.21–1.54, P < 0.001; Table 4). All the P value for interactions showed no significant interactions. Table 4. Results of multivariable Cox proportional hazards regression models stratified by age, sex and the year before and after the introduction of the pneumococcal polysaccharide vaccine to estimate the risk of incident pneumonia in patients diagnosed with and without hypothyroidism (2001–15) Factors . Propensity score matching (1:1) . . P for interaction . . aHRa (95% CI) . P value . . Age, years 0.53  20–64 1.34 (1.22–1.48) <0.001  ≥65 1.39 (1.24–1.55) <0.001 Sex 0.53  Male 1.46 (1.27–1.67) <0.001  Female 1.36 (1.25–1.48) <0.001 Year 0.78  2001–07 1.40 (1.27–1.53) <0.001  2008–14 1.37 (1.21–1.54) <0.001 Factors . Propensity score matching (1:1) . . P for interaction . . aHRa (95% CI) . P value . . Age, years 0.53  20–64 1.34 (1.22–1.48) <0.001  ≥65 1.39 (1.24–1.55) <0.001 Sex 0.53  Male 1.46 (1.27–1.67) <0.001  Female 1.36 (1.25–1.48) <0.001 Year 0.78  2001–07 1.40 (1.27–1.53) <0.001  2008–14 1.37 (1.21–1.54) <0.001 aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Table 4. Results of multivariable Cox proportional hazards regression models stratified by age, sex and the year before and after the introduction of the pneumococcal polysaccharide vaccine to estimate the risk of incident pneumonia in patients diagnosed with and without hypothyroidism (2001–15) Factors . Propensity score matching (1:1) . . P for interaction . . aHRa (95% CI) . P value . . Age, years 0.53  20–64 1.34 (1.22–1.48) <0.001  ≥65 1.39 (1.24–1.55) <0.001 Sex 0.53  Male 1.46 (1.27–1.67) <0.001  Female 1.36 (1.25–1.48) <0.001 Year 0.78  2001–07 1.40 (1.27–1.53) <0.001  2008–14 1.37 (1.21–1.54) <0.001 Factors . Propensity score matching (1:1) . . P for interaction . . aHRa (95% CI) . P value . . Age, years 0.53  20–64 1.34 (1.22–1.48) <0.001  ≥65 1.39 (1.24–1.55) <0.001 Sex 0.53  Male 1.46 (1.27–1.67) <0.001  Female 1.36 (1.25–1.48) <0.001 Year 0.78  2001–07 1.40 (1.27–1.53) <0.001  2008–14 1.37 (1.21–1.54) <0.001 aAnalysis adjusted for age, sex and baseline comorbidities. Open in new tab Discussion In this population-based retrospective cohort study, we found that hypothyroidism was an independent risk factor for developing pneumonia. Thyroxine treatment attenuated the increased risk of pneumonia associated with hypothyroidism. Thus, TRT may result in better physiological control of thyroid levels in the body, which conferred improved immune status (19). This study is the first to use a longitudinal approach to evaluate whether hypothyroidism is a determining factor for the emergence of pneumonia, and we confirmed that clinically diagnosed hypothyroidism is a significant factor that contributes to the development of pneumonia. The association between the low T3 syndrome and pneumonia has been assessed previously (13,14), but there are only a few studies that have examined the association between hypothyroidism and pneumonia. In a study among patients with primary total knee arthroplasty, hypothyroidism was associated with a significantly higher risk of postoperative pneumonia than that in the matched controls (20). Another cohort study, which evaluated the risk of heart failure after community-acquired pneumonia, showed that patients with pneumonia had a higher prevalence of baseline hypothyroidism that those without pneumonia (21). Both of the above-mentioned studies mainly explored the relationship between other diseases and pneumonia, wherein the association between pneumonia and thyroid function was incidentally identified. Therefore, the association between hypothyroidism and pneumonia risk can be more accurately explored through well-designed research. The underlying mechanism that leads to pneumonia in hypothyroidism may be the impaired immune function. Thyroid hormones have shown an immunomodulatory property in response to environmental changes or stress (19). Patients with hypothyroidism may have abnormal lymphocyte function and decreased natural killer cell activity (7), which possibly makes it more difficult for them to eradicate pathogens and confers susceptibility to infection. The use of TRT may improve lymphocyte function by restoring the patients with hypothyroidism to a euthyroid status (22). Moreover, thyroxine supplementation of thyroxine has been shown to enhance bacterial clearance and promote survival (23). There were several possible reasons why TRT only partially attenuated the increased risk of pneumonia: first, hypothyroidism required long-term treatment; second, a previous study reported that even if patients received thyroxine treatment to restore normal thyroid function, they may manifest some symptoms of organ damage (24); finally, although the patients were treated with thyroxine, we could not confirm whether the patients with hypothyroidism were treated to regain an appropriate level of thyroid function. Over- and under-treatment of hypothyroidism may lead to a poor prognosis (25). Therefore, TRT may be used to restore thyroid function to decrease the pneumonia risk with close monitoring of the thyroid level. The strengths of this study included its nationwide, population-based study design, which could trace nearly all cases of hypothyroidism and subsequent pneumonia in Taiwan because the national insurance system covers all clinical practice establishments for endocrine and infectious diseases. However, this study had some limitations. First, the diagnoses of hypothyroidism and pneumonia that rely on the ICD-9-CM may be less accurate than diagnoses in a clinical, prospective study. The primary outcome included community- and hospital-acquired pneumonia, but we could not distinguish between them from the ICD-9-CM codes. Potential information biases might have been introduced because of misclassifications based on the ICD-9-CM diagnosis codes in the LHID. Due to the anonymization of patient data, we could not obtain information on laboratory examination (e.g. thyroid function) or imaging data for pneumonia from the LHID; thus, we could not confirm the exact thyroid status, distinguish the overt and subclinical hypothyroidism or confirm the pneumonia diagnosis by radiological evidence. However, we have attempted to mitigate this limitation by restricting our definition of hypothyroidism to diagnoses on at least three separate occasions, regardless of inpatient or outpatient services. In addition, a previous study reported that a diagnosis of pneumonia based on the ICD-9-CM codes in the LHID has high accuracy and validity (16). Second, there was no information on the physiological thyroid function between those who were treated and those who were not treated to determine whether a reduced risk was associated with physiological control of hypothyroidism. Lastly, we could not obtain information from the LHID on potential confounding factors (e.g. body mass index and lifestyle factors such as smoking history), whereby a bias related to unknown or unmeasured confounders might exist. Nonetheless, some health consequences would, at least in part, be reflected and adjusted in the presentation of the baseline comorbidities (e.g. smoking and chronic obstructive pulmonary disease; high body mass index and diabetes). Conclusions In summary, this population-based retrospective cohort study revealed that patients clinically diagnosed with hypothyroidism might be at increased risk for the future development of pneumonia. Moreover, in patients with hypothyroidism, the risk of pneumonia may be reduced by thyroxine replacement treatment. Additional prospective cohort studies, which include thyroid function tests and a more accurate clinical diagnosis of pneumonia based on radiological findings, are needed to confirm the effects of hypothyroidism and TRT on the risk of developing pneumonia. Acknowledgements The authors would like to thank the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan, for maintaining and processing the database, and the Health and Welfare Data Science Center of Tzu Chi University for providing administrative, technical and funding support. Declaration Funding: this work was supported by the Hualien Tzu Chi Hospital (TCRD-108-05) and the Health and Welfare Data Science Center of Tzu Chi University. The study sponsors were not involved in the design, conduct, analysis or reporting of this work. Ethical approval: the study protocol was approved by the Institutional Review Board of Hualien Tzu Chi Hospital (IRB 108-126-C). 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Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2021. Published by Oxford University Press. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Family Practice – Oxford University Press

Published: Apr 27, 2021

Keywords: hypothyroidism; pneumonia; thyroxine; immune system

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