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Introduction
Neoplastic diseases in older adults are associated with disability and mortality 1. A study carried out in France reported that about a third of oncogeriatric patients present disabilities 2. Frequently, the usual forms of neoplastic complication are infections, being community-acquired pneumonia (CAP), one of the most common 3. Cancer causes immunological changes such as neutropenia, cellular immunity deficit, and dysfunction of humoral immunity 4. Therefore, about 80 % of oncologic patients develop any kind of infection during treatment 3,5,6. However, the risk of getting infections is not only increased by the presence of cancer; there are other predisposing factors for the appearance of infectious diseases 5,7.
A systematic review described advanced age, immunosuppression, cardiovascular diseases, and type 2 diabetes mellitus (T2DM) as predictors of CAP 8. Besides, a meta-analysis concluded that diabetic patients had an increased risk of suffering from cancer; however, important variables such as glycated hemoglobin (HbA1c) and duration of T2DM were not available in a considerable number of studies. Thus, it was difficult to determine whether the increased risk of cancer was attributable to T2DM 9. Additionally, a previous study described T2DM as the only comorbid risk factor for death causes by CAP in non-oncologic geriatric patients 10 due to the association between insulin resistance and physical inactivity, which could lead to an autoimmune dysfunction 11. Besides, a Spanish cohort study reported that 9% of older adults developed CAP at least once, being age, immunosuppression, T2DM, and heart failure the main risk factors 12. Although CAP can develop in any age group, the risk in older adults was four times higher 8.
CAP can also coexist with other comorbidities. Previous studies described the association between hypertension and CAP in older adults with cerebrovascular diseases 13; however, there is not yet a physiopathological connection to explain the relationship between CAP and hypertension in oncologic patients 10. A study carried out by Shen Y. et al. mentioned that hypertension can coexist with lung cancer, resulting in an increased risk of suffering from venous thromboembolism; therefore, the impact of hypertension and cancer should be evaluated 14.
Previous studies have evaluated the association between T2DM and CAP, as well as its possible association with hypertension; however, there is no consensus. Likewise, this association could be more relevant in older adults with cancer due to their immunological status. For this reason, we aimed to assess the role of hypertension and T2DM as risk factors for CAP in oncogeriatric patients.
Methods
Design and population
We conducted a secondary data analysis from a prospective cohort study in older adults from the Geriatrics Service of the Centro Médico Naval (CEMENA, by its initials in Spanish) during 2013-2015. The Geriatrics Service of CEMENA provides medical care to active or retired naval veterans and their family members. This study included male adults over 60 years with the pathological diagnosis of cancer and was diagnosed at CEMENA between September 2012 to November 2013; and have not begun treatment yet. All the participants received oncologic therapy with curative intent.
We included 317 patients in the study and 86 were excluded: 16 patients due to the presence of dementia and 33 because they obtained a score ≤23 in the Mini-Mental State Examination (MMSE), a tool used to evaluate cognitive impairment. Besides, 18 patients did not decide to participate in the study: 4 patients did not count with the variables of interest; 12 still did not have indications for oncologic treatment sessions, and 3 requested early retirement during the development of the study. Finally, data from 231 participants could be analyzed.
Procedure
The patients included in the study were asked to sign an informed consent. A month after signing for inclusion, a form indicating the report of the case was developed. This form included medical history, sociodemographic data, anthropometric measurements, continuous measurements of blood pressure, laboratory tests related to pathological findings of T2DM and CAP, questionnaires for mental assessments, and data associated with the oncologic disease for which they were recruited.
Variables
Outcome: community-acquired pneumonia (CAP)
CAP was defined by the clinical and radiological diagnostic criteria made by internists, pneumologists, and geriatricians of CEMENA. This information was collected from the medical records of the patients up to one year after their inclusion in the study. We considered the outcome if the patient presented at least one pneumonic episode during a year of follow-up. The patients with hospital-acquired pneumonia or aspiration pneumonia were excluded.
Other variables
Sociodemographic characteristics
We included the following sociodemographic variables: age (years) and marital status (single, married, divorced, widowed). The sociodemographic information was obtained from the medical record of the participant.
Medical background
The following variables were included: chronic obstructive pulmonary disease (yes or no) and body mass index (BMI) expressed in kg/m2. The measurements of size and weight to evaluate the nutritional status were obtained at the beginning of the follow-up. Polypharmacy was also considered, defined as the use of 5 or more drugs, under medical prescription 15.
Functional assessment
The Short Physical Performance Battery (SPPB) was used to evaluate the physical performance of the participants. SPPB is an instrument that includes three timed tasks: standing balance, walking or gait speed, and five repetitive chair stands. The timed results of each subtest are rescaled according to predefined cut points for obtaining a score ranging from 0 (worst performance) to 12 (best performance) 16.
We used the Lawton Index, a questionnaire about instrumental activities of daily living (IADL): use of the telephone, shopping, food preparation, housekeeping, laundry, transportation method, use of medications, and handling finances. The Lawton index scores range from 0 to 8 17.
Mental assessment
We used the Montreal Cognitive Assessment (MoCA), a questionnaire to evaluate cognitive impairment in older adults. It was considered the education level to obtain the score (maximum of 30 points) 18.
The five-item Yesavage questionnaire was used to measure depressive symptoms in the participants 19. This questionnaire scores vary from 0 to 5.
Statistical analysis
We used the statistical software STATA v14.0 for our analysis. The descriptive results were described using measures of central tendency, dispersion measures, absolute and relative frequencies. The bivariate analysis comparing the results of patients with or without CAP was performed using the Chi-square test, Fisher´s exact test, and the Student t-test, as appropriate.
Multivariate analysis to evaluate the association between exposure variables and CAP was performed using Cox regression models. Three models were elaborated (1 crude and 2 adjusted models) to assess our association of interest. The adjusted models were carried out with an epidemiologist criterion including age, chronic obstructive pulmonary disease, the number of drugs, functional and cognitive tests, body mass index, and type of cancer. The reported measure was the hazard ratio (HR) with their respective 95% confidence interval (95%CI).
Ethical aspects
The study was developed, preserving the functional, cognitive, psychological, and social integrity of the patients included in the study. We obtained the informed consent of the participant's prior data collection. Also, the research project was evaluated and approved by CEMENA’s Ethics Institutional Review Board.
Results
General description of the study sample
A total of 231 older adults with the diagnosis of cancer were analyzed. The mean age of the participants was 78.6 ± 4.2 (range: 74-92 years) and all of them were men. 33 (14.29%) patients developed CAP during the follow-up, 53 (21.65%) had hypertension, and 56 (22.65%) T2DM. We found that the participants who developed CAP had a higher mean age (78.2 vs. 75.2; p=0.001), a lower SPPB mean (5.05 vs. 8.92; p=0.0001), a lower MoCA mean (15.48 vs. 23.26; p=0.0001), a higher mean of drugs used (7.02 vs. 4.62; p=0.02), as well as a higher prevalence of lung cancer (33.33% vs. 16.16%; p=0.0001) and lymphoma (24.24% vs. 11.62%; p=0.001), compared to those who did not develop CAP during follow-up (Table 1).
Table 1 General description of the study population (N=231).
| Variables | n | % | Mean ± SD | CAP during follow-up | ||
| Yes | No | p-value | ||||
| n=33 (14.29%) | n=198 (85.71%) | |||||
| Age (year-specific) | 78.6 ± 4.2 | 78.2 ± 3.3 | 75.2 ± 3.6 | 0.001 | ||
| Marital status | ||||||
| Single | 19 | 8.23 | 1 (3.03) | 18 (89.09) | ||
| Married/Partner | 127 | 54.98 | 17 (51.52) | 110 (55.56) | ||
| Divorced | 35 | 15.15 | 7 (21.21) | 28 (14.14) | ||
| Widowed | 50 | 21.65 | 8 (24.24) | 42 (2.12) | ||
| Comorbidities | ||||||
| Hypertension | 53 | 21.65 | 14 (42.42) | 39 (19.70) | 0.001 | |
| COPD | 39 | 16.02 | 11 (33.33) | 28 (14.14) | 0.0001 | |
| T2DM | 56 | 22.65 | 16 (48.48) | 40 (20.20) | 0.0001 | |
| Body mass index | 24.31 ± 3.01 | 23.31 ± 2.31 | 25.28 ± 2.23 | 0.05 | ||
| Functional assessment | ||||||
| SPPB | 7.91 ± 1.04 | 5.05 ± 1.07 | 8.92 ± 1.13 | 0.0001 | ||
| Lawton index | 3.27 ± 0.49 | 1.62 ± 0.24 | 3.88 ± 0.76 | 0.05 | ||
| Cognitive assessment | ||||||
| Yesavage questionnaire | 2.07 ± 0.45 | 2.81 ± 0.43 | 2.01 ± 0.23 | 0.04 | ||
| MoCA | 22.08 ± 1.98 | 15.48 ± 4.23 | 23.26 ± 3.64 | 0.0001 | ||
| Number of drugs used | 5.87 ± 1.13 | 7.02 ± 0.51 | 4.62 ± 1.33 | 0.02 | ||
| Location of cancer | ||||||
| Prostate | 57 | 24.68 | 4 (12.12) | 53 (26.77) | 0.08 | |
| Stomach | 38 | 16.45 | 2 (6.06) | 36 (18.18) | 0.1 | |
| Colon/rectum | 39 | 16.88 | 4 (12.12) | 35 (17.68) | 0.1 | |
| Lung | 43 | 18.61 | 11 (33.33) | 32 (16.16) | 0.0001 | |
| Pancreas | 22 | 9.52 | 3 (9.09) | 19 (9.60) | 0.2 | |
| Lymphoma | 31 | 13.42 | 8 (24.24) | 23 (11.62) | 0.0001 | |
| Kidney | 1 | 0.43 | 1 (3.03) | 0 (0) |
SD: standard deviation; CAP: community-acquired pneumonia; COPD: chronic obstructive pulmonary disease; T2DM: type 2 diabetes mellitus; SPPB: Short Physical Performance Battery; MoCA: Montreal Cognitive Assessment.
In the oncogeriatric population included, the most common types of cancer in T2DM patients were: prostate cancer (26.79%), stomach (21.43%), pancreas (17.86%), colon/rectum (16.07%) and lung (14.29%). In contrast, the most common types of cancer in hypertensive patients were: prostate cancer (24.53%), colon/rectum (20.75%), stomach (18.87%), lung (15.09%) and pancreas (11.32%) (Table 2).
Table 2 Frequency of cancer location according to hypertension or type 2 diabetes mellitus.
| Location of cancer | Hypertension n=53 (21.65%) | T2DM n=56 (22.65%) | ||
| Yes | No | Yes | No | |
| Prostate | 13 (24.53) | 44 (83.01) | 15 (26.79) | 42 (75.00) |
| Stomach | 10 (18.87) | 28 (52.83) | 12 (21.43) | 26 (46.43) |
| Colon/rectum | 11 (20.75) | 28 (52.83) | 9 (16.07) | 30 (53.57) |
| Lung | 8 (15.09) | 35 (66.04) | 8 (14.29) | 35 (62.50) |
| Pancreas | 6 (11.32) | 16 (30.19) | 10 (17.86) | 11 (19.64) |
| Lymphoma | 4 (7.58) | 27 (50.94) | 2 (3.57) | 29 (51.79) |
| Kidney | 1 (1.89) | 0 (0) | 0 (0) | 1 (1.79) |
T2DM: type 2 diabetes mellitus
Hypertension or type 2 diabetes mellitus as risk factors of community-acquired pneumonia in older adults with cancer
The development of CAP was more frequent in patients with hypertension (42.42% vs. 19.70%; p=0.0001) and T2DM (48.48% vs. 20.20%; p=0.0001), compared to those without these conditions (Table 1).
In the Cox regression models, adjusted for potential confounders, a statistically significant association was found between T2DM (HR=1.49; 95%CI: 1.21-1.79), hypertension (HR=1.32; 95%CI: 1.24-1.50), and the development of CAP (Table 3).
Table 3 Cox regression models to evaluate hypertension and type 2 diabetes mellitus as predictors of community-acquired pneumonia in oncogeriatric patients.
| Variables | Crude model HR (95%CI) | Model 1: HR (95%CI) | Model 2: HR (95%CI) |
| Hypertension | |||
| No | Reference | Reference | |
| Yes | 1.42 (1.31-1.56) | 1.32 (1.24-1.50) | |
| T2DM | |||
| No | Reference | Reference | |
| Yes | 1.57 (1.25-1.88) | 1.49 (1.21-1.79) |
T2DM: type 2 diabetes mellitus; HR: hazard ratio; CI: confidence intervals.
Models 1 and 2 were adjusted for age, chronic obstructive pulmonary disease, number of drugs used, functional tests, cognitive tests. body mass index and type of cancer.
Discussion
A total of 231 patients were evaluated, of which 14.29% developed CAP. The presence of CAP was higher in patients with lung cancer and lymphomas; furthermore, we found T2DM and hypertension were predictors of CAP incidence.
Previous studies have described the role of T2DM as a risk factor of suffering from a respiratory infection and increasing mortality 20,21, which could be higher in oncogeriatric patients 6. Besides, this association was also described in patients with cardiovascular disease; however, they did not mention hypertension as a predictor of CAP incidence or mortality 22,23 or they did not find a significant association with this comorbidity and CAP 23. In addition, other studies pointed out a significant association between T2DM and respiratory infections; nevertheless, these studies were not conducted in oncogeriatric patients who have suffered immunological and functional alterations due to cancer and therapy 6,20,21.
A previous study reported that patients with hyperinsulinemia had a higher probability of suffering cancer because insulin and insulin-like growth factor 1 (IGF-1) are the principal systemic hormones that activate the signaling routes involved in mitosis and the inhibition of apoptosis in the different human tissues 24. Besides, it is necessary to consider aggravating factors for the development of cancer, such as body weight and physical inactivity that are also related to T2DM pathogenesis 25,26. Prostate cancer was the most common cancer type in T2DM participants; this was also described in previous studies due to its association with increased levels of IGF; however, higher levels of IGF were also found in some types of cancer in women 27.
Studies have only investigated whether cardiovascular diseases are predisposing factors for CAP; however, they did not consider hypertension 22, or they did not find an association with it 23. Nevertheless, the association between hypertension and CAP in older adults could be due to antihypertensive therapy. Previous studies have evaluated the role of angiotensin-converting enzyme (ACE) inhibitors in CAP incidence because they can cause cough in a substantial proportion of users 28,29. Evidence suggests the use of beta-blockers, calcium channel blockers, and lipophilic ACE inhibitors increased the risk of CAP. However, this finding could differ according to genetic susceptibility rather than the ACE inhibitor by itself 28. Recent findings support this hypothesis due to the association between ACE receptors and a higher risk of COVID-19 susceptibility and severity 30.
In this study, we found a statistically significant association between both chronic diseases and the development of CAP. Hypertension and T2DM pathogenesis occur with endothelial damage; however, the immunological alterations due to T2DM lead to a higher risk of CAP in older adults with cancer 31. This could explain the greater association between T2DM and CAP. In addition, we found association between hypertension and the occurrence of CAP and despite we did not found several previous studies with this finding in older adults with cancer, they have described high systolic pressure as a risk factor for mortality and cancer incidence 23,32.
This is to our knowledge the first study that evaluated the association between hypertension and T2DM as predictors of CAP in oncogeriatric patients, who are more vulnerable to adverse outcomes. We found an association between T2DM, hypertension and the development of CAP. This finding could be due to the immunological and physiological changes occurring in oncogeriatric patients; however, functional reserve has an important role 33,34.
It has been described that older adults with T2DM and frailty have a higher risk of disability or death 29. Also, sarcopenia and poor physical performance, which are one of the main physiopathological components of frailty, are risk factors for CAP in older adults 34. In our study, the association between T2DM and CAP persisted after adjusting for physical performance. Then, it is necessary to conduct research studies to improve the functionality of older adults with comorbidities and cancer to reduce their mortality.
This study has some limitations: 1) Due the follow-up of patients was only for 2 years, it exists the probability that later CAP events have not been recorded; 2) We did not collected antihypertensive therapy data and time of the disease from patients evaluated; however, this findings should be used to test pathophysiological hypothesis in future cohorts studies; 3) Main variables related to T2DM as antidiabetic treatment or complications as HbA1c and time of the disease were not collected; 4) We could not include relevant variables such as the severity of the CAP or the cancer severity; 5) The patients evaluated was formed exclusively by ex-marine men, whose physical performance and functionality could be different due to their military training; therefore, these results could not be representative to other oncogeriatric population; 6) We did not record the chemotherapy dose applied; then, this could lead to immunological changes and a higher risk of CAP; 7) During the follow-up we did not record information about previous influenza or pneumococcal vaccine, development of hematological complications such as neutropenia and mucositis that can increase the risk of CAP in oncologic patients 35.
In conclusion, T2DM and hypertension at the time of cancer diagnosis were associated with the development of CAP in oncogeriatric patients. It is necessary to carry out future studies evaluating the role of hypertension in the pathogenesis of CAP. Future intervention studies are needed to improve the functionality and prevent CAP in this vulnerable population.
