INTRODUCTION

Chronic Obstructive Pulmonary Disease (COPD) is defined as a common, preventable, and treatable disease characterized by respiratory symptoms and a persistent and irreversible reduction in airflow caused by alveolar abnormalities after exposure to harmful particles or substances.¹In 2016, the estimated prevalence of this disease was 251 million cases. In 2015, approximately 3.17 million people worldwide died from COPD, accounting for an alarming 5% of all deaths recorded that year.²

Currently, pharmacological treatment of COPD is the cornerstone for achieving an adequate lung function and a potential reduction of exacerbations, which is based on the combination of inhaled corticosteroids and beta-adrenergic agonists.^3,4It is the former that can lead to the occurrence of several adverse effects, albeit to a lesser extent than oral corticosteroids.⁵

In other words, the use of inhaled corticosteroids has been associated with an increased likelihood of developing infectious processes, with community-acquired pneumonia (CAP) being the most common and well-documented. The risk of this is further elevated by patient-specific characteristics such as advanced age and comorbidities.⁶Therefore, it is important to understand the risk-benefit profile of using these medications before recommending and/or initiating therapy with them.⁷Previous studies have demonstrated an association between the use of inhaled corticosteroids and CAP in patients with COPD^8,9,10,11. Therefore, the aim of this article is to determine if the use of inhaled corticosteroids is a risk factor for community-acquired pneumonia in patients with Chronic Obstructive Pulmonary Disease at the Hospital Víctor Lazarte Echegaray during the period 2017-2020, with the expectation of finding a relationship between the two variables.

METHODS

RESULTS

Out of the total sample of 405 patients with COPD, there was no missing information in the medical records. Among them, 81 patients had CAP, while 324 patients did not. The percentage of inhaled corticosteroid use was higher in patients with CAP (91.4%) compared to those without CAP (88.3%). However, no statistical significance was found between these groups, with a p-value of 0.429. (Table 1)

The mean and standard deviation of age for both groups were 76.1 ± 9.6 and 65.6 ± 11.5, respectively, showing a significant difference in the mean age between the two groups, as well as statistical significance with a p<0.001. The percentage of male gender was higher in patients with CAP (59.3%) compared to those without CAP (54.3%), but there was no statistically significant difference between the groups with a p-value of 0.424. The percentage of malnutrition in patients with CAP was 8.6%, higher than in patients without CAP (3.4%), with a p-value of 0.040, demonstrating a statistically significant difference through the chi-square test. However, when the Fisher's exact test was applied, a p-value of 0.055 was obtained. he percentage of smoking in patients with CAP was 4.9%, lower than in patients without CAP (7.1%), and there was no statistically significant difference between the two groups with a p-value of 0.486. (Table 2)

A logistic regression model (multivariable analysis) was performed to adjust the Odds ratio of inhaled corticosteroid use for variables that have a demonstrated effect on CAP. In the simultaneous evaluation, the use of inhaled corticosteroids showed an Odds ratio of 1.17 (p=0.737, 95% CI: 0.48-2.99), age had an Odds ratio of 1.09 (p<0.001, 95% CI: 1.06-1.12), male gender had an Odds ratio of 1.45 (p=0.169, 95% CI: 0.85-2.53), malnutrition had an Odds ratio of 1.18 (p=0.768, 95% CI: 0.39-3.57), and smoking had an Odds ratio of 2.10 (p=0.228, 95% CI: 0.63-7.06). Among these variables, only age showed statistical significance. (Table 3)

DISCUSSION

This case-control study, conducted on a population of 405 patients with COPD at Hospital Víctor Lazarte Echegaray between 2017 and 2020, aimed to identify whether the use of inhaled corticosteroids and other associated factors constitute a risk for the development of CAP.

In the multivariate analysis (Table 3), it is described that the use of inhaled corticosteroids is not significantly associated with the diagnosis of CAP. Therefore, it is assumed that their use is not a risk factor. This finding is consistent with the study by Almagro P et al. in Spain in 2019¹⁴, which states that the conclusion that pneumonia cases increase in COPD patients treated with inhaled corticosteroids is not fully supported by data and cannot be considered confirmed. Supporting this stance, they argue that the incidence of pneumonia is not homogeneous in different studies and randomized clinical trials conducted over the years, suggesting that other factors such as the specific drug, dose, and different characteristics of the study population, including the misdiagnosis of pneumonia itself, may affect this risk.

Contradictory findings were reported in the TORCH study (Towards a Revolution in COPD Health) by Crim C et al. in 2009¹⁵, which first reported the risk of pneumonia due to the use of inhaled corticosteroids. The authors found a relative risk of pneumonia of 1.52 (1.32-1.76), as well as an incidence rate of pneumonia per 100,000 people: 5200 for non-users of inhaled corticosteroids and 8800 for users. This finding is also consistent with the study by Lee JH et al. in Korea in 2020¹⁶, where pneumonia was diagnosed more frequently in users of inhaled corticosteroids compared to non-users (33.7% vs. 24.5%, p<0.001), with an incidence rate per 100,000 people: 8904 for users of inhaled corticosteroids and 6206 for non-users. Similarly, Cheng H et al. conducted a meta-analysis in 2021¹⁷, analyzing 59 randomized clinical trials, including recent studies, which revealed that all types of inhaled corticosteroids increase the risk of pneumonia in COPD patients, with a dose-response relationship confirming the causality between the two variables in question.

In our study, the only independent factor significantly associated with acquiring CAP in COPD patients is age, affirming that the risk of CAP increases by 9% with each year of age, with a mean age of 76.1 years. Similar findings were reported by Mullerova et al. in the UK in 2012¹⁸and Crim C et al. in 2015¹⁹, indicating in both studies that COPD patients over the age of 65 are significantly associated with a higher risk of CAP.

However, Sheng Hao Lin et al. in 2016²⁰concluded that both age greater/equal to 55 years and a reduced BMI (<25 kg/m2) are considered independent risk factors for developing CAP in COPD patients. They based this on the reasoning that older individuals have a deteriorated functional state and those with a decreased BMI may have a strong association with the immune response. However, in the multivariate analysis, malnutrition (BMI <18.5 kg/m2) did not show a significant association, so malnutrition cannot be considered a risk factor for CAP in COPD patients.

On the other hand, no significant difference was observed between males and females. In other words, both male and female COPD patients have similar risks of developing CAP. Jain NK et al. in India in 2011²¹state that gender differences vary in terms of clinical presentation, radiological expression of COPD, and comorbidities each gender presents, which suggests that there is no difference between the sexes in the presentation of complications. They even refer to a sociocultural factor that often goes unnoticed, stating that the prevailing notion that COPD mainly affects men may put women at particular risk of underdiagnosis.

Regarding smoking, it could not be demonstrated as a risk factor for CAP in COPD patients. Dionne CW et al. in 2017 in the UK²²also found no differences in the risk of CAP between non-smokers and current smokers, indicating that smoking does not have an additional impact on the risk of pneumonia in COPD patients. Furthermore, the study refers to the existing pathophysiological differences among COPD subgroups that could contribute to the observed differences in the risk of CAP. Although there are theoretical mechanisms related to the increased risk of pneumonia due to smoking, such as physiological and structural changes caused by smoking, increased bacterial virulence, and smoking-induced dysregulation of immune function, further research is needed to establish smoking as a risk factor.

In conclusion, our study has limitations. While it provides some clarity regarding the relationship between the variables under investigation, being a retrospective case-control study does not establish an absolute reality. This warrants the need for more complex studies. Additionally, the information obtained from the patients' medical records was used, and it is important to note that the veracity of the data could not be verified; therefore, it was assumed to be true. In other words, there is a possibility of information bias.

CONCLUSION

It is concluded that the use of inhaled corticosteroids is not a risk factor for CAP in patients with COPD. It is recommended to promote further research studies in order to obtain a more representative sample and keep the information updated based on our current reality.