Inhaled Corticosteroids as an Associated Risk Factor for Asthmatic Pneumonia: A Literature Review

Asthma patients have commonly been prescribed inhaled corticosteroids (ICSs) as the first line of control therapy. ICSs are associated with an increased risk of pneumonia in chronic obstructive airway disease (COPD) patients. However, the evidence remains controversial in asthma patients. Several observational studies reported an increased risk of pneumonia; however, COPD patients were not excluded clearly in these studies. In observational studies that excluded COPD patients and in randomized controlled trials, ICS use was not found to be associated with the risk of pneumonia. Hence, COPD patients should be excluded in future studies, and the currently available evidence demonstrates that ICS use is not associated with an increased risk of pneumonia in asthma patients.


Introduction And Background
Asthma is a chronic airway disease that has significant morbidity, mortality, and healthcare burden. Glucocorticoids are the cornerstone of maintenance therapy for persistent asthma to prevent exacerbations and optional control and are recommended therapy in major guidelines [1]. Inhaled corticosteroid (ICS) improves asthma control. Subsequently, it improves the quality of life as proven in GOAL study (The Gaining Optimal Asthma Control Study), a randomized controlled trial (RCT) conducted in 2002 [2]. Both systemic and inhaled steroids are widely used in both acute exacerbations and chronic persistent asthma. They also are associated with significant side effects. Systemic steroids are associated with osteoporosis, hyperglycemia, fluid retention, and immunosuppression. ICS is associated with local effects such as oropharyngeal candidiasis and dysphonia, even though they have less systemic side effects.
Pneumonia is a condition commonly associated with chronic lung diseases such as asthma, chronic obstructive airway disease (COPD), and interstitial lung diseases. It has significant morbidity, mortality, and a global healthcare burden. In 2017, influenza and pneumonia had an age-adjusted death rate of 14.3 according to the Centers for Disease Control and Prevention (CDC) [3]. Nearly one-half (48%) of patients hospitalized with community-acquired pneumonia developed severe sepsis, and 4.5% of them developed septic shock [4]. Hence, it is important to recognize risk factors of pneumonia and patient population that are susceptible to pneumonia. Whether ICS increases the risk of lung infections has been a matter of debate in recent years. Clinical equipoise is observed in determining the association of ICS with pneumonia, tuberculous, and non-tuberculous mycobacterial infections in both asthma and COPD patients. The evidence supporting the risk of pneumonia in COPD patients appears to be stronger [5][6][7]. However, fewer studies are focusing on asthma patients, and data remains controversial. In asthma patients, asthma itself is an independent risk factor for invasive pneumococcal disease [8,9]. Additionally, ICS has also been associated with mycobacterial infections in both asthma and COPD patients [10,11]. In this review, we would like to focus on the risk of pneumonia associated with ICS use in asthma patients.

Review Methods
The literature search was conducted on PubMed and Google Scholar by using keywords "asthma," "inhaled corticosteroids," and "pneumonia". The search was then narrowed down by using the Boolean operator "AND", as given in Table 1.  Articles published in languages other than English and of irrelevant content such as studies including only COPD population or those on risk of infections other than pneumonia were excluded. A total of six observational studies, three RCTs, and one meta-analysis, including 86 RCTs, will be discussed in this review.

Discussion
The available evidence in literature can be divided into observational studies and RCTs. Depending on the study protocol, COPD patients were excluded in some studies but not in others. Interestingly, the risk of pneumonia varies depending on whether COPD patients were excluded and also varies among observational studies and RCTs.

Observational Studies
Observational studies conducted on the risk of pneumonia in asthma and COPD patients are given in Table 2.  In studies in which COPD patients were excluded, the risk of pneumonia was found to be not as high as in studies in which COPD patients were not excluded. McKeever et al. performed a nested case-control study using the Health Improvement Network database [14]. COPD patients were excluded in McKeever's study. The study reported that patients with asthma and pneumonia or upper respiratory tract infections were more likely to be using steroids (OR: 1.24; 95% CI: 1.15-1.33) after adjusting for confounders. Festic et al. investigated the risk of pneumonia requiring admission with the prehospital use and after adjusting for the multiple confounding variables with logistic regression, reporting OR separately for asthma and COPD patients [15]. They concluded that prehospital ICS use was not associated with an increased risk of pneumonia in asthma or COPD patients  [17]. After adjusting for the confounders, they did not notice any association of ICS with pneumonia in asthma patients.

Randomized Controlled Trials
The strongest evidence comes from the retrospective analysis of the data from double-blinded clinical trials sponsored by AstraZeneca ( Table 3).   [19]. In the clinical trial safety outcomes, they did not report increased lower respiratory tract infections conferred to fluticasone compared with placebo. Noonan et al. conducted an RCT of 12 weeks' duration with budesonide and formoterol formulations, but pneumonia incidence was not reported [20].
Perhaps, the best overview of RCTs on the subject can be O'Byrne et al.'s meta-analysis [21]. The study included 26 trials and a total of 14,993 patients in the primary dataset, with all trials having at least one treatment arm with budesonide and one placebo. The relative risk (RR) for pneumonia as an adverse effect was 0.52 (95% CI: 0.36-0.76; P = 0.001) and RR for pneumonia as a serious adverse effect was 1.29 (95% CI: 0.53-3.12; P = 0.58). The results were not supportive of an increased risk of pneumonia with ICS use. The secondary dataset of the study included 60 trials with 33,496 patients exposed to budesonide and 2,273 patients exposed to fluticasone and showed similar results. The meta-analysis demonstrated that the use of ICS in asthma patients has no evidence for an increased risk of pneumonia. There was no increased risk with higher doses of budesonide or any difference between budesonide and fluticasone in the trials analyzed in the secondary dataset.

Fluticasone versus Budesonide
In observational studies in which COPD patients were not excluded, fluticasone was demonstrated to have an increased risk of pneumonia compared with budesonide ( Table 4).   [14]. However, in To et al.'s study where COPD patients were excluded, there was no difference in pneumonia risk among low-, medium-, and high-dose groups [16]. In RCTs, there was no difference in pneumonia risk among fluticasone and budesonide [21].

Conclusions
We noticed that the observational studies that reported an increased risk of pneumonia with ICS use did not exclude COPD. When COPD patients were excluded, observational studies did not report an increased risk of pneumonia associated with ICS use. All the clinical trials reported no increased risk conferred by ICS use with pneumonia in asthma patients. Fluticasone seems to be associated with a slightly higher risk of pneumonia in observational studies. However, the findings were not replicated in RCTs. We conclude that ICS use is not associated with increased risk of pneumonia in asthma patients and that COPD patients should be excluded in future studies concerning the risk of pneumonia in asthma patients associated with ICS use.