Low incidence of pneumonia in COPD patients treated with inhaled corticosteroids undergoing pulmonary rehabilitation
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Based on meta-analyses results, it is currently acknowledged that there is an increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD) undergoing inhaled corticosteroids (ICS) treatment. However, this is not found to be true in those with asthma. No data on this risk are available for COPD patients involved in pulmonary rehabilitation program (PR).
For 1 year, we prospectively studied 2 cohorts of COPD patients—undergoing PR and not undergoing PR. The first group included 438 patients undergoing PR of which 353 were treated with ICS, and 85 were treated with bronchodilators only. The second group was comprised of 76 COPD patients who were treated with ICS, but not PR. The control group consisted of 49 ICS-treated patients with asthma. The diagnosis of pneumonia, when suspected, had to be confirmed with a chest x-ray.
Overall, 6 cases of pneumonia were diagnosed in the first study group: 5 ICS-treated patients and 1 patient treated only with bronchodilators. This corresponded to a rate of 1.41 and 1.17%, respectively, compared to a rate of 6.6% in COPD patients not treated with PR, which was significantly higher (p = 0.029) than that in the first study group. No case of pneumonia was registered among patients with asthma.
These findings suggest that a significantly lower incidence of pneumonia is found in COPD patients treated with ICS and PR than in patients treated with ICS but not with PR. This observation deserves to be investigated in large populations of PR-treated COPD patients, possibly in multi-centric cohort studies.
KeywordsCOPD Inhaled corticosteroids Pneumonia Pulmonary rehabilitation
chronic obstructive pulmonary disease
forced expiratory volume in 1 s
hospital acquired pneumonia
According to the guidelines of chronic obstructive pulmonary disease (COPD) management, inhaled corticosteroids (ICS) should be prescribed only to patients with a severe or very severe disease (stage 3 or 4), as assessed by a forced expiratory volume in 1 s (FEV1) lower than 50% of the predicted value or by frequent (more than 2/year) exacerbations . In recent years, an increasing number of reports disclosed that in COPD patients treated with ICS, there was a higher risk of developing pneumonia [2, 3]. Systematic reviews and meta-analyses confirmed the significantly higher risk of pneumonia in ICS-treated COPD patients compared with non-ICS treated patients; no significant effect on the mortality rate was detected [4, 5, 6, 7].
In a meta-analysis, a 12-month budesonide treatment did not increase the risk of pneumonia . According to a review, “the immunosuppressive effects of ICS on the respiratory epithelium and the disruption of the lung microbiome are most likely to be implicated”, and the conventional ICS doses are most likely too high . In a UK cohort of 23,013 COPD patients, it was reported that there was a greater risk of pneumonia in patients receiving higher ICS doses . In the same study, based on the lower risk of pneumonia observed in patients treated with extra-fine particle ICS compared with those treated with fine-particle ICS , it was suggested that the kind of the inhalant preparation administered could possibly influence the risk of pneumonia. Thus far, no such studies have been conducted on COPD patients treated with ICS and undergoing pulmonary rehabilitation (PR). This treatment consists of a multidisciplinary care program individually tailored and designed for patients with chronic respiratory impairment in order to optimize physical and social performance and autonomy . PR was shown to reduce COPD exacerbations, often related to respiratory infections, by targeting risk factors such as physical inactivity, decreased exercise capacity and impaired physical functions . This study, carried out in 2016, was conceived to evaluate the incidence of pneumonia in a cohort of COPD patients undergoing PR and treated with ICS or bronchodilators as compared to a control group not treated with PR.
The study prospectively evaluated a cohort of COPD patients undergoing PR based on the insufficient control of the disease despite appropriate drug treatment . To be admitted to the PR program, patients must have a FEV1 lower than 80% of the predicted, as measured by spirometry. Patients were divided in three groups: the first group included PR patients treated with ICS; the second group included PR patients treated only by bronchodilators; and, the third group included non-PR patients treated with ICS. For all COPD patients, the level of exercise capacity was measured by a 6-min walking test  A further group of ICS-treated patients with asthma and a low risk of pneumonia, as shown by a meta-analysis of available randomized trials , served as a control group.
In 2016, all PR patients underwent four or 6-month interval rehabilitative treatments depending on the severity of the disease. PR was performed as previously described . The program, based on a schedule of 12 sessions within a 6-week period, involved exercise training on a cycle-ergometer or treadmill, upper-limb and trunk exercises, respiratory muscle training, and COPD education. Patients were instructed to contact the attending nurse in case of any important health-related events. When symptoms or signs of pneumonia were detected by the general practitioner or the ED physician, the diagnosis of pneumonia had to be confirmed with a chest x-ray.
Differences in incidence of pneumonia were analyzed by the Chi squared test, a p value lower that 0.05 being regarded as positive.
Demographic data and functional values from the different groups of patients
Mean age (years)
Mean FEV1 value (% predicted)
Mean 6-min walking test
COPD patients undergoing PR
303 males, 135 females
COPD patients on PR treated with ICS
234 males, 119 females
COPD patients on PR treated only with bronchodilators
69 males, 16 females
COPD patients not on PR treated with ICS
47 males, 29 females
Asthmatic patients treated with ICS
28 males, 21 females
Discussion and conclusions
Pneumonia events in the general population, in COPD patients and in COPD patients treated with ICS
General population Torres et al. 
COPD patients Kew et al. 
COPD patients treated with fluticasone Kew et al. 
COPD patients treated with budesonide Kew et al. 
1.07–4.2 cases per 1000 person-year. In Italy 1.7 cases per 1000 person-year
Controls in trials with fluticasone (follow-up 22 months): 72 per 1000 Controls in trials with budesonide (follow-up 10 months): 28 per 1000
Follow-up 22 months: 116 per 1000
Follow-up 10 months: 31 per 1000
According to a meta-analysis, PR has several potential benefits, e.g., relieving dyspnea and fatigue, improving exercise capacity, and health-related quality of life, thus enhancing the sense of control that individuals have over their condition. The authors stated that additional RCTs comparing pulmonary rehabilitation and conventional care in COPD are not warranted . Instead, studies on large populations of PR-treated patients are necessary to confirm our observation of reducing the risk of pneumonia by using ICS. On the other hand, a favorable clinical course was reported in hospitalized patients with severe COPD undergoing PR treatment affected by acquired pneumonia while in hospital (HAP) . The zero mortality rate mentioned is relevant, considering the substantial mortality due to HAP. The underlying factors of these outcomes of PR on pneumonia incidence could be possibly due to the beneficial effects of physical activity and patient education. Indeed, in a study on 441 adults undergoing upper abdominal surgery, patients were randomized to receive pre-operative physiotherapy and education (study group) or simply an information booklet (control group). The incidence of HAP was halved in the study group compared with the control group, with an absolute risk reduction of 15% .
Also, the risk of pneumonia is affected by the extent of the subjects physical activity. In fact, in a large population of 109,352 runners and 40,798 walkers, higher doses of running and walking (with no difference between the two) were associated with a lower risk of pneumonia, and a mortality rate decrease of 13%. This outcome appeared to be independent of the effect of exercise on cardiovascular diseases . However, studies are needed to specifically address the incidence of pneumonia in active COPD patients according to the type and extent of their physical exercise. The absence of the risk of pneumonia in patients with asthma, which has been demonstrated by a meta-analysis , although a significant reduction in physical activity has been reported in patients with severe asthma , warrants further investigation.
ER, CI wrote and coordinated the draft of the manuscript. IM, FL, LL, GGRS, AB, BLG collected data, carried out the bibliographic search, contributed to the draft of the manuscript and made substantial contribution to the revision of the article. LP revised the final draft of the manuscript. All authors read and approved the final manuscript.
The authors thank Mrs Elisabeth Stabler for language revision.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Availability of data and materials
The datasets analysed during the current study are available from the corresponding author on reasonable request.
Consent for publication
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All patients signed informed consent.
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