A look at preventing exacerbations

Thursday, 13 Jul 2017

Clinicians should focus on preventing exacerbations in COPD patients with less severe disease as this is where there are potential gains.

According to Dr Frits Franssen, from the Centre of Expertise for Chronic Organ Failure (CIRO) and the Maastricht University Medical Centre in the Netherlands, research has shown exacerbations in patients with disease were associated with larger decreases in FEV1 than patients with more severe disease[1].

He said there was also evidence of a distinct phenotype of susceptibility to exacerbations, which included patients with otherwise mild COPD[2].

“Traditionally there is a focus on more severe patients because they have the most exacerbations. For the future, it would make more sense to target exacerbations in non-COPD patients or those with very mild airflow obstruction. I think there is more to gain in that population.”

Speaking at the Respiratory Insights Forum in Melbourne, Dr Franssen said that since the European Medicines Agency confirmed the risk of pneumonia with all inhaled corticosteroids[3], there has been increasing interest in other treatments for exacerbations.

He said there was substantial evidence that bronchodilators could prevent exacerbations[4][5] but the mechanisms by which they did so was not clear[6].

Multiple causes of exacerbations

The range of possible mechanisms included lowering mucous production, improving mucociliary clearance, anti-inflammatory effects and decreasing hyperinflation.

Dr Franssen told the forum that eformoterol but not tiotropium had been shown to enhance mucociliary clearance in COPD[7]. Another study[8] showed tiotropium did reduce mucociliary clearance time but there was no clinical data showing a relationship between mucus hypersecretion and the effects of bronchodilation on exacerbations, he said

Tiotropium[9] and olodaterol[10] inhibited pulmonary inflammation in animal models of COPD but the clinical relevance of these effects remains unknown, he said.

“Hyperinflation may result in alveolar stress and release of inflammatory cytokines,” he said. “However it is difficult to find original evidence that hyperinflation correlated with exacerbation history.”

Dr Franssen said there was another argument that exacerbations occur when the normal pattern of symptom fluctuations exceeds individual thresholds[11].

“Bronchodilators may increase the threshold at which exacerbations occur rather than change the course of disease,” he said.

 “But exacerbations might also be related to an anxiety attack for example or a weather change so I think that giving these patients bronchodilators won’t prevent any infection but will impact on their thresholds and how they perceive their symptoms.”


[1] Dransfield MT, Kunisaki KM, et al. Acute exacerbations and lung function loss in smokers with and without COPD. AJRCCM. 2016;195(3).

[2] Hurst JR, Vestbo J, et al. Susceptibility to exacerbation in COPD. NEJM. 2010;363:1128-38.

[3] European Medicines Agency. 29/4/16

[4] Calverley PM, Anderson JA, et al. Salmeterol and Fluticasone Propionate and Survival in COPD. NEJM. 2007; 356:775-89.

[5] Puhan MA, Bachmann LM, et al. Inhaled drugs to reduce exacerbations in patients with COPD: a network meta-analysis. BMC Medicine. 2009;7:2.

[6] Beeh KM, Burgel PR, et al. How do long acting bronchodilators prevent exacerbations of COPD? AJRCCM. 2017. In Press.

[7] Meyer T, Reitmeir P, et al. Effects of formoterol and tiotropium bromide on mucus clearance in patients with COPD. Respiratory Medicine. 2011; 105(6):900-06.

[8] Tagaya E, Yagi O, et al. Effect of tiotropium on mucus hypersecretion and airway clearance in patients with COPD. Pulm Pharmacol Ther. 2016;39:81-84.

[9] Pera T, Zuidhof A, et al. Tiotropium inhibits pulmonary inflammation and remodeling in a guinea pig model of COPD. Eur Resp J. 2011;38:789-96.

[10] Wex E, Kollak I, et al. The long acting beta2-adrenoceptor agonist olodaterol attenuates pulmonary inflammation. Br J Pharmacol. 2015;172(14)3537-47.

[11] Vestbo J & Lange P. Prevention of COPD exacerbations: medications & other controversies. ERJ Open Res. 2015;1:000011-2015.


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