Inhaled corticosteroids and the increased risk of pneumonia: what's new? A 2015 updated review

Abstract

There is a considerable amount of evidence that supports the possibility of an increased risk of pneumonia associated with prolonged use of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD). However, as yet, no statistically significant increase in pneumonia-related 30-day mortality in patients on ICS has been demonstrated. The lack of objective pneumonia definitions and radiological confirmations have been a major source of bias, because of the similarities in clinical presentation between pneumonia and acute exacerbations of COPD. One of the newer fluticasone furoate studies overcomes these limitations and also provides an assessment of a range of doses, suggesting that the therapeutic window is quite narrow and that conventional dosing has probably been too high, although the absolute risk may be different compared to other drugs. Newer studies were not able to rule out budesonide as responsible for pneumonia, as previous evidence suggested, and there is still need for evidence from head-to-head comparisons in order to better assess possible intra-class differences. Although the exact mechanisms by which ICS increase the risk of pneumonia are not fully understood, the immunosuppressive effects of ICS on the respiratory epithelium and the disruption of the lung microbiome are most likely to be implicated. Given that COPD represents such a complex and heterogeneous disease, attempts are being made to identify clinical phenotypes with clear therapeutic implications, in order to optimize the pharmacological treatment of COPD and avoid the indiscriminate use of ICS. If deemed necessary, gradual withdrawal of ICS appears to be well tolerated. Vaccination against pneumococcus and influenza should be emphasized in patients with COPD receiving ICS. Physicians should keep in mind that signs and symptoms of pneumonia in COPD patients may be initially indistinguishable from those of an exacerbation, and that patients with COPD appear to be at increased risk of developing pneumonia as a complication of ICS therapy.

Keywords: adverse effects; chronic obstructive pulmonary disease (COPD); inhaled corticosteroids; mortality; phenotypes; pneumonia.

Figure 1.

Complexity and heterogeneity of the inflammatory response in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and pneumonia and possible impact of inhaled corticosteroids (ICS). ❶ There is a paradoxical double effect of ICS consisting of increased episodes of pneumonia despite their protective effect on exacerbations. ICS-induced pneumonia events have shown unmodified or even lower mortality rates, perhaps by modulating effect on the local anti-inflammatory response after pneumonia onset. The inhibition of nuclear factor kappa B (NF-ƙB) [Singanayagam et al. 2010], lower neutrophil and lymphocyte counts [Jen et al. 2012], and a reduced systemic inflammatory response (lower interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels] [Ferrer et al. 2014] have been implicated. ❷ Many pneumonia events associated with the use of fluticasone propionate (FP) are preceded by an AECOPD [Calverley et al. 2011]. ❸ The presence of chronic bacterial colonization of the airways has been implicated is the frequency and severity of AECOPD [Patel et al. 2002], particularly in patients with bronchiectasis [Patel et al. 2004]. ❹ ICS are known to increase bacterial load in stable COPD [Garcha et al. 2012], but the role of these changes in the development of an AECOPD is uncertain [Sethi et al. 2007]. ❺ COPD patients have alterations in their lung microbiome that may result in chronic infection with potentially pathogenic microorganisms (PPM) [Miravitlles and Anzueto, 2015], and the use of ICS may further alter this microbiome [Pragman et al. 2012; Huang et al. 2014]. ❻ Chronic use of systemic steroids is a known risk factor for pneumonia [Wolfe et al. 2006]. Nevertheless, some studies have shown benefits when treating pneumonia with systemic corticosteroids to mitigate the immune response [Torres et al. 2015; Tagami et al. 2015; Blum, 2015]. ❼ The role of systemic steroids in the treatment of AECOPD is well established [GOLD, 2015]. ❽ Alternatives to ICS for the prevention of AECOPD include mycolitics, PDE-4 inhibitors such as roflumilast, and prophylactic antibiotics [GOLD, 2015; Criner et al. 2015]. There is also a potential role the new LABA/LAMA combinations (see the text).