Risk factors for lung disease progression in children with cystic fibrosis

Abstract

We read with interest the recent paper by VAN HORCK et al. [1], which studied 545 children followed for 5 years with longitudinal data from the Dutch Cystic Fibrosis registry. Data from 2009 to 2014 showed that proton pump inhibitor (PPI) use was associated with annual decline of % predicted forced expiratory volume in 1 s and future pulmonary exacerbation rates. In a discussion of potential mechanisms, the authors considered that bacteria are normally killed by acid conditions in the stomach but that gastric pH is raised following PPI use. It was therefore hypothesised that with extra-oesophageal reflux, surviving pathogens could reach the upper airway and be aspirated.We have described the microbiomes isolated from the gastric juice and sputum of PPI-treated adults with cystic fibrosis (CF) lung disease [2]. This showed that all gastric and sputum cultures grew bacteria and/or fungi. Possible communication between the gut and lung microbiome in CF were indicated by describing identical strains of Pseudomonas aeruginosa in sputum and gastric juice from the same patient.The swallowing of expectorated sputum is a normal homeostatic mechanism that could explain our observation of identical microorganisms in the gut and lung environments. We also documented symptoms of extra-oesophageal, gastroduodenal reflux, a known precursor to aspiration. This indicates the possibility of gut to lung movement of micro-organisms, considered by VAN HORCK et al. [1], and a potential mechanism long-recognised in lung disease. Micro-aspiration and potential gut to lung microbial movement has also been shown in radiolabel studies of normal subjects [3,4].In supporting data we have looked at the relationship between pH and the microbiology of gastric juice. We found that microbes, including P. aeruginosa, were detected in gastric juice where pH was ⩾4.0 [5]. This supports the concept that PPI use could encourage the survival of micro-organisms in gastric juice, which could be translocated to the lung following reflux and micro-aspiration.A recent global survey of patients, carers and clinicians has indicated that "relieving gastrointestinal symptoms" and "simplifying treatment" were in the top three of 10 consensus research priorities identified in CF [6]. We therefore agree with the view expressed by VAN HORCK et al. [1], that the association between PPI use and lung disease progression in CF requires investigation. We feel that such "aerodigestive" studies may be relevant for other chronic lung diseases where reflux has been implicated [7] and where PPI treatment is common. For example, non-CF patients with co-existing bronchiectasis and reflux have increased chronic infection, and reduced pulmonary function and quality of life [8], with associated increase in mortality [9].

Exposure to bile and gastric juice can impact the aerodigestive microbiome in people with cystic fibrosis

“…CF patients may also take acid inhibition medication to enhance the efficacy of pancreatic enzyme replacement therapy; a mainstay of modern CF patient care, associated with better life expectancy 43,44 . While generally considered a safe therapeutic approach, the role of ant-acid treatment and reflux in CF is an area of current debate 45,46 . Recent reviews and patient and public involvement identify this as an important research gap 47 .…”