The use of impedance pH measurements to determine the effect of gastro-oesophageal reflux in patients with idiopathic pulmonary fibrosis and cystic fibrosis

Abstract

Introduction For many decades gastrooesophageal reflux has been implicated in patients suffering from lung disease and in lung allograft injury. From the early 1970s studies have taken place investigating reflux in idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF). However, these early studies were small and used primitive techniques to assess reflux. In addition, the role of microaspiration secondary to reflux has often been postulated as a cause of deteriorating lung function in these patients but has been under studied. It is also known that many of these patients require a lung transplant due to end-stage lung disease. Asymptomatic reflux and aspiration may be associated with allograft dysfunction post lung transplant. Early anti-reflux surgery has been suggested to improve long-term survival by treating reflux. This thesis reports a prospective assessment of reflux/aspiration in patients with IPF and CF. In addition, the study reports the largest European series of fundoplication in lung transplant patients. Methods Over a 2 year period patients with IPF and CF were recruited from specialist clinics. All patients completed objective assessment of oesophageal physiology using manometry and impedance-pH. Symptom and quality of life assessment using RSI, Demeester and GIQLI questionnaires were performed on all patients at the time of recruitment. For those patients taking proton pump inhibitor, questionnaires were done ‘on’ and ‘off’ their medication. IPF patients then had a bronchoscopy and lavage (BAL) whilst CF patients produced sputum. Cytospins of the BAL and sputum were produced and differential cell counts were performed and the cells were stained with Oil Red O and Prussian Blue (Perls). ELISA and mass spectrometry assays were also performed on the samples for pepsin and bile salts respectively. Lung transplant patients attended for impedance-pH studies over 3 years and those with symptomat ic reflux or reflux and deteriorating lung function were referred for a laparoscopic fundoplication. Lung function assessment, symptom and quality of life questionnaires were performed before surgery and at 6 weeks and 6 months after surgery Results IPF Patients: Thirty eight patients with IPF were initially approached and 29 consented to be studied. Nine patients dropped out from the study after consent. Twenty patients with IPF completed both the oesophageal physiology and BAL aspects of the investigation. In 12 patients there was objective evidence of reflux including 6 patients with proximal reflux. 60% of patients had an abnormal RSI score whilst taking a PPI and scores for the other questionnaires were not significantly different ‘on’ and ‘off’ PPI. Lung function was not related to the degree of reflux. The principal cell type identified was macrophages and both Oil Red O and haemosiderin scores were well above the normal range. Bile salts were detectable in 17/20 IPF patients but the levels were not higher than the normal range. 11/20 patients had higher than normal levels of pepsin in the BAL. CF Patients: Twenty-six patient with CF consented to the study but 15 dropped out. Eleven CF patients attended for oesophageal investigation and each provided 2 samples of sputum. 9/11 had reflux, including five with proximal reflux. All patients were taking acid- suppression medication and questionnaire assessments were abnormal whilst on their medication with 82% still having a GIQLI score below 121 despite medication for reflux. Twenty one samples of sputum were processed altogether. The principal cell type was neutrophils. Bile salts were detectible in all samples but these were at very low concentrations. Elevated pepsin was seen in 7/11 sputum samples with the median concentration ten times above the normal level. Lung Transplant Patients 16 lung transplant patients with symptomatic reflux or deteriorating lung function and reflux on impedance-pH had a laparoscopic fundoplication. Symptom questionnaire and quality of life assessment was significantly improved in all patients. Half the patients had presented with declining lung function and all showed an improvement in respiratory function after surgery. Summary We have demonstrated that reflux is present in patients with IPF, CF and in patients after lung transplant. Using impedance-pH we have identified patients with proximal reflux. The presence of reflux appears to affect the patients’ quality of life and despite PPI therapy the majority still had symptoms. High levels of haemosiderin stained macrophages in IPF indicate oxidative stress which may or may not be secondary to reflux. Pepsin levels are elevated in both IPF and CF patients, possibly indicating microaspiration. Conclusion Despite PPI therapy there is significant reflux in IPF and CF identifying a clinical gap in patient treatment that should be considered in management. Our results in the post lung- transplant group indicate there is a role for surgery in treating reflux and potentially reducing microaspiration. This has been shown to stabilise lung function in this cohort and may have implications for the treatment of reflux in patients with lung disease before transplantation.