Ans Pauwels

Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique

Background Oesophageal intraluminal impedance is currently used for assessment of reflux in gastro-oesophageal reflux disease (GORD). Oesophageal mucosa integrity may have a key role in heartburn perception in non-erosive reflux disease (NERD). Severe erosive oesophagitis is associated with low impedance baseline. We hypothesised that impedance baseline measurements could be used to evaluate changes in oesophageal mucosa integrity in man. Methods We measured oesophageal impedance baseline before, during and after acid perfusion in rabbits and healthy subjects. Transepithelial resistance (TER) was determined and dilated intercellular spaces (DIS) were assessed in isolated rabbit oesophageal mucosa. Impedance baseline was measured retrospectively at different levels of the oesophagus in impedance-pH recordings from asymptomatic volunteers and patients with GORD. Results In healthy subjects and rabbits, impedance baseline dropped dramatically during perfusion of control solution (pH 7.2) but after perfusion, impedance recovered. In rabbits, after perfusion with saline pH 1.5 and 1.0 impedance values remained a 39.1±7.0% and 63.9±6.5% (p<0.05) lower respectively. There was a positive correlation between in vivo basal impedance and in vitro TER values (r=0.72, p=0.0021). Tissue showed no erosions but both acidic solutions induced DIS. In healthy subjects, after perfusion with saline pH 2.0 and 1.0 the impedance baseline remained lower a 21.9±6.5% and 52.7±5.0%, (p<0.0001) respectively. Patients with GORD have a lower impedance baseline than healthy volunteers at the distal oesophagus. Conclusions Impedance baseline measurements might be used to evaluate the status of the oesophageal mucosa and to study the role of the impaired mucosal integrity in acid-induced heartburn in healthy volunteers and in patients with GORD.

Acid and weakly acidic solutions impair mucosal integrity of distal exposed and proximal non-exposed human oesophagus

Background Oesophageal mucosa dilated intercellular spaces (DIS) may be important for symptom perception in non-erosive reflux disease (NERD). Patients with NERD might have DIS even in the proximal oesophagus. We aimed to assess the effect of oesophageal perfusions with acid and weakly acidic solutions on ‘exposed’ and ‘non-exposed’ oesophageal mucosa and its relationship to symptoms in healthy subjects. Methods 14 healthy volunteers underwent upper gastrointestinal endoscopy with biopsies at 3 and 13 cm proximal to the oesophagogastric junction (OGJ). In following sessions, subjects received 30 min perfusions with neutral, weakly acidic, acidic and acidic-bile acid solutions at 5 cm above the EGJ (separated 4 weeks). Biopsies were taken 20 min after perfusions. Electron microscopy was used to measure DIS. Subjects scored heartburn during perfusions using a visual analogue scale. Results (1) Oesophageal perfusion with acid solutions, with or without bile acids, provoked DIS in the ‘exposed’ oesophageal mucosa; (2) oesophageal perfusion with weakly acidic solutions provoked identical changes to those observed after perfusion with acid solutions; (3) distal oesophageal perfusions not only provoked changes in the ‘exposed’ but also in the more proximal ‘non-exposed’ mucosa; and (4) in spite of the presence of perfusion-induced DIS, most healthy subjects did not perceive heartburn during the experiments. Conclusions The human oesophageal mucosa is very sensitive to continuous exposure with acidic and weakly acidic solutions. In spite of the presence of intraluminal acid and DIS, healthy subjects did not experience heartburn, suggesting that NERD patients should have other critical factors underlying their symptoms.

Azithromycin Reduces Gastroesophageal Reflux and Aspiration in Lung Transplant Recipients

Azithromycin (AZI) is a macrolide antibiotic that improves lung function in lung transplant recipients (LTx). Gastroesophageal reflux (GER) has been implicated in the pathogenesis of chronic rejection after LTx. Macrolide antibiotics may affect GER by modifying esophageal and gastric motility. The purpose of this study was to evaluate the effect of AZI on GER and gastric aspiration after LTx. Acid and weakly acidic GER was measured with 24-h pH-impedance monitoring in 47 LTx patients (12 patients “on” AZI). Gastric aspiration was assessed in a separate group of 30 LTx patients before and after AZI by measurements of pepsin and bile acid in bronchoalveolar lavage fluid (BALF). Patients “on” AZI had a significant lower total number of reflux events [41 (30–61) vs. 22.5 (7–37.5)], number of acid reflux events [24 (16–41) vs. 8 (4–18)], esophageal acid exposure [2.9% (0.7–7.3) vs. 0.2% (0.1–2.0)], bolus exposure [0.73% (0.5–1.4) vs. 0.21% (0.12–0.92)], and proximal extent of reflux [14 (9–24) vs. 5 (2–7)]. AZI reduced the concentration of bile acids in BALF without affecting levels of pepsin. LTx patients “on” AZI have less GER and bile acids aspiration. This effect might be due to enhanced esophageal motility and accelerated gastric emptying.

Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis.

Objectives: Increased gastroesophageal reflux (GER) is common in children with cystic fibrosis (CF). We studied the occurrence of acid, weakly acidic (WA), and weakly alkaline (WALK) reflux in children with CF and evaluated a possible surrogate marker for risk of gastric content aspiration. Patients and Methods: Twenty-four children with CF underwent impedance-pH monitoring for detection of acid (pH < 4), WA (pH 4-7), and WALK-GER (pH ≥ 7). In 11 children, cough was objectively recorded with esophageal manometry and the symptom association probability was calculated to determine the reflux-cough relation. Presence of bile acids (BA) was measured in the saliva of 65 patients with CF and 23 healthy children, respectively. Results: Sixteen of the 24 children had increased GER (esophageal acid exposure). The majority of reflux events were acidic in nature. WA reflux was less common and WALK reflux was rare. The sequence reflux-cough was found in 8 of the 11 children and 1 of 11 children had a positive symptom association probability for reflux-cough. The sequence cough-reflux was found in only 3 of the 11 children. Only a small fraction of the total esophageal acid and volume exposure was secondary to cough. Twenty-three of the 65 children with CF had BA in saliva compared with none of the healthy controls. Conclusions: Although WA-GER is uncommon, acid GER is prevalent in children with CF. It is a primary phenomenon and is not secondary to cough. One third of the children with CF have BA in saliva, which may indicate an increased risk for aspiration. However, the impact of salivary BA and potential aspiration on CF pulmonary disease needs further investigation.

Botulinum toxin reduces Dysphagia in patients with nonachalasia primary esophageal motility disorders.

BACKGROUND & AIMS Endoscopic injection of botulinum toxin (BTX) has shown benefits for patients with diffuse esophageal spasm (DES) and nutcracker esophagus (NE) in small uncontrolled trials. We investigated the effect of BTX on symptoms of patients with DES or NE and assessed manometry findings in a prospective, double-blind, randomized, controlled study. METHODS We assessed 22 patients with dysphagia-predominant, manometry-confirmed DES or NE (6 men; age, 63 ± 2 y) at a tertiary care medical center. Patients were given injections of BTX (8 × 12.5 U) or saline (8 × 0.5 mL) in 4 quadrants, at 2 and 7 cm above the esophagogastric junction. After 1 month, patients crossed over between groups and received endoscopic injections of BTX or saline. When the study began and 4 weeks after each injection, the patients were assessed by esophageal manometry and completed a symptom questionnaire (to determine solid and liquid dysphagia, chest pain, and regurgitation and heartburn; all scored 0-4). Responders were defined based on modified Vantrappen criteria for achalasia. RESULTS After BTX injections, patients had significant decreases in total symptom scores (sum of solid and liquid dysphagia and chest pain; from 7.6 ± 0.7 to 4.8 ± 0.8; P = .01); this decrease was not observed in patients who received saline injections. Moreover, BTX injection stabilized unintentional weight loss (weight gain of 0.3 ± 0.3 after BTX injection vs further weight loss of 1.6 ± 0.5 kg after saline injection; P = .01). Fifty percent of patients had a response 1 month after BTX injection, compared with 10% after saline injection (P = .04); 30% still had a response 1 year after BTX injection. BTX injection also caused a significant decrease in the mean esophagogastric junction pressure, compared with baseline (15.8 ± 1.7 vs 24.0 ± 2.8 mm Hg; P = .02). CONCLUSIONS In a prospective controlled study of patients with DES and NE, injections of BTX reduced symptoms and stabilized unintentional weight loss. TRIAL REGISTRY http://www.targid.eu, ML2669, ML6294.

Mechanisms of Increased Gastroesophageal Reflux in Patients With Cystic Fibrosis

OBJECTIVES:Up to 80% of patients with cystic fibrosis (CF) may have increased gastroesophageal reflux (GER). It has been suggested that increased GER is due to low basal lower esophageal sphincter (LES) pressure and a high number of transient LES relaxations (TLESRs). The aim of our study was to reassess the mechanisms of GER in adult CF patients using state of the art upper-gastrointestinal physiology techniques: high-resolution manometry impedance (HRM-MII).METHODS:We studied 12 CF patients (age 32 range (19–58), 5 males/7 females) and 11 age-matched healthy volunteers (age 27 range (20–36), 4 males /7 females). HRM-MII was performed in a semi-recumbent position for 30 min during fasting and for 2 h after a standard meal (1,000 kcal). We measured total reflux and proximal extent of reflux with impedance; basal LES pressure, TLESRs, and gastroesophageal pressure gradient (GEPG) with HRM.RESULTS:Basal LES pressure was lower in CF patients compared with healthy controls, both in the pre- and postprandial period (preprandial 13 (7–22) vs. 24 (13–26) mm Hg, P=0.04; postprandial 10 (8–14) vs. 18 (10–31) mm Hg, P=0.01) and TLESRs were the main mechanism for reflux both in CF and in controls. We could not find a difference in the number of TLESRs in CF patients compared with healthy (14 (10–20) vs. 13 (10–24), P=not significant). However, reflux during TLESRs was more frequent in CF compared with healthy volunteers (80 (70–95) vs. 42 (20–78) %, P=0.0058). GEPG during TLESRs was significantly higher in CF than in controls during inspiration (13.5 (9.5–15.8) vs. 7 (4–9.9) mm Hg, P=0.004). This difference was due to a lower inspiratory intra-thoracic pressure in CF patients (−8.2 (−10.2–(−4.6) vs. −0.08 (−5.7–2.7) mm Hg, P=0.002). Compared with controls, CF patients had significantly higher number of reflux episodes (13 (6–20) vs. 7 (3–9), P=0.014) and CF patients also showed a higher proportion of reflux episodes with a high proximal extent compared with healthy volunteers (49 (22–50) vs. 0 (0–17) %, P=0.0028).CONCLUSIONS:CF patients have increased GER with a high proximal extent. Although we could not find a higher number of TLESRs in CF, there is a higher proportion of TLESRs associated with reflux. Unlike non-CF GER disease patients (with increased intra-abdominal pressure), reflux during TLESRs in CF is probably due to an increased GEPG mainly generated by a greater inspiratory negative intra-thoracic pressure.

Bile Acids in Sputum and Increased Airway Inflammation in Patients With Cystic Fibrosis

BACKGROUND Up to 80% of patients with cystic fibrosis (CF) may have increased gastroesophageal reflux and aspiration of duodenogastric contents into the lungs. We aimed to assess aspiration in patients with CF by measuring duodenogastric components in induced sputum and to investigate whether the presence of bile acids (BAs) in sputum was correlated with disease severity and markers of inflammation. METHODS In 41 patients with CF, 15 healthy volunteers, 29 patients with asthma, and 28 patients with chronic cough, sputum was obtained after inhalation of hypertonic saline. Sputum supernatant was tested for BA and neutrophil elastase. Spirometry and BMI were assessed on the day of sputum collection. RESULTS Two of 15 healthy patients (13%), eight of 29 patients (28%) with asthma, four of 28 patients (14%) with chronic cough, and 23 of 41 patients (56%) with CF had BA in sputum. BA concentrations were similar in patients who are positive for BA with genotype F508del homozygote, F508del heterozygote, and other CF mutations and were not related with BMI and age. Patients with CF with BA in sputum had a higher concentration of neutrophil elastase compared with patients without BA in sputum (31.25 [20.33-54.78] μg/mL vs 14.45 [7.11-27.88] μg/mL, P < .05). There was a significant correlation between BA concentrations and dynamic lung volumes (FEV(1) % predicted [r = -0.53, P < .01], FVC% [r = -0.59, P < .01]) as well as with number of days of antibiotic IV treatment (r = 0.58, P < .01). CONCLUSIONS BAs are present in the sputum of more than one-half of patients with CF, suggesting aspiration of duodenogastric contents. Aspiration of BA was associated with increased airway inflammation. In patients with BA aspiration, the levels of BA were clearly associated with the degree of lung function impairment as well as the need for IV antibiotic treatment.

The Sputum Colour Chart as a predictor of lung inflammation, proteolysis and damage in non-cystic fibrosis bronchiectasis: a case-control analysis.

Non‐cystic fibrosis bronchiectasis (NCFB) is characterized by a vicious cycle of airway infection, inflammation and structural damage with inappropriate mucus clearance. Our aim was to relate the value of proteolytic enzymes, proteolytic enzyme activity and inflammatory markers to disease severity and symptoms in patients with NCFB.

Bile Acids Aspiration Reduces Survival in Lung Transplant Recipients with BOS Despite Azithromycin

Azithromycin (AZM) improved bronchiolitis obliterans syndrome (BOS) and reduced aspiration in lung transplant (LTx) recipients. We hypothesize that AZM could improve graft and overall survival more efficiently in LTx patients with BOS who have bile acid (BA) aspiration by protecting against the aspiration‐induced progression of BOS. The goal was to compare FEV1 (% baseline), BOS progression and overall survival in LTx recipients treated with AZM for BOS, both with versus without BA aspiration. Therefore, LTx recipients treated with AZM for BOS were recruited and broncho‐alveolar lavage (BAL) samples were analyzed for the presence of BA and neutrophilia before the start of AZM treatment. Short‐term effect of AZM on FEV1 and BAL neutrophilia was assessed, progression of BOS and survival were followed‐up for 3 years and results were compared between patients with/without BA aspiration. 19/37 LTx patients had BA in BAL. BA aspiration predisposed to a significantly worse outcome, in terms of decline in FEV1, progression of BOS ≥ 1 and survival. AZM does not seem to protect against the long‐term allograft dysfunction caused by gastroesophageal reflux (GER) and aspiration and an additional treatment targeting aspiration may be indicated in those LTx patients.

Gastric emptying and different types of reflux in adult patients with cystic fibrosis

Aliment Pharmacol Ther 2011; 34: 799–807