Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials.

Importance: Alzheimer disease (AD), a neurodegenerative disease characterized by ß-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression. Objective: To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting ß-amyloid oligomers, in participants with prodromal to mild (early) AD. Design, Setting, and Participants: Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2. Data were analyzed up until January 2019 and August 2019, respectively. Interventions: Participants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Results: There were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was -0.17 (95% CI, -0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary end point. Conclusions and Relevance: Crenezumab was well tolerated but did not reduce clinical decline in participants with early AD. Trial Registration: ClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657.

Safety, Tolerability, and Pharmacokinetics of High-Volume Subcutaneous Crenezumab, With and Without Recombinant Human Hyaluronidase in Healthy Volunteers.

Compared with intravenous formulations, subcutaneous (s.c.) formulations of therapeutic monoclonal antibodies may provide increased patient access and more convenient administration options, although historically high-volume s.c. administration (> 10-15 mL) has been challenging. We report results from two phase I studies in healthy participants (GP29523 and GP40201) that evaluated s.c. crenezumab, an anti-Aß monoclonal antibody in development for individuals at risk for autosomal-dominant Alzheimer's disease. GP29523 assessed safety, tolerability, and pharmacokinetics (PK) in 68 participants (aged 50-80 years) who received single ascending doses (600-7,200 mg) of crenezumab or placebo (4-40 mL). GP40201 assessed safety, tolerability, and PK in 72 participants (aged 18-80 years) who received different combinations of dose (1,700-6,800 mg), infusion volume (10-40 mL), and flow rate (2-4 mL/minute), with/without recombinant human hyaluronidase (rHuPH20). There were no serious or dose-limiting adverse events in either study. There were no meaningful differences in pain scores among reference placebo (4 mL), test placebo (4-40 mL), or crenezumab (600-7,200 mg) in GP29523, or across treatments with varying infusion volume, flow rate, dose, or rHuPH20 co-administration or concentration in GP40201. Transient erythema was the most common infusion site reaction in both studies. In GP40201 at volumes of ≥ 20 mL, rHuPH20 co-administration appeared to reduce infusion site swelling incidence, but, in some cases, was associated with larger areas of infusion site erythema. Crenezumab exhibited approximately dose-proportional PK, and s.c. bioavailability was 66% and independent of dose or rHuPH20 co-administration. High-dose, high-concentration, high-volume s.c. crenezumab formulated with/without rHuPH20 was well-tolerated in healthy participants, with an acceptable safety profile.

Safety, Tolerability, and Pharmacokinetics of Crenezumab in Patients with Mild-to-Moderate Alzheimer's Disease Treated with Escalating Doses for up to 133 Weeks.

BACKGROUND: Crenezumab is a fully humanized, monoclonal anti-amyloid-ß immunoglobulin G4 antibody. OBJECTIVE: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. METHODS: In this multicenter, double-blind study, participants (aged 50-90 years) with mild-to-moderate Alzheimer's disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. RESULTS: Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose-proportional and maintained for each dose level. CONCLUSION: Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials.

Evolving pharmacological approaches in gastroesophageal reflux disease.

INTRODUCTION: Proton pump inhibitors (PPIs) have considerably improved quality of life in patients with gastroesophageal reflux disease (GERD). However, many patients remain symptomatic despite standard PPI therapy. AREAS COVERED: This review focuses on evolving therapeutic strategies related to the pathophysiological processes of GERD and insufficient response to PPIs. Several clinical trials evaluated new PPI formulations and newer types of acid-suppressive drugs. These studies have evaluated traditional end points in GERD, but have not shown clinical superiority to current PPIs. Novel therapeutic strategies targeting underlying mechanisms of GERD, such as transient lower esophageal sphincter relaxations (TLESRs) and esophageal hypersensitivity, are being developed for add-on therapy to PPIs. Prokinetic drugs may also have some potential in the add-on treatment of GERD with insufficient response to PPIs. Add-on studies are hampered by insufficient information on optimal patient selection and lack of established end points. EXPERT OPINION: Newer drugs for symptomatic control in GERD have largely focused on improved acid suppression, without evidence of clinical superiority. Drugs targeting esophageal motility and sensitivity to be used as add-onc therapy in PPI insufficient responders have not reached Phase III trials to date, due to difficulties with patient selection, tolerability and end points.

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.

Interobserver and intraobserver variability in pH-impedance analysis between 10 experts and automated analysis.

OBJECTIVE: To determine interobserver and intraobserver variability in pH-impedance interpretation between experts and accuracy of automated analysis (AA). STUDY DESIGN: Ten pediatric 24-hour pH-impedance tracings were analyzed by 10 observers from 7 world groups and with AA. Detection of gastroesophageal reflux (GER) episodes was compared between observers and AA. Intraobserver agreement was assessed in 3 observers after 3 to 5 months. RESULTS: Overall, 1242 liquid and mixed GER events were detected, 490 (42%) were scored by the majority of observers, yielding moderate agreement (Cohen's kappa [κ] = 0.46). Intraclass co-efficient for numbers of GER per study was 0.84 (P < .001). AA has 94% sensitivity rate and 74% specificity rate compared with majority consensus (≥6 observers). Agreement for gas GER was poor (κ = 0.11). Intraobserver agreement was κ = 0.49, κ = 0.71, and κ = 0.85 in 3 observers. CONCLUSION: Interobserver agreement in combined pH-multichannel intraluminal impedance analysis in experts is moderate; only 42% of GER episodes were detected by the majority of observers. Detection of total GER numbers is more consistent. Considering these poor outcomes, AA seems favorable compared with manual analysis because of its reproducibility. However, the lower specificity rate suggests the need for refinement of AA before widespread use can be advocated.

Baclofen improves symptoms and reduces postprandial flow events in patients with rumination and supragastric belching.

BACKGROUND & AIMS: In patients with clinically suspected rumination, esophageal impedance manometry differentiates episodes of rumination (involuntary straining with intragastric pressure increases) from aerophagia/supragastric belching. Treatment options are limited and focused on behavioral therapy. Baclofen, an agonist of the γ-aminobutyric acid B receptor, increases lower esophageal sphincter pressure and decreases swallowing rate. We investigated its effects in these patients. METHODS: High-resolution manometry-impedance recordings were taken from 12 patients (8 women; mean age, 45 years; range, 18-89 years) with clinically suspected rumination or supragastric belching before and during treatment with baclofen (10 mg, 3 times daily). After 30 minutes of recordings, patients received a 1000-kcal solid meal; recordings were then continued for 1 hour. Patients were asked to register symptoms with an event marker. The number of symptoms registered and number and type of flow events were compared before and during treatment. RESULTS: An average of 20 symptom markers (range, 14-34) were recorded at baseline (10 [range, 4-25] for belching and 9 [range, 0-11] for regurgitation). This was significantly reduced to 6 (range, 2-22) (3 [range, 1-15] for belching and 1 [range, 0-13] for regurgitation) during baclofen treatment (P = .01). The number of flow events (473 at baseline [42 reflux, 192 rumination, 188 supragastric belching, and 42 aerophagia]) was significantly reduced to 282 (32 reflux, 99 rumination, 123 supragastric belching, and 13 aerophagia) during baclofen therapy (P = .02). The reduction in flow events correlated with the increase in lower esophageal sphincter pressure (r = -0.62; P = .03) and reduction in swallowing frequency (r = 0.64; P = .02). CONCLUSIONS: Baclofen is an effective treatment for patients with rumination or supragastric belching/aerophagia.

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.

Conservative management of esophageal perforations during pneumatic dilation for idiopathic esophageal achalasia.

BACKGROUND & AIMS: Esophageal perforation is the most serious adverse event of pneumatic dilation (PD) for achalasia; it is usually managed by surgical repair. We investigated risk factors for esophageal perforation after PD and evaluated safety and long-term outcome of nonsurgical management strategies. METHODS: We analyzed medical records of patients with achalasia who were treated with PD from 1992-2010 at the University Hospital Gasthuisberg in Leuven, Belgium; all patients with esophageal perforation were contacted to determine long-term outcomes. Achalasia outcomes were assessed by using the Vantrappen criteria. RESULTS: Of 830 PD procedures performed on 372 patients with manometry-confirmed achalasia (57 ± 1 years, 51% male), 16 were complicated by transmural esophageal perforation (4.3% of patients, 1.9% of dilations). Age >65 years was the only significant risk factor for complications (odds ratio, 3.5; 95% confidence interval, 1.2-10.2). All patients were treated conservatively with broad-spectrum antibiotics and nothing by mouth. In 6 patients (38%) the clinical course was further complicated by a pleural effusion, which required a drain in 4 patients. One patient (6%) died of mediastinal hemorrhage within 12 hours after PD. Patients with complications were discharged after 19 ± 2.3 days, compared with 4 ± 0.2 days for those without complications (P < .0001). Long-term outcomes (mean follow-up, 84 ± 14 months) were determined for 12 patients (75%); 11 had excellent or good outcomes (69%), and 1 had a moderate outcome (6%). CONCLUSIONS: Age >65 years is a significant risk factor for esophageal perforation after PD. Nonsurgical management of transmural esophageal tears is feasible, with favorable short-term and long-term outcomes, but is not devoid of complications.

Nocturnal gastroesophageal reflux revisited by impedance-pH monitoring.

BACKGROUND/AIMS: Impedance-pH monitoring allows detailed characterization of gastroesophageal reflux and esophageal activity associated with reflux. We assessed the characteristics of nocturnal reflux and esophageal activity preceding and following reflux. METHODS: Impedance-pH tracings from 11 healthy subjects and 76 patients with gastroesophageal reflux disease off acid-suppressive therapy were analyzed. Characteristics of nocturnal supine reflux, time distribution and esophageal activity seen on impedance at 2 minute intervals preceding and following reflux were described. RESULTS: Patients had more nocturnal reflux events than healthy subjects (8 [4-12] vs 2 [1-5], P = 0.002), with lower proportion of weakly acidic reflux (57% [35-78] vs 80% [60-100], P = 0.044). Nocturnal reflux was mainly liquid (80%) and reached the proximal esophagus more often in patients (6% vs 0%, P = 0.047). Acid reflux predominated in the first 2 hours (66%) and weakly acidic reflux in the last 3 hours (70%) of the night. Most nocturnal reflux was preceded by aboral flows and cleared by short lasting volume clearance. In patients, prolonged chemical clearance was associated with less esophageal activity. CONCLUSIONS: Nocturnal weakly acidic reflux is as common as acid reflux in patients with gastroesophageal reflux disease, and predominates later in the night. Impedance-pH can predict prolonged chemical clearance after nocturnal acid reflux.

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.

Gastric juice from patients "on" acid suppressive therapy can still provoke a significant inflammatory reaction by human bronchial epithelial cells.

BACKGROUND: Patients with reflux-related respiratory symptoms are frequently treated with proton pump inhibitors (PPI). It is unclear whether aspiration of gastric juice (GJ) from patients "on" PPI can provoke a similar bronchial inflammatory reaction than that observed in patients "off" medication. The goal of this study was to evaluate the effect of GJ from patients with and without PPI treatment on production of IL-8 by human primary bronchial epithelial cells (PBEC). STUDY: PBEC were exposed during 24 hours to GJ (1/1000) from patients "on" (n=10) and "off" (n=13) PPI and to nonacidic gastric components (pepsin and bile acids). IL-8 concentration in supernatant was measured with enzyme-linked immunosorbent assay. Endotoxin level in GJ samples was analyzed with a LAL assay. RESULTS: Exposure of PBEC to GJ from patients "on" PPI provoked a higher production of IL-8 than GJ from patients "off" PPI [279 pg/mL (36 to 498) vs. 11 pg/mL (9 to 27)]. A correlation was found between pH of GJ and IL-8 production (r=0.659, P=0.0006). No correlation was found between IL-8 production and concentration of bile acids or pepsin. Filtration (0.20 [mu]m) of GJ from patients "on" PPI reduced IL-8 production. A positive correlation was found between IL-8 production and endotoxin levels of GJ samples (1/1000) (r=0.654, P=0.0007). CONCLUSIONS: Exposure of bronchial epithelial cells to GJ from patients "on" PPI is able to induce high IL-8 production. These results suggest that aspiration of GJ in patients treated with PPI might still be able to provoke a significant bronchial inflammatory reaction.

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.

Utility of non-endoscopic investigations in the practical management of oesophageal disorders.

The current available methods for diagnosis of GORD are symptom questionnaires, catheter and wireless pH-metry, impedance-pH monitoring and Bilitec(@). Osophageal pH monitoring allows both quantitative analysis of acid reflux and assessment of reflux-symptom association. Impedance-pH monitoring detects all types of reflux (acid and non-acid) and allows assessment of proximal extent of reflux, a relevant parameter for understanding symptoms perception and extraoesophageal symptoms. Bilitec provides a quantitative assessment of duodeno-gastro-oesophageal reflux. Oesophageal motor abnormalities have been associated with GORD symptoms as well as chest pain and dysphagia. High-resolution manometry contributed to re-classify oesphageal motor disorders. However, barium swallows are still essential for evaluation of oesophageal anatomy and combined oesophageal manometry-impedance can assess oesophageal motility and bolus transit simultaneously in a non-radiological way. Still in experimental phase, high-frequency ultrasound allows monitoring of the oesophageal wall thickness and exaggerated longitudinal muscle contraction that might be associated to chest pain and dysphagia. This chapter provides a critical evaluation of the clinical application of these techniques.

Weakly acidic reflux.

The advent of pH impedance monitoring has allowed assessment of the role of weakly acidic reflux, in addition to the traditionally considered acid reflux, in the pathophysiology of gastroesophageal reflux disease. Typical reflux symptoms studied off proton pump inhibitor (PPI) therapy are mainly associated with acid reflux events, while weakly acidic reflux is only significantly associated with symptom occurrence when assessed on PPI therapy. A major role in weakly acidic reflux in the absence of acid suppressive therapy has only been established for reflux-related cough. Further studies are needed to address the impact of weakly acidic reflux on the management and therapeutic choices in gastroesophageal reflux disease patients with symptoms that persist on PPI therapy. There is a lack of outcomes studies addressing the issue of reflux inhibitors and surgery for weakly acidic reflux that persists in patients on PPIs.

Nocturnal weakly acidic reflux promotes aspiration of bile acids in lung transplant recipients.

BACKGROUND: Gastroesophageal reflux (GER) and aspiration of bile acids have been implicated as non-alloimmune risk factors for the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. The aim of our study was to investigate the association between GER and gastric aspiration of bile acids and to establish which reflux characteristics may promote aspiration of bile acids into the lungs and may feature as a potential diagnostic tool in identifying lung transplantation (LTx) patients at risk for aspiration. METHODS: Twenty-four stable LTx recipients were studied 1 year after transplantation. All patients underwent 24-hour ambulatory impedance-pH recording for the detection of acid (pH <4) and weakly acidic (pH 4 to 7) reflux. On the same day, bronchoalveolar lavage fluid (BALF) was collected and then analyzed for the presence of bile acids (Bioquant enzymatic assay). RESULTS: Increased GER was detected in 13 patients, of whom 9 had increased acid reflux and 4 had exclusively increased weakly acidic reflux. Sixteen patients had detectable bile acids in the BALF (0.6 [0.4 to 1.5] micromol/liter). The 24-hour esophageal volume exposure was significantly increased in patients with bile acids compared to patients without bile acids in the BALF. Acid exposure and the number of reflux events (total, acid and weakly acidic) were unrelated to the presence of bile acids in the BALF. However, both nocturnal volume exposure and the number of nocturnal weakly acidic reflux events were significantly higher in patients with bile acids in the BALF. CONCLUSIONS: Weakly acidic reflux events, especially during the night, are associated with the aspiration of bile acids in LTx recipients and may therefore feature as a potential risk factor for the development of BOS.

Cough and gastroesophageal reflux: from the gastroenterologist end.

Gastroesophageal reflux (GER) is one of the three most common causes of chronic unexplained cough. Diagnosing GER-related cough is challenging since many patients do not have esophagitis or an increased esophageal acid exposure during 24 h esophageal pH-metry. A significant time association between acid reflux and cough can be demonstrated in a subgroup of patients, even if the total esophageal acid exposure is normal. Establishing an exact time relationship between reflux and cough requires objective measurements of both cough and reflux episodes. A variety of techniques for cough assessment are available, including sound recordings and continuous measurement of gastroesophageal pressures. The Symptom Association Probability (SAP) has been suggested as the most reliable algorithm to establish the non-chance association between GER and cough. Although the relationship between acid reflux and cough is generally accepted, the response rate of patients with chronic unexplained cough to proton pump inhibitor treatment (PPI) is poorer compared to that in patients with typical GERD symptoms. Combined impedance-pH recordings, a new technique for the measurement of all types of reflux, have recently shown that not only acid but also weakly acidic GER may be associated with cough. Moreover, measurements in patients "on" PPI therapy demonstrated that weakly acidic reflux may persist during PPI treatment and may be associated with cough. Aspiration of gastric contents into the lungs and a vagally mediated reflex arc, originating from the distal esophagus, have been proposed as pathophysiological mechanisms in GER-related cough. More recently, reflux induced bronchial hypersensitivity has been proposed as a third underlying mechanism. Treatment of GER-related cough remains challenging. So far, long term PPI treatments produce unsatisfactory results. In patients not responding to PPI, weakly acidic GER might still be the cause of cough. In these patients other therapeutic strategies i.e. abolishing all types of GER might need to be considered. Antireflux surgery has been performed successfully in a group of patients with GER-related cough. However, controlled, prospective outcome studies are necessary to confirm the role of antireflux treatments in the management of GER-related cough.

Airway colonization and gastric aspiration after lung transplantation: do birds of a feather flock together?

BACKGROUND: Both gastroesophageal reflux and airway colonization with Pseudomonas aeruginosa (P aeruginosa) are common in lung transplantation (LTx) recipients. There is mounting evidence that, due to their interaction with the epithelium, both may be involved in chronic allograft dysfunction/bronchiolitis obliterans syndrome (BOS) after LTx. We investigated whether gastric aspiration and airway colonization with P aeruginosa after LTx are associated. METHODS: In this retrospective, cross-sectional, case-control study, 24 stable double (SS) LTx recipients were included. Markers of gastroesophageal reflux (pepsin, bile acids) and airway inflammation (neutrophilia and interleukin-8 (IL-8)) were evaluated in bronchoalveolar lavage (BAL) samples of post-operatively colonized (n = 12) and non-colonized matched-control LTx recipients (n = 12). RESULTS: BAL bile acid levels, but not pepsin levels, as well as neutrophilia and IL-8 protein levels were significantly elevated in colonized compared with non-colonized patients. Furthermore, bile acid levels, but not pepsin levels, correlated positively with BAL neutrophilia and IL-8 protein levels. CONCLUSIONS: Bile acid aspiration and airway colonization by P aeruginosa after LTx seem to be associated. This relationship between reflux and airway colonization and their role in the development of chronic allograft dysfunction/BOS after LTx should be further elucidated; nevertheless, induction of IL-8-mediated neutrophilic airway inflammation may be a putative mechanism.

Reflux cough.

Cough can be an extraesophageal manifestation of gastroesophageal reflux disease. This article summarizes recent progress in our understanding of the pathophysiology, diagnosis, and treatment of the reflux cough syndrome. Recent studies have provided further evidence for a role of weakly acidic gastroesophageal reflux in inducing cough. It has also been established that although reflux may induce cough, cough may also trigger reflux in some patients, and distinguishing between the two requires objective detection of cough burst (ie, by esophageal manometry). Treatment of the reflux cough syndrome is an issue of ongoing controversy and further studies.