Relevance of measuring substances in bronchoalveolar lavage fluid for detecting aspiration-associated extraesophageal reflux disease

We read with great interest the paper by Ozdemir et al (1) on the assay of lipid-laden macrophages (LLMs) in broncho-alveolar lavage (BAL) fluid of patients with chronic cough as a marker of micro-aspiration of refluxate into airways. The Authors found that patients with abnormal extra-esophageal reflux as measured by 24-hour impedance-pH monitoring had higher LLM positivity in BAL specimens than those with normal reflux and accordingly, they suggested that this BAL finding should be used to diagnose aspiration in reflux-related chronic cough. The measurement of LLMs from BAL specimens is one of the most widely used tests to identify aspiration-associated extra-esophageal reflux disease (AERD), particularly in children (2). This test is based on the hypothesis that refluxate is phagocytosed by alveolar macrophages and that staining for those in the BAL fluid would verify the presence of AERD. However, previous studies have demonstrated conflicting results, because an increase in LLMs has been observed not only in reflux patients, but also in those without reflux and in any disorder leading to pulmonary inflammation (3,4). On the other hand, search for pepsin and bile acids in BAL has been shown to represent a more valid and specific biomarker of micro-aspiration in patients with objective evidence of abnormal reflux burden since, up to now, no studies measured their presence in BAL of healthy volunteers or patient-controls without evidence of reflux disease (5). Thus, the detection of the above substances in BAL has been overall considered as a strong confirmation of gastric contents coming up from the stomach into the airways. Ozdemir et al stated that BAL pepsin levels have been studied very poorly to diagnose gastro-esophageal reflux (GERD) in patients with respiratory symptoms and quote the only investigation by Decalmer et al (6), in which the Authors found in controls lower levels of pepsin than those detected in chronic cough patients. However, it must be emphasized that in this study various respiratory conditions beyond GERD were considered to elucidate the presence of unexplained chronic cough and this may have been an important confounding factor. In our laboratory the detection of pepsin and bile acids in BAL of patients with GERD was also performed in a recent study (7) using impedance-pH monitoring, which is nowadays considered to be the best test for measuring gastro-esophageal reflux, also in case of atypical manifestations of GERD (8-10). We found that patients with idiopathic pulmonary fibrosis (IPF) had significantly higher esophageal acid exposure and greater number of acid refluxes than controls, but also weakly acidic refluxes were remarkably increased. Moreover, more bile acids and pepsin were measured in BAL as a sound marker of gastric aspiration in the upper airways of these patients. Further studies carried out in patients with various pulmonary conditions corroborated our findings (11,12). So far, we would like to emphasize that the detection of various substances in BAL can be of great help in the diagnosis of micro-aspiration of refluxate which is able to induce chronic cough and other respiratory symptoms, but the assay of bile acids or pepsin levels seems to provide us with a more valid and reliable marker of contents reaching the larynx and pharynx from the stomach

Pathophysiological studies are mandatory to understand the benefit of proton pump inhibitors in patients with idiopathic pulmonary fibrosis

none4noWe read with great interest the paper by Lee et al on the protective effect of proton pump inhibitors (PPIs) for survival in patients with GERD and idiopathic pulmonary fibrosis (IPF). The Authors reviewed a very large number of consecutive adult patients with IPF (n=786) and concluded that the prevalence of GERD is lower in Korean patients than in other countries and that PPI use for at least 4 months may have a protective effect against IPF-related mortality. Although these data appear interesting, relevant limitations of this study were its retrospective nature and the fact that the diagnosis of GERD was not based on sound methods, in that only 18 out of 107 patients had erosive esophagitis at endoscopy, while the remaining ones had NERD (n=66) or typical reflux symptoms without EGD (n=23). Moreover, no functional tests were performed (or described) in them. This is particularly relevant since it has been shown in previous series that a large number of IPF patients lack of GERD symptoms despite objective evidence of GERD at endoscopy or reflux monitoring. Indeed, in IPF patients a phenomenon so called “silent reflux” has been described and the consequent microaspiration into the lungs has been mainly implicated in the pathogenesis of this condition. In contrast with the paper of Lee et al (1), many previous studies have reported a higher prevalence of GERD in patients with IPF, and this important relationship has been sustained by pathophysiological investigations which allowed to detect objectively the presence of an abnormal reflux. For instance, Lee et al did not mention a study in IPF individuals performed with 24-hour impedance pH monitoring, which is nowadays considered to be the best test for measuring gastroesophageal reflux, also in case of atypical manifestations. In this study, patients with IPF had significantly higher esophageal acid exposure and greater number of acid refluxes than controls, but also weakly acidic refluxes were remarkably increased (9). Furthermore, more bile acids and pepsin were detected in both broncheoalveolar lavage fluid and saliva as strong confirmation of the risk of gastric aspiration in upper airways of these patients. Similarly, in an earlier pathophysiological study in a group of scleroderma patients with various degrees of pulmonary fibrosis based on high resolution computed tomography, not only acid but also weakly acidic refluxes were found much higher in patients with more severe than in those with mild or moderate pulmonary fibrosis (10). In conclusion, we would like to emphasize that reflux monitoring plays a fundamental role in confirming the presence of GERD in IPF patients and, therefore, the benefit of PPI use in them should be evaluated in carefully investigated subjects in order to provide stronger evidence that PPI may be helpful for their well being and survivalnoneSavarino, Edoardo; Zentilin, Patrizia; Marabotto, Elisa; Savarino, VincenzoSavarino, EDOARDO VINCENZO; Zentilin, Patrizia; Marabotto, Elisa; Savarino, Vincenz

HCV and fat: Something is missing

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Vonoprazan Fumarate for the Treatment of Gastric Ulcers: A Short Review on Emerging Data

Potassium-competitive acid blockers (P-CABs), such as vonoprazan, represent a novel and heterogeneous class of drugs that competitively block the potassium binding site of gastric H+/K+ ATPase, thus potentially overcoming the limitations of proton-pump inhibitors. Different studies evaluated the efficacy of vonoprazan versus proton-pump inhi-bitors (PPIs) for the treatment of acid-related disorders, and, therefore, P-CABs present the same indications of PPIs: gastroesophageal reflux disease, gastric and duodenal ulcer heal-ing, management of upper gastrointestinal bleeding, non-steroidal anti-inflammatory drug (NSAID)-associated ulcers and Helicobacter pylori eradication therapy. The aim of this review was to evaluate the role of vonoprazan for the treatment of peptic ulcer disease (PUD) and the management of gastric ulcer occurring after endoscopic submucosal dissection (ESD). Indeed, vonoprazan (at the dose of both 10 and 20mg) showed similar results to PPIs in patients taking long-term NSAIDs, in the absence of severe adverse effects, and provided a more rapid and effective treatment of ulcers induced by ESD. However, studies in medical literature are heterogeneous, mainly performed with a retrospective design, and often carried out in Japan only. For these reasons, further prospective, randomized studies are warranted in order to help physicians, patients, and policymakers regarding the use of vonoprazan in clinical practice

Optimal management of constipation associated with irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common chronic functional disorder of the gastrointestinal tract, meanly characterized by recurrent abdominal pain or discomfort and altered bowel habit. It is a complex disorder involving biological, environmental, and psychosocial factors. The diagnosis is achieved according to the Rome III criteria provided that organic causes have been excluded. Although IBS does not constitute a life-threatening condition, it has a remarkable prevalence and profoundly reduces the quality of life with burdening socioeconomic costs. One of the principal concerns about IBS is the lack of effective therapeutic options. Up to 40% of patients are not satisfied with any available medications, especially those suffering from chronic constipation. A correct management of IBS with constipation should evolve through a global approach focused on the patient, starting with careful history taking in order to assess the presence of organic diseases that might trigger the disorder. Therefore, the second step is to examine lifestyle, dietary habits, and psychological status. On these bases, a step-up management of disease is recommended: from fiber and bulking agents, to osmotic laxative drugs, to new molecules like lubiprostone and linaclotide. Although new promising tools for relief of bowel-movement-related symptoms are being discovered, a dedicated doctor-patient relationship still seems to be the key for success

Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility

Irritable bowel syndrome with diarrhoea (IBS-D) and functional diarrhoea (FDr) are the two major functional bowel disorders characterized by diarrhoea. In spite of their high prevalence, IBS-D and FDr are associated with major uncertainties, especially regarding their optimal diagnostic work-up and management. A Delphi consensus was performed with experts from 10 European countries who conducted a literature summary and voting process on 31 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation criteria. Consensus (defined as >80% agreement) was reached for all the statements. The panel agreed with the potential overlapping of IBS-D and FDr. In terms of diagnosis, the consensus supports a symptom-based approach also with the exclusion of alarm symptoms, recommending the evaluation of full blood count, C-reactive protein, serology for coeliac disease, and faecal calprotectin, and consideration of diagnosing bile acid diarrhoea. Colonoscopy with random biopsies in both the right and left colon is recommended in patients older than 50 years and in presence of alarm features. Regarding treatment, a strong consensus was achieved for the use of a diet low fermentable oligo-, di-, monosaccharides and polyols, gut-directed psychological therapies, rifaximin, loperamide, and eluxadoline. A weak or conditional recommendation was achieved for antispasmodics, probiotics, tryciclic antidepressants, bile acid sequestrants, 5-hydroxytryptamine-3 antagonists (i.e. alosetron, ondansetron, or ramosetron). A multinational group of European experts summarized the current state of consensus on the definition, diagnosis, and management of IBS-D and FDr

Proton pump inhibitors: use and misuse in the clinical setting

Introduction: The introduction of proton pump inhibitors (PPIs) into clinical practice has greatly improved our therapeutic approach to acid-related diseases for their efficacy and safety. Areas Covered: The following evidence-based indications for PPI use are acknowledged by many scientific societies: treatment of the various forms and complications of gastroesophageal reflux disease, eradication of H. pylori infection in combination with two or more antibiotics, short- and long-term therapy of H. pylori-negative peptic ulcers, healing, and prevention of NSAID/COXIB-associated gastric ulcers, co-therapy with endoscopic procedures to control upper digestive bleeding and medical treatment of Zollinger Ellison syndrome. Expert Commentary: Despite the above well-defined indications, however, the use of PPIs continues to grow every year in both western and eastern countries and the endless expansion of the PPI market has created important problems for many regulatory authorities for two relevant features: the progressive increase of the costs of therapy and the greater potential harms for the patients. The major reasons for the misuse of PPIs are the prevention of gastro-duodenal ulcers in patients without risk factors and the stress ulcer prophylaxis in non-intensive care units, steroid therapy alone, anti-platelet or anti-coagulant treatment in patients without risk of gastric injury and the overtreatment of functional dyspepsia

Barrett's esophagus in 2016: From pathophysiology to treatment

Esophageal complications caused by gastroesophageal reflux disease (GERD) include reflux esophagitis and Barrett's esophagus (BE). BE is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). The carcinogenic sequence may progress through several steps, from normal esophageal mucosa through BE to EAC. A recent advent of functional esophageal testing (particularly multichannel intraluminal impedance and pH monitoring) has helped to improve our knowledge about GERD pathophysiology, including its complications. Those findings (when properly confirmed) might help to predict BE neoplastic progression. Over the last few decades, the incidence of EAC has continued to rise in Western populations. However, only a minority of BE patients develop EAC, opening the debate regarding the cost-effectiveness of current screening/surveillance strategies. Thus, major efforts in clinical and research practice are focused on new methods for optimal risk assessment that can stratify BE patients at low or high risk of developing EAC, which should improve the cost effectiveness of screening/surveillance programs and consequently significantly affect health-care costs. Furthermore, the area of BE therapeutic management is rapidly evolving. Endoscopic eradication therapies have been shown to be effective, and new therapeutic options for BE and EAC have emerged. The aim of the present review article is to highlight the status of screening/surveillance programs and the current progress of BE therapy. Moreover, we discuss the recent introduction of novel esophageal pathophysiological exams that have improved the knowledge of the mechanisms linking GERD to BE

Vonoprazan for treatment of gastroesophageal reflux: pharmacodynamic and pharmacokinetic considerations

This review provides an update on the pharmacokinetic properties of vonoprazan and their correlates with pharmacodynamics; preliminary data on the therapeutic efficacy of vonoprazan as compared to lansoprazole in GERD patients Expert opinion: At variance from all available PPIs, vonoprazan acts directly on H+,K+-ATPase irrespectively of its activity, providing a fast onset of action without requiring acid activation and specific administration timing. Clinical and pharmacological investigations have confirmed a more rapid, potent and prolonged inhibition of acid secretion, including a better nighttime acid control, and a less antisecretory variability, as compared with PPIs. Preliminary data in patients with erosive esophagitis (EE) have shown the non-inferiority of vonoprazan to lansoprazole in terms of symptom relief and healing rate. Since these pharmacokinetic advantages, it is expected that it will have a significant favorable impact on GERD management. However, the clinical use of vonoprazan raises also some issues about its efficacy and safety in the long-term that deserve verification and careful investigation

EoE CONNECT, the European Registry of Clinical, Environmental, and Genetic Determinants in Eosinophilic Esophagitis: rationale, design, and study protocol of a large-scale epidemiological study in Europe

Best practice analysis; Clinical practice patterns; Eosinophilic esophagitisAnálisis de las mejores prácticas; Patrones de práctica clínica; Esofagitis eosinofílicaAnàlisi de les millors pràctiques; Patrons de pràctica clínica; Esofagitis eosinofílicaBackground: The growing prevalence of eosinophilic esophagitis (EoE) represents a considerable burden to patients and health care systems. Optimizing cost-effective management and identifying mechanisms for disease onset and progression are required. However, the paucity of large patient cohorts and heterogeneity of practice hinder the defining of optimal management of EoE. Methods: EoE CONNECT is an ongoing, prospective registry study initiated in 2016 and currently managed by EUREOS, the European Consortium for Eosinophilic Diseases of the Gastrointestinal Tract. Patients are managed and treated by their responsible specialists independently. Data recorded using a web-based system include demographic and clinical variables; patient allergies; environmental, intrapartum, and early life exposures; and family background. Symptoms are structurally assessed at every visit; endoscopic features and histological findings are recorded for each examination. Prospective treatment data are registered sequentially, with new sequences created each time a different treatment (active principle, formulation, or dose) is administered to a patient. EoE CONNECT database is actively monitored to ensure the highest data accuracy and the highest scientific and ethical standards. Results: EoE CONNECT is currently being conducted at 39 centers in Europe and enrolls patients of all ages with EoE. In its aim to increase knowledge, to date EoE CONNECT has provided evidence on the effectiveness of first- and second-line therapies for EoE in clinical practice, the ability of proton pump inhibitors to induce disease remission, and factors associated with improved response. Drug effects to reverse fibrous remodeling and endoscopic features of fibrosis in EoE have also been assessed. Conclusion: This prospective registry study will provide important information on the epidemiological and clinical aspects of EoE and evidence as to the real-world and long-term effectiveness and safety of therapy. These data will potentially be a vital benchmark for planning future EoE health care services in Europe.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The establishment and design of the EoE CONNECT registry was developed with a grant from the United European Gastroenterology through the National Societies Link Award program. The maintenance of the database is financed by EUREOS (European Society of Eosinophilic Oesophagitis). Funding agencies had no role in the study design, in the writing of this manuscript, or the decision to submit for publication