The Association Between Proton Pump Inhibitors and COVID-19 is Confounded by Hyperglycemia in a Population-Based Study.

Background and Aims: There is conflicting evidence regarding the association between proton pump inhibitors (PPI) and the risk of acquisition and severity of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Aim: To evaluate the association between PPI exposure and infection and development of severe disease in patients infected with SARS-CoV2in a large population-based historical cohort. Methods: Data were extracted from a health maintenance organization database in Israel that insures over 1,200,000 individuals from across the country. All patients who underwent SARS-CoV-2 testing between March and November 2020 were included. Logistic regression and matched analyses were used to compare patients prescribed and exposed to PPIs to those not prescribed PPIs regarding SARS-CoV-2 positivity. In addition, among SARS-CoV-2 positive patients (n = 44,397) the likelihood of developing severe disease, defined by a composite endpoint of death, ICU admission and prolonged hospitalization, was compared in those exposed and not exposed to PPIs. Results: Among 255,355 adult patients who underwent SARS-CoV-2 testing by PCR, 44,397 (17.4%) were positive for SARS-CoV-2 and 12,066 (4.7%) patients were prescribed PPIs in the 3 months before testing. In a multivariable logistic regression model controlling for age, gender, smoking status, BMI, diabetes mellitus, hypertension, COPD, history of ischemic heart disease and fasting blood glucose (FBG) levels, no significant association was found between PPIs and SARS-CoV-2 positivity (p = 0.09 aOR 0.94, 95% CI - 0.88-1.01). Among SARS-CoV-2 positive patients, 910 (2%) had a severe infection. Multivariate logistic regression controlling for the abovementioned confounders, showed no such association between PPIs and severe COVID-19 (p = 0.28). Elevated FBG levels were significantly associated with both PPI exposure (p < 0.001) and severe COVID-19 infection (p < 0.001). These results were reinforced by a matched analysis (n = 655 pairs). Conclusion: PPIs are spuriously associated with severe COVID-19 due to the presence of elevated FBG as a confounder. Our study accounted for the FBG levels of patients and known risk factors for severe COVID-19 infection, which may be the reason for the discrepancy in prior studies. These results may aid in understanding potential confounders when evaluating potential associations of PPIs with other respiratory or viral diseases.

The POEM bottom-up technique for achalasia.

BACKGROUND: POEM (Per Oral Endoscopic Myotomy) is rapidly becoming a valid option for surgical myotomy in achalasia patients. Several techniques to perform POEM are described, but all concentrate on the division of the circular muscle fibers in a proximal-to-distal fashion. Our aim is to present the distal-to-proximal, or the bottom-up technique using the Flush/Dual knife, which overcomes the disadvantages of the standard technique. METHODS: A retrospective study on a prospectively maintained database was performed on all patients treated by POEM in our institution. Clinical presentation, operating time, adverse events, and outcomes were studied. RESULTS: POEM was performed on 105 achalasia patients. The first 15 cases were performed using the standard technique and were compared to the next 90 cases performed using the bottom-up technique. The average preop Eckardt scores in the standard and bottom-up groups were 9.5 and 8.8, respectively, declining to 1.4 and 0.5, 3 months post myotomy (p < 0.001). The average procedure time was 111.2 min for the standard technique and 74.3 for the bottom-up technique. (p = 0.002). Perioperative adverse events included 14 instances of pneumoperitoneum, 3 tunnel leaks, and 4 patients with fever on postoperative day one. Pneumoperitoneum needing decompression and postoperative fever were more prevalent in the standard technique group. CONCLUSIONS: As POEM is becoming more common for the treatment of achalasia, refinements of the technique and instruments used are valuable. We compared our experience of the standard technique to our bottom-up technique and found the latter to be equally effective as well as safer, faster, and easier. We, therefore, suggest considering performing POEM in this technique.

G-EYE colonoscopy is superior to standard colonoscopy for increasing adenoma detection rate: an international randomized controlled trial (with videos).

BACKGROUND AND AIMS: Colorectal cancer (CRC) is largely preventable with routine screening and surveillance colonoscopy; however, interval cancers arising from precancerous lesions missed by standard colonoscopy still occur. An increased adenoma detection rate (ADR) has been found to be inversely associated with interval cancers. The G-EYE device includes a reusable balloon integrated at the distal tip of a standard colonoscope, which flattens haustral folds, centralizes the colonoscope's optics, and reduces bowel slippage. The insufflated balloon also aims to enhance visualization of the colon during withdrawal, thereby increasing the ADR. METHODS: In this randomized, controlled, international, multicenter study (11 centers), patients (aged ≥50 years) referred to colonoscopy for screening, surveillance, or changes in bowel habits were randomized to undergo either balloon-assisted colonoscopy by using an insufflated balloon during withdrawal or standard high-definition colonoscopy. The primary endpoint was the ADR. RESULTS: One thousand patients were enrolled between May 2014 and September 2016 to undergo colonoscopy by experienced endoscopists; 803 were finally analyzed (standard colonoscopy n = 396; balloon-assisted colonoscopy n = 407). Baseline parameters were similar in both groups. Balloon-assisted colonoscopy provided a 48.0% ADR compared with 37.5% in the standard colonoscopy group (28% increase; P = .0027). Additionally, balloon-assisted colonoscopy provided for a significant increase in detection of advanced (P = .0033) flat adenomas (P < .0001) and sessile serrated adenomas/polyps (P = .0026). CONCLUSION: Balloon-assisted colonoscopy yielded a higher ADR and increased the detection of advanced, flat, and sessile serrated adenomas/polyps when compared with standard colonoscopy. Improved detection by the G-EYE device could impact the quality of CRC screening by reducing miss rates and consequently reducing interval cancer incidence. (Clinical trial registration number: NCT01917513.).

The Effect of Ramelteon on Heartburn Symptoms of Patients With Gastroesophageal Reflux Disease and Chronic Insomnia: A Pilot Study.

BACKGROUND: There is a bidirectional relationship between gastroesophageal reflux disease (GERD) and sleep. It has been demonstrated that antireflux treatment can improve sleep quality in GERD patients with nighttime reflux. MATERIALS AND METHODS: Patients with heartburn and/or regurgitation ≥3 times/week and insomnia for ≥3 months were included. Patients were assessed at baseline with the demographic, GERD symptom assessment scale, Epworth sleepiness scale, Berlin sleep apnea, Pittsburgh sleep quality index, and the Insomnia severity index questionnaires. Subjects underwent an upper endoscopy followed by pH testing. Subsequently, subjects were randomized, in a double-blind, placebo-controlled trial, to receive either ramelteon 8 mg or placebo before bedtime for 4 weeks. During the last week of treatment, subjects completed a daily GERD symptom and sleep diary and underwent actigraphy. RESULTS: Sixteen patients completed the study, 8 in each arm (mean age and M/F were 48.5 vs. 57.8 y, and 8/0 vs. 6/2, respectively). Patients who received ramelteon demonstrated a statistically significant decrease in symptom score as compared with those who received placebo for daytime heartburn (-42% vs. -29%), nighttime heartburn (-42% vs. 78%), 24-hour heartburn (-42% vs. -3%), and 24-hour acid regurgitation (-26% vs. 19%) (all P<0.05). Insomnia severity index score was significantly reduced in patients receiving ramelteon as compared with placebo (-46% vs. -5%, P<0.05). Ramelteon group also demonstrated a significant improvement in sleep efficiency and sleep latency, as compared with placebo, P<0.05). No significant adverse events were observed with ramelteon. CONCLUSIONS: Ramelteon significantly improved symptoms in patients with GERD. In addition, ramelteon significantly improved patients' sleep experience. Further studies are needed in the future (NCT01128582).

The relationship between type 2 diabetes mellitus and failure to proton pump inhibitor treatment in gastroesophageal reflux disease.

BACKGROUND: There is limited information regarding the contribution of diabetes mellitus (DM) to proton pump inhibitor (PPI) failure in gastroesophageal reflux disease (GERD) patients. AIM: To determine whether type 2 DM is a risk factor for PPI failure and the potential predictive factors for PPI failure among type 2 DM patients with GERD. DESIGN: A case-control study was performed using hospital medical records of GERD patients treated with a PPI. The prevalence of type 2 DM and other risk factors (established >1 y before study enrollment) was determined in the PPI failure (treatment with more than once daily PPI) as compared with PPI responders. RESULTS: A total of 732 GERD patients receiving PPI therapy, including 285 who failed PPI treatment, were included. The overall prevalence of PPI failure was significantly higher in diabetic versus nondiabetic patients. The relationship between PPI failure and type 2 DM depended on body mass index. Only in obese patients the odds ratio of PPI failure was significantly higher in type 2 DM as compared with non-DM patients. In the subgroup of GERD patients with type 2 DM (n=349), PPI failure was significantly associated with female sex, the presence of general comorbidities, and adequate DM control. Duration of DM, type of antidiabetic medication prescribed, and DM-associated complications were not associated with PPI failure. CONCLUSIONS: PPI failure was significantly associated with type 2 DM in obese patients. Among GERD patients with type 2 DM, failure of PPI treatment was significantly associated with female sex and the presence of general comorbidities.

Comparison of distribution of intraesophageal pH during nighttime recumbency among patients with gastroesophageal reflux disease.

BACKGROUND: Nighttime reflux has been demonstrated to be associated with a more aggressive presentation of gastroesophageal reflux disease (GERD). However, it has remained unknown until now if the difference in nighttime reflux between the different GERD groups is related to the distribution of intraesophageal pH level or duration of acid exposure. AIM: To compare distribution of intraesophageal pH during nighttime between patients with erosive esophagitis (EE) versus those with nonerosive reflux disease (NERD). METHODS: Patients with heartburn symptoms at least 3 times per week were included in this study. Patients were not receiving any antireflux treatment. All patients underwent an upper endoscopy to determine if esophageal inflammation was present or absent. Subsequently, patients underwent ambulatory 24-hour esophageal pH monitoring. Only those with NERD and EE were included in this study. Nighttime period was defined as the time from the moment patients entered the bed to fall asleep and until they woke up the next morning. Distribution of intraesophageal pH during nighttime was generated using a special computer program that analyzed all registered pH measurements. RESULTS: Nineteen patients were found to have NERD and 31 EE. Time in bed was not different between the 2 groups. The mean number of acid reflux events, mean reflux time pH<4, and mean % total time pH<4 during nighttime were significantly lower in the NERD group as compared with the EE group (13.05±4.6, 19.7±7.09, 3.6±1.2% vs. 25.44±4.4, 29.3±7.97, 5.3±1.5%, respectively, all P<0.05). Symptom index for EE was 43.8% versus 21% for NERD, P<0.05. Overall, the distribution of intraesophageal pH during nighttime was similar between NERD and EE patients for all pH ranges. CONCLUSIONS: Patients with EE demonstrated a significantly higher nighttime esophageal acid exposure as compared with NERD, but the overall distribution of the acid exposure was similar between the 2 groups. This suggests that duration rather than intensity of nighttime intraesophageal acid exposure accounts for the difference between EE and NERD.

Renal artery stenosis with significant proteinuria may be reversed after nephrectomy or revascularization in patients with the antiphospholipid antibody syndrome: a case series and review of the literature.

Renal artery stenosis (RAS) is a disease which might present as hypertension, renal insufficiency or proteinuria and even as nephrotic syndrome. While 90% of cases are secondary to atherosclerosis, the rest of the cases are usually related to fibromuscular dysplasia. Recently, RAS has also been documented in patients with the antiphospholipid syndrome (APS). Although cases of nephrotic syndrome induced by RAS have been published, cases of patients with APS and nephrotic syndrome attributed to RAS were not reported in the literature. In this paper, three young male patients with APS, hypertension and significant proteinuria secondary to RAS are presented. The patients were treated with nephrectomy or revascularization in addition to prior treatment with warfarin, with improvement of the hypertension and the proteinuria. The relationship between renal artery stenosis, nephrotic range proteinuria and APS is reviewed. We suggest that renal artery stenosis should be included in the differential diagnosis of the nephrotic syndrome and that APS should be included in the differential diagnosis of renal artery stenosis especially in young male patients with proteinuria.

Oesophageal sensation in response to high PCO(2) and acidic solutions in nonerosive reflux disease.

BACKGROUND: Heartburn is commonly associated with the presence of acid in the oesophageal lumen. However, in patients with nonerosive reflux disease (NERD), the mechanism by which acid traverses the mucosa is not clear. We hypothesized that the luminal acid signal traverses the oesophageal epithelium in the form of the highly permeant gas CO(2) , which then is reconverted to H(+) in the submucosa. MATERIALS AND METHODS: Ten patients with heartburn, normal upper endoscopy and increased oesophageal acid exposure (NERD patients) and 10 healthy subjects were enrolled. Perceptual responses to intraoesophageal acid (0·1 N HCl solution) and a high PCO(2) solution were determined using a randomized cross over design. Stimulus-response functions to perfusions were quantified by three parameters: lag time to symptom perception, intensity rating and perfusion sensitivity score. RESULTS: In NERD patients, the difference in lag time to typical symptom perception, intensity rating and perfusion sensitivity score between high PCO(2) and acid perfusions was statistically significant (P = 0·02, 0·01 and 0·02, respectively). However, the difference in the same perfusion parameters between acid and high PCO(2) perfusions was nonsignificant in healthy controls. When NERD and controls were compared, the difference between the different perfusion variables was nonsignificant (adjusted to age). CONCLUSIONS: In NERD subjects, acid perfusion reliably evoked heartburn symptoms of greater intensity than in healthy controls. Nevertheless, a high PCO(2) perfusion failed to produce symptoms in either group.

Gastro-oesophageal reflux disease: beyond proton pump inhibitor therapy.

Gastro-oesophageal reflux disease (GORD or GERD) is a very common disorder, and advancement in drug development over the years has markedly improved disease management. Proton pump inhibitors (PPIs) remain the mainstay of treatment for GERD due to their profound and consistent inhibitory effect on acid secretion. However, PPIs do not reduce the number of reflux events and do not provide long-term cure for GERD. In addition, although the safety profile of PPIs is excellent, recent population-based studies have suggested that long-term PPI use may be associated with a variety of adverse events. They include osteoporosis-related hip and spine fractures, community-acquired and nosocomial pneumonia, various enteric and non-enteric infections, fundic gland polyps and many others. Consequently, there is growing interest by patients and physicians alike in current, as well as future, non-PPI-related therapeutic strategies for GERD. This includes repositioning histamine H(2) receptor antagonists and prokinetics in our current GERD therapeutic algorithms and a resurgence of non-medical therapeutic modalities for GERD, such as anti-reflux surgery, endoscopic treatment, alternative and complementary medicine and psychological interventions. Furthermore, there will be renewed efforts in further developing new medical and non-medical therapeutic modalities for GERD.

Non-esophageal symptoms cannot differentiate between erosive reflux esophagitis and non-erosive reflux disease in a referred population.

BACKGROUND: Non-esophageal symptoms are highly prevalent in non-erosive reflux disease (NERD). However, their prevalence in erosive esophagitis (ErE) is unclear. The aims of this study were to compare patients with pH-positive NERD and ErE in terms of non-esophageal symptoms and to investigate whether such symptoms can differentiate between these two conditions. MATERIAL AND METHODS: A prospective observational study of ErE and pH-positive NERD patients matched for age and gender with a nested case-control analysis. Symptoms were scored on validated scales. The association between the scale scores and diagnosis was evaluated in a random group comprising 67% of the total (group A) and was validated on the rest (group B). RESULTS: 124 ErE and 248 pH-positive NERD patients were studied. In group A, pH-positive NERD patients scored higher than ErE patients on all symptom scales. Scores on chest, constipation, sleep and urinary symptoms scales were significantly associated with diagnosis. A composite weighted score on these scales was 41.5% sensitive and 86.0% specificity in the differentiation of ErE from pH-positive NERD patients. When applied to group B, the sensitivity and specificity of this score were 48.8% and 70.3%, respectively. CONCLUSIONS: Digestive and non-digestive symptoms occurred with a significant higher prevalence in pH-positive NERD compared with ErE patients. However a composite score on scales of constipation, chest, sleep and urinary symptoms was not enough sensitive and specific to differentiate these two conditions.

Dexlansoprazole MR: a review.

Dexlansoprazole MR is the R-enantiomer of lansoprazole that is delivered by a novel system, the dual delayed release formulation. The drug has been shown to be efficacious in healing erosive esophagitis as compared with lansoprazole. When compared to placebo, dexlansoprazole provided significantly higher maintenance rates for healed esophageal mucosa in patients with erosive esophagitis and symptom control in patients with non-erosive reflux disease. Dexlansoprazole could be taken without regard to food. Overall, dexlansoprazole is well tolerated and has a comparable side-effect profile to lansoprazole.

Pharmacological management of GERD: where does it stand now?

Gastroesophageal reflux disease (GERD) is very common and advances in drug development over recent years have markedly improved GERD management. A wide range of medications are currently used in GERD treatment, including antacids, Gaviscon, sucralfate, histamine-2 receptor antagonists and prokinetics. However, proton pump inhibitors (PPIs) remain the mainstay of treatment for GERD owing to their profound and consistent inhibitory effect on acid secretion. Despite the presence of a wide armamentarium of therapeutic modalities for GERD, many areas of unmet needs remain. Drug development has focused primarily on improving PPI efficacy, reducing the transient lower esophageal sphincter relaxation rate, attenuating esophageal sensitivity and developing esophageal mucosal protectants.

Advancements in the analysis of esophageal pH monitoring in GERD.

Ambulatory 24 h esophageal pH monitoring enables quantification of esophageal acid exposure and assessment of the temporal relationship between symptoms and acid reflux events. Analysis of pH monitoring is currently divided into upright and recumbent periods based on the patient's body position. However, in this Review, we demonstrate that physiologic studies have shown that sleep, and not recumbency, has a greater impact on gastroesophageal reflux during night-time. The physiologic studies are further supported by clinical trials demonstrating that gastroesophageal reflux characteristics during the recumbent-awake period are similar to those in the upright rather than the recumbent-asleep period. The introduction of the integrated pH monitoring and actigraphy data analysis program offers better separation of the recumbent-awake and recumbent-asleep periods. The physiologic studies and clinical trials, as well as the availability of a better tool to measure pH during sleep, support a paradigm shift in the analysis of pH monitoring data from body position (upright or recumbent) to state of consciousness (awake or asleep).

An algorithm for diagnosis and treatment of refractory GERD.

Patients with gastro-esophageal reflux disease (GERD) who are not responding to proton pump inhibitors (PPIs) given once daily are very common. These therapy-resistant patients have become the new face of GERD in clinical practice in the last decade. Upper endoscopy appears to have a limited diagnostic value. In contrast, esophageal impedance with pH testing on therapy appears to provide the most insightful information about the subsequent management of these patients. Commonly, doubling the PPI dose or switching to another PPI will be offered to patients who failed PPI once daily. Failure of such therapeutic strategies is commonly followed by assessment for weakly or residual acidic reflux. There is growing information about the potential value of compounds that can reduce transient lower esophageal sphincter relaxation rate. Esophageal pain modulators are commonly offered to patients with functional heartburn although supportive clinical studies are still missing.

Prevalence of celiac disease in an adult Jewish population in Israel.

BACKGROUND: In the last decade the frequency of celiac disease diagnosis has increased in adults. OBJECTIVES: To determine disease prevalence (including silent and potential disease) in this population group. METHODS: We performed serologic screening of celiac disease in a representative and homogenous sample of a young adult general population in Israel, namely, 18 year old military conscripts, in 2003. Serologic screening was performed on serum samples randomly obtained from 850 healthy recruits (male/female = 1.1). Immunoglobulin A anti-tissue transglutaminase was determined by enzyme-linked immunosorbent assay. In cases of IgA deficiency, lgG anti-endomysial antibodies were determined. A small intestinal biopsy was offered to all patients with positive serology. RESULTS: The prevalence of overt CD diagnosed prior to recruitment was 0.12% (0.1% in men and 0.14% in women). The overall prevalence based on positive serology was 1.1%. Six of nine subjects with positive serology agreed to undergo endoscopy and intestinal biopsies. In all cases, biopsies were compatible with celiac disease (five biopsies were graded as Marsh 3a and one as Marsh 3b). One subject previously reporting irritable bowel-like symptoms was diagnosed with overt atypical CD. The prevalence of overt CD diagnosed by screening was 0.12%. The ratio, of overt to silent CD was 1:8. No cases of potential CD were encountered. CONCLUSIONS: Our findings suggest that CD is highly prevalent in the young adult population in Israel. Serologic screening for CD is a reliable and simple method for diagnosing this disease before symptoms or complications develop.

CMV-related thrombocytopenia treated with foscarnet: a case series and review of the literature.

Severe thrombocytopenia as a complication of CMV infection in immune competent adults is uncommon with only a few cases reported in the literature. The mechanism of CMV-related thrombocytopenia is unclear, resulting in a wide range of treatments used. The use of the antiviral agent ganciclovir was reported in five cases, with variable results. The use of foscarnet, which does not share the myelosuppressive effects of ganciclovir, in adult immune competent patients has not been reported. We review the literature and report two cases of CMV-related thrombocytopenia that were treated with foscarnet. In both cases a recent acute infection with CMV was well established and viral eradication following treatment with foscarnet was demonstrated. In one patient thrombocytopenia resolved following treatment with foscarnet and viral eradication. In the other patient, thrombocytopenia resolved following splenectomy, which was performed after viral eradication. Due to the therapeutic consequences of this diagnosis, it may be worthwhile to perform CMV screening in selected patients with thrombocytopenia. In case CMV viremia is demonstrated, viral eradication seems to have a positive influence on the resolution of thrombocytopenia. Foscarnet is a reasonable first line anti CMV agent in this setting.

Nonerosive Reflux Disease (NERD) - An Update.

Recognizing nonerosive reflux disease (NERD) as a distinct presentation of gastroesophageal reflux disease (GERD) was one of the most important developments in the field of GERD in the last decade. Whilst the definition of NERD has not changed significantly over the years, the disorder accounts for the majority of the GERD patients and those who failed proton pump inhibitor (PPI) treatment. Recent developments in NERD focused primarily on understanding the pathophysiology and natural history. The introduction of esophageal impedance + pH has led to the assessment of other forms of gastroesophageal reflux in causing NERD. Therapeutic modalities still focus on acid suppression, but there is growing recognition that other therapeutic strategies should be considered in NERD.