Occult Reflux Research Articles

Investigation of pepsin levels in bronchial lavage in patients with interstitial lung disease and chronic cough

AimPepsin is an enzyme that helps digest protein secreted only from the gastric chief cell in an inactive state. Pepsin is a good marker for acidic gastroesophageal reflux (GER). Its presence in sputum or saliva is considered pathologic. In GER, cough is stimulated by broncho-esophageal neurogenic reflex and aspiration of gastric contents into the airways. GER is the most common cause of cough. Gastric acid reflux is also thought to play a role in Interstitial Lung Disease (ILD) etiology. In many studies, pepsin and bile acid levels in bronchial lavage were high in patients with interstitial lung disease and chronic cough. In our study, we aimed to evaluate pepsin levels in bronchial lavage in patients with ILD and chronic cough and to investigate the relationship between symptoms and reflux treatment. MethodsBetween January 2021 and February 2022, 212 patients who underwent bronchoscopy in our tertiary clinic were evaluated. These patients were divided into three groups: 52 patients with interstitial lung disease, 81 patients with chronic cough, and 79 patients who underwent bronchoscopy with a pre-diagnosis of lung cancer as the control group. Bronchial lavage obtained by bronchoscopy was analyzed for pepsin levels. ResultsShortness of breath and cough were the most common symptoms in all three groups. Pepsin levels were 16.71 ± 8.6 ng/ml in the chronic cough group, 15.6 ± 8.9 ng/ml in the ILD group, and 10.58 ± 5.4 ng/ml in the lung cancer (control) group. Pepsin levels in the ILD and chronic cough group were statistically significantly higher than in the lung cancer group (p:0.00). There was no statistical difference between the ILD group and the chronic cough group regarding pepsin levels. It was found that pepsin levels were lower in the three groups who received anti-reflux treatment. There was no difference in pepsin levels between ILD subgroups. ConclusionPepsin levels in bronchial lavage were higher in the ILD and chronic cough groups. This suggests that reflux may be involved in the etiology of chronic cough and ILD. Low pepsin values in patients receiving anti-reflux therapy have shown that occult reflux may occur. In our study, the high level of pepsin in bronchial lavage, especially in the chronic cough and ILD group, may be instructive in the etiology and treatment planning of the disease.

Clinical implications of primary “occult” vesicoureteral reflux in male children

ObjectivesTo compare characteristics and outcomes of vesicoureteral reflux (VUR) detected solely on isotopic cystography (IC) (“occult” VUR) with voiding cystourethrography (VCUG)-detected VUR.Materials and methodsBetween 2015 and 2020, we retrospectively enrolled all male children first undergoing VCUG and, if negative, IC in the same session. Kidney injury (KI) was defined by abnormal estimated glomerular filtration rate and/or blood pressure and/or proteinuria.ResultsWe enrolled 421 males with a median age of 3 months and a follow-up of 5.3 years. None exhibited KI initially, but 10% of those with VUR developed KI during follow-up. Two hundred and twenty-two patients (52.7%) did not show VUR, 152 (36.1%) had VCUG-diagnosed VUR, and 47 (11.2%) had occult VUR. Therefore, 47/199 patients (23.6%) with VUR had occult VUR. Among these, 34/47 (72.3%) had dilated VUR, and 22/47 (46.8%) exhibited split renal function < 45% and/or scar (scintigraphic damage). Compared to patients with occult VUR, those with VCUG-diagnosed VUR showed a similar prevalence of febrile urinary tract infection (fUTI) before and after VUR diagnostics and KI at the last follow-up but a higher prevalence of dilated VUR, of scintigraphic damage, and underwent surgery more frequently. At multiple logistic regression analysis, patients with VCUG-diagnosed VUR presented an increased risk of fUTI either before or after VUR diagnosis and of KI, while patients with occult VUR presented an increased risk of fUTI before (and among patients with dilated VUR also after) VUR diagnosis and of KI.ConclusionOccult VUR affects 23.6% of male children with VUR with a non-negligible risk of VUR-associated KI and fUTI. IC could select, among males with recurrent fUTIs and negative VCUG, those requiring surgery for a possible dilated occult VUR.Clinical relevance statementVesicoureteral reflux may be overlooked in 25% of boys during VCUG, yet they are at risk of fUTIs and KI. In case of recurrent infections post-negative cystourethrography, IC could detect occult reflux, guiding surgical intervention.

Revisiting the Mucosa of the Gastric Cardia: A Scope to Modify an Upper Gastrointestinal Endoscopy.

Introduction The mucosa in the cardiac region of the stomach has been less understood. Cardiac mucosa (CM) with less parietal and oxyntic cells has been defined as a normal mucosa. Studies have shown that CM can be the result of occult reflux. Oxyntic mucosa (OM) is normal, and it changes to CM with age. In advancing age, it is more common to find CM instead of OM and oxyntocardiac mucosa (OCM). This study is an attempt to examine the distribution of the three different types of mucosa in various age groups. Materials and methods The study was conducted in the Department of Anatomy and Department of Forensic Medicine and Toxicology of Gauhati Medical College, Guwahati, Assam, India, from 2017 to 2019. Once the stomach was opened, histological specimens were prepared, and the type of mucosa was observed and recorded. Then, thedistribution of thetypes of mucosa in various age groups was analyzed. Results The distribution of mucosavaries significantlyacross different age groups, and CM increases with age. Conclusion Our present study suggests that CM frequency increases with age. This is in accordance with studies that suggestthat CM is a result of occult reflux with age. This observation creates a scope to revise the approaches for upper gastrointestinal (GI) endoscopy.

Diagnosing and treating occult vesicoureteric reflux using PIC cystography: Is it influenced by abnormalities on DMSA?

Positioning the Instillation of Contrast cystography (PICc) is used to identify occult vesicoureteric reflux (VUR) in patients with recurrent urinary tract infections (UTI) despite optimized bladder and bowel function and without VUR demonstrated on conventional imaging. To determine the incidence of finding occult VUR in such patients usingPICc and the benefit, if any, of treating it. We also assessed if this was influenced by abnormalities on the pre-operative DMSA. This was a retrospective review of PICc in our hospital between 2016 and 2018 and involved three paediatric urologists. The primary indication for PICc was two or more culture proven UTIs despite optimized bladder and bowel function and no reflux on voiding cystourethrography (VCUG) or indirect radionuclide cystography (I-RNC). All children had a preoperative DMSA scan to document any abnormalities. PICc was performed in a standardized way to each ureteric orifice. If occult reflux was found, it was treated concomitantly by cystoscopic injection of Deflux®. To assess the influence of the pre-operative DMSA status, the cohort was subdivided into two groups based on the DMSA scan: Group 1-abnormal DMSA, Group 2-normal DMSA. The median follow-up was 26 months (range 3-39 months). PICc was performed in 25 patients [23 females and 2 males; median age: 7 years (range 2-16 years; IQR=4)]; 17 from Group 1 and 8 from Group 2. Occult VUR was identified in 22 patients (88%); 15/17 (88.2%) in Group 1 and 7/8 (87.5%) in Group 2 (p=0.9). After cystoscopic treatment, 21/25 (84%) became infection free and this was not influenced by the preoperative DMSA status (p=0.6). Fig 1. In this challenging group of patients, looking for and treating occult reflux appears to be clinically useful and beneficial. The ability to test and treat at the same sitting is an added advantage of PICc. The DMSA results did not influence the diagnostic or therapeutic aspect of the process. Our results concur with other published literature. There is a high incidence of finding occult reflux using PICc in this cohort of patients. Concomitant cystoscopic treatment led to 84% of children becoming infection free on follow up. Abnormalities on DMSA did not influence either the likelihood of finding occult reflux or the likelihood of successful treatment.

The value of DMSA scintigraphy in the diagnostic evaluation of vesicoureteric reflux

In terms of treatment planning, the radiologic phenomenon of vesicoureteric reflux has become less important than its inherent risk of further urinary tract infections and loss of renal function. Whilst radiologic and sonographic voiding cystourethrography continues to be the gold standard in the mere detection of vesicoureteric reflux, dimercaptosuccinic acid scanning is important for risk stratification. Also it serves to confirm renal involvement in uncertain situations with urinary tract infection and fever. In older children, it is the standard in primary diagnostics. Furthermore, it enables the diagnosis of occult reflux in many cases. Therefore, dimercaptosuccinic acid scanning is an indispensable tool in the diagnostic evaluation of vesicoureteric reflux.

Positioning the Instillation of Contrast Cystography: Does It Provide Any Clinical Benefit?

To outline positioning the instillation of contrast cystography (PICC)'s benefits in clinical practice. A total of 198 patients underwent PICC with the following indications: patients with positive preoperative conventional voiding cystourethrography (VCUG) for a single ureteric side, patients with urinary tract infection (UTI), and negative VCUG for both ureteric sides. Patients with positive VCUG served as the control group. Preoperative, intraoperative, and postoperative features of all patients were compared. The reflux rate for the contralateral vesicoureteric reflux (VUR) investigation group was 39.1%. Only the cystoscopic view of the anatomically deficient ureteric orifice was found to be a significant predictor of contralateral reflux (P = .002). For patients who presented with UTI, the reflux rate was 58.3%. Resolution of infection was assessed for patients who presented with UTI, and 54.1% of these patients had a complete response in the follow-up period. When the patients were classified as PICC positive and negative, infection-free rates were 58.3% and 48%, respectively (P = .296). PICC is an effective diagnostic method for revealing occult reflux. However, the clinical significance of this finding is vague. In patients with UTI, PICC was useful for diagnosing occult VUR and clearing the symptoms in more than half of the patients. Further, the symptom-free state in the follow up period was slightly higher but not more significant than it was in those with no VUR diagnosed.

Does Early Treatment of Urinary Tract Infection Prevent Renal Damage?: In Reply

We appreciate the comments of Dr Noe on our study1 regarding the role of the early treatment of infants with their first episode of urinary tract infection. These comments have given us the opportunity to clarify some issues. It has been well documented in both experimental and clinical studies that a scar develops only at the site of a previous infection in the kidney.2 In our study the comparison between initial and follow-up scans showed that 49% of infants who had a positive initial dimercaptosuccinic acid (DMSA) scan result had a complete resolution of the renal findings. In 51% of the infants the defects were improved, but they persisted in representing a scar formation in the site of the initial lesion. This supports our conclusion that the initial damage was the result of the acute infection and not a preexisting lesion. Also, exclusion from the study of infants with any previously known urinary tract pathology minimizes the possibility that the DMSA findings of the second scan were the result of previous damage. Furthermore, our patients were under 12 months of age and almost half of them were under 3 months so the possibility of a previous undetected infection looks unlikely. In our study, infants who experienced a relapse before the second scan were excluded, so the findings of the follow-up scan were not influenced by a new infection. Nevertheless, it is difficult on the basis of DMSA alone to determine if the DMSA findings represented acute inflammatory changes or an already permanent lesion.Dr Noe pointed out that our conclusion is discouraging. On the contrary, we have demonstated that early and appropriate treatment of urinary tract infection results in fewer children with renal involvement. Concerning the relationship between vesicoureteral reflux and scarring formation, we found that scarring was recorded more often when vesicoureteral reflux was present, but this difference did not reach a significant level. This finding is in accordance with those of other studies3,4 that have indicated that renal parenchymal infection rather than reflux is the prerequisite for acquired renal scarring. Nevertheless, we agree that the detection of occult reflux would be useful.

The PIC Cystogram: Its Place in the Treatment Algorithm of Recurrent Febrile UTIs

Purpose. A common pediatric dilemma involves management of children with recurrent febrile urinary tract infections (UTIs) who have normal voiding cystourethrograms. Vesicoureteral reflux (VUR) has been demonstrated in such cases by performing a cystogram which positions the instillation of contrast (PIC) at the ureteral orifice. We describe the evidence supporting this diagnostic test. Materials and Methods. The literature was searched to identify and subsequently evaluate all studies investigating PIC cystography. Results. In patients with febrile UTIs and negative VCUGs, the PIC cystogram has been demonstrated to identify occult reflux (PIC-VUR). When identified and treated, these patients have a significant reduction in the incidence of febrile UTIs. Conclusions. Although the current literature on PIC cystography is limited, it appears to be a clinically useful test in a select group of patients with recurrent febrile UTIs, that are not found to have VUR on a conventional VCUG. A prospective randomized trial is underway to further define its role in the treatment algorithm of febrile UTIs.

Multi-institutional experience with PIC cystography—incidence of occult vesicoureteral reflux in children with febrile urinary tract infections

Objectives It has been reported that all children with febrile urinary tract infections (FUTIs) and normal voiding cystourethrogram (VCUG) findings show occult reflux (vesicoureteral reflux [VUR]) when examined by cystography performed with positioning of the instillation of contrast at the ureteral orifice (PIC cystography). In this study, we evaluated the reproducibility of this finding using a prospective multi-institutional collaborative examination to determine whether PIC-VUR is as common in such cases as previously shown. Methods From March 2002 to October 2003, four institutions performed PIC cystography consecutively and prospectively in pediatric cases of FUTI (greater than 101°F) who had not shown VUR by conventional VCUG. We correlated the ureteral orifice (UO) configuration and position with the status of PIC-VUR. Results PIC cystography was performed in 39 children (31 girls and 8 boys; 75 FUTIs). We identified PIC-VUR in 32 (82%) of 39 children, involving 58 (74%) of 78 ureters. The likelihood of demonstrating PIC-VUR was increased 37-fold if the UO showed a patulous configuration and was increased 9-fold if the UO showed a lateral configuration. PIC-VUR was noted uniformly in UOs showing hydrodistension. Conclusions This multi-institutional registry showed that the incidence of PIC-VUR (82%) in children with FUTI and normal standard VCUG findings is similar to that previously reported. We consider that PIC-VUR likely accounts for the FUTIs.

Management of Barrett's Esophagus With and Without Dysplasia

Barrett's esophagus (BE), a premalignant lesion to esophageal adenocarcinoma is associated with long-standing, gastroesophageal reflux disease (GERD). BE is a multi-phase process: during the initiation phase, genetically predisposed individuals (mostly white men) suffering from clinical or occult reflux damage their distal esophagus and form a new cell phenotype (incomplete intestinal metaplasia). During the formation phase, this phenotype occupies an area of variable surface (short or long-segment BE). During the progression phase, the metaplastic epithelium either remains dormant or progresses to dysplasia and adenocarcinoma. We review the recent clinical and basic research literature that explores the interaction of the refluxate (acid, bile, etc.) with BE. Acid and bile reflux variably affect BE and may cause dysplasia or adenocarcinoma. Regardless of the underlying biology, a patient with BE may suffer from GERD symptoms or may remain asymptomatic. Acid may be synergistic to bile or it could be antagonistic and protective. Acid suppressive therapy, if profound and continuous enough to abolish symptoms and esophageal acid exposure, may decrease proliferation, increase differentiation and reduce BE surface. Overexpression of cyclooxygenase-2 (COX-2), not entirely independent of acid/bile reflux, may increase proliferation and increase the invasiveness and metastatic potential of Barrett's metaplasia and neoplasia. Clinically, both acid and bile reflux need to be inhibited, either with potent acid-suppressing drugs or anti-reflux surgery. Cyclooxygenase inhibition using aspirin, NSAIDs or the safer COX-2 inhibitors added to these anti-reflux therapies may enhance the therapeutic benefit. Many questions remain unanswered. We still do not know why only a fraction of patients with GERD develop BE, what factors of the refluxate (acid, bile, etc.) initiate metaplasia and/or promote carcinogenesis, which patients are at risk for malignancy, and what is the best chemopreventive strategy. Ablation therapies and endoscopic mucosal resection are still under study.