Page 51 – Practical Gastro

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus involving eosinophils and leading to esophageal damage, including fibrosis. EoE is increasing in prevalence, and although it is thought that food allergies may play a role in its pathogenesis, it is unknown if early infant exposures increase the risk of EoE. The authors of this study developed a case-control study using the United States military health system database (TRICARE Management Activity’s Military Health System) which contains medical data on all service members and their families.

All included patients with EoE were born between 2001 and 2014, and the diagnosis of EoE was determined by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Such patients with EoE required a complete birth and maternal record, had to be in the military health system since birth, and needed EoE to be diagnosed after 6 months of age. Patient controls were matched by sex and date of birth at a ratio of 2:1 to patients with EoE. Early infant risk factors were defined as occurring prior to 6 months of age and included prematurity, Cesarean section delivery, chorioamnionitis, prolonged rupture of membranes, eczema, seborrheic dermatitis, erythema toxicum neonatorum, milk protein allergy, hematochezia, asthma, gastroesophageal reflux, feeding problems, infant colic, oral candidiasis, and medication exposure (specifically outpatient antibiotics, histamine-2 receptor antagonists (H2RAs), and proton pump inhibitors (PPIs)). Univariate and multivariable conditional logistic regression modeling was performed to determine unadjusted and adjusted odds ratios.

In total, 1410 children with EoE were compared with 2820 patient controls. Median age of EoE diagnosis was 4.2 years (range 0.5 – 13.7 years), and 68.7% were boys. Adjusted conditional logistic regression demonstrated an increased risk of developing EoE if patients were exposed to antibiotics, H2RAs, or PPIs in the first 6 months of life. Other risk factors for EoE included prematurity, milk protein allergy, hematochezia, eczema, seborrheic dermatitis, erythema toxicum neonatorum, gastroesophageal reflux, and feeding problems.

This study demonstrates that potential exposuresin the first 6 months of life may increase the risk of EoE long-term. Exposures such as prematurity, antibiotics, and acid suppression medication use suggest that changes in the microbiome during early infancy may predispose to EoE. Judicious use of antibiotics and acid suppression medication in early infancy is encouraged.

Witmer C., Susi A., Min S., Nylund C. Early infant risk factors for pediatric eosinophilic esophagitis. Journal of Pediatric Gastroenterology and Nutrition 2018; 67: 610-615.

Infant Colic and Long-Term Outcomes

Infant colic is typically defined as excessive amounts of crying in the first 3 months of life. Many infants with colic are referred to pediatric gastroenterology as parents and providers often have concerns that there is a gastrointestinal cause for this condition although the potential association between gastrointestinal disorders and colic is debatable. It is also unclear as to the long-term outcome of infants with colic.

The authors of this study evaluated data from two prior studies. The Baby Biotics study was a randomized, controlled trial evaluating the effect of a probiotic (Lactobacillus reuteri DSM 17938) in infants with colic who were both breast feeding and formula fed. The Baby Business study was a randomized controlled trial that consisted of a parental education program to improve infant sleep. All infants were recruited prior to 3 months of age, and follow up data existed between 2 to 3 years of age for the Baby Biotics trial and 2 years of age for the Baby Business study. Long-term outcome data was obtained on these children using the validated Child Behavior Checklist.

Long-term data was available for 627 infants (124 from the Baby Biotics study and 503 from the Baby Business study). There were 99 infants in the Baby Biotics study who were defined as a “true colic cohort” (colic symptoms at recruitment but no symptoms at 6 months of age). Additionally, there were 182 infants in the Baby Business study who were defined as a “no colic cohort” (no colic at recruitment and had no colic throughout the study). The “true colic cohort” was thus compared to the “no colic cohort”. Demographic data on these two groups were similar except that patient age at follow up was significantly greater in the true colic group (34 months versus 25 months, P<0.01) and fewer mothers had higher education backgrounds in the true colic group (61.5% vs. 76.4%, P<0.01). Long-term follow up demonstrated that there was no difference between groups in regards to internalizing behavioral problems as well as parental perceptions of crying, feeding, sleeping, and family function.

This study appears to demonstrate that infant colic does not lead to long-term behavioral difficulties and suggests that probiotic use during infancy has no benefit in later childhood behavior.

Bell G., Hiscock H., Tobin S., Cook F., Sung V. Behavioral outcomes of infant colic in toddlerhood: a longitudinal study. Journal of Pediatrics 2018; 201: 154-159.

John Pohl, M.D., Book Editor, is on the Editorial Board of Practical Gastroenterology

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #19

Eosinophilic Esophagitis: When to Suspect and Why to Treat with Proton Pump Inhibitor

Rhonda F. Souza

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease driven by food allergens that manifests with symptoms of esophageal dysfunction andeosinophil-predominate esophageal inflammation. Recent consensus guidelines now include proton pump inhibitor therapy as an alternative first-line treatment. This review will provide an overview of when to suspect and how to diagnosis EoE, concepts surrounding pathogenesis and increasing incidence of this newly recognized esophageal condition, and a discussion on why proton pump inhibitors are now being used as a first-line treatment strategy.

Acknowledgment: Rhonda F. Souza, M.D. has served as a consultant and receives research support from Ironwood Pharmaceuticals. This work was supported by the National Institutes of Health (R01 DK103598, R01 DK063621, R21 DK111369 to R.F.S.)

Rhonda F. Souza, M.D. Department of Medicine and the Center for Esophageal Diseases, Baylor University Medical Center at Dallas and the Center for Esophageal Research, Baylor Scott and White Research Institute, Dallas, TX

INTRODUCTION

Eosinophilic esophagitis (EoE) is a chronic, immune- or antigen-mediated esophageal disorder characterized clinically by symptoms of esophageal dysfunction and histologically by the infiltration of eosinophils in the esophageal epithelium.¹ EoE was rarely recognized before the 1990s. Current epidemiologic data estimate that the prevalence of EoE is 50 to 100 cases per 100,000 individuals in the United States with a cost of diagnosing and treating this condition between 0.5 to1.4 billion dollars per year.^2,3This is quite astounding for a disease that was essentially unknown just twenty years ago. Management of patients with EoE draws upon the expertise of providers in the areas of primary care, gastroenterology, allergy and immunology, and nutrition. The length of time that patients with EoE go undiagnosed and untreated significantly correlates with the risk of developing esophageal strictures, a major complication of EoE.⁴ For primary care providers, suspicion of EoE and prompt referral to specialists are critical in the care of these patients. This review will provide an overview of when to suspect and how to diagnosis EoE, concepts surrounding pathogenesis and increasing incidence of this newly recognized esophageal condition, and a discussion on why proton pump inhibitors (PPIs) are being used as first-line agents to treat this antigen-mediated esophageal disorder.

When to Suspect and How to Diagnose EoE

EoE affects children and adults of all ages in all racial and ethnic groups, with reports of EoE from countries all around the world. EoE affects both sexes but males predominate by a factor of approximately 3 to 1. Providers should suspect EoE when patients present with symptoms of esophageal dysfunction. Esophageal dysphagia is reported by 60-100% of EoE patients and, in more than 25% of these patients, food impaction has occurred.⁵Patients often complain of chest pain, heartburn and upper abdominal pain. A history of atopic disease such as rhinitis, asthma, or atopic dermatitis is found in 50-60% of EoE patients.⁶ In addition, a family history of EoE or dysphagia should further increase your clinical suspicion for EoE.7 When endoscopy is performed, endoscopic signs of EoE are evaluated. Endoscopic features of EoE are described using the EoE endoscopic reference score, EREFS, which stands for exudates, rings, edema, furrows, and strictures.⁸ However, none these features are specific for EoE and the esophagus can appear totally normal in approximately 5-10% of cases. An esophageal biopsy showing at least 15 eosinophils per high power field (HPF) is required for the diagnosis. Other typical histologic findings include eosinophil microabscessess, basal zone and/or papillary hyperplasia, and dilated intercellular spaces. There also can be striking fibrosis in the lamina propria. Thus, a patient with symptoms of esophageal dysfunction and at least 15 eosinophils/HPF on esophageal biopsy would be suspected of having EoE, but EoE is only diagnosed after other non-EoE disorders (i.e. vasculitis, eosinophilic gastroenteritis, Crohn’s disease, connective tissue disease) that can cause esophageal eosinophilia and esophageal symptoms have been excluded (Table 1).⁷

Pathogenesis of EoE

There is significant evidence that EoE is an allergic disorder. Atopy is more common in EoE patients than in the general population.⁶ Most patients will exhibit sensitization to food or aeroallergens with formal allergy testing. In fact, 15% of EoE patients have food anaphylaxis, a very good reason to refer to an allergist early in the care of these patients.¹Perhaps the most compelling evidence that EoE is a food allergy comes from the dramatic response to elemental diets, which eliminate dietary allergens.⁹ Well, if EoE is caused by a food allergy, then why do eosinophils home exclusively to the esophagus?

Eotaxin-3, a potent chemoattractant for eosinophils, has been shown to be increased (>50 fold) in esophageal biopsy specimens from patients with EoE compared to controls, and eotaxin-3 could draw eosinophils into the esophagus.¹⁰ To understand the driving force behind eotaxin-3 upregulation, a brief discussion of immune system activation is warranted. Every day, we ingest millions of antigens that have the potential to evoke an immune response. If one of these antigens gets the attention of an antigen presenting cell, and that cell presents the antigen appropriately, then it is possible to activate the immune system, and this can stimulate the differentiation of naïve CD4+ T cells into Th1 or Th2 cells. Th2 cells secrete cytokines like interleukin (IL)-5, IL-4, and IL-13, and overproduction of Th2 cells is characteristic of a number of allergic disorders, including EoE. In human esophageal epithelial cells cultured in vitro, the Th2 cytokines IL-4 and IL-13 have been shown to stimulate eotaxin-3 production and secretion.¹¹ Thus, these data suggest that the pathogenesis of EoE starts with a genetically-susceptible individual, for whom some food allergen activates the immune system by binding to antigen presenting cells which, in this genetically susceptible person, induces a Th2 response with the production of Th2 cytokines like IL-5, IL-4, and IL-13. IL-5 activates eosinophils that reside in the bone marrow while IL-13 and IL-4 stimulate the production of eotaxin-3 by the esophageal epithelial cells. Eotaxin-3 is a potent chemoattractant that causes the activated eosinophils to home to the esophagus, and the eosinophils cause epithelial injury from their degranulation products. (Figure 1) So this is a reasonable model for the pathogenesis of EoE, but why is this happening now?

Proposed Hypothesis to Explain the Increase in Frequency of EoE

EoE was not even recognized until the early 1990s, and its incidence has increased dramatically ever since. So why didn’t we see EoE before 1990, and why are we seeing so much more of it now? The answer is we really don’t know, but a number of hypotheses have been proposed (Reviewed in ¹²). The hygiene hypothesis holds that modern hygienic conditions result in far fewer encounters with bacterial, viral, and parasitic infections during childhood, and this paucity of pathogen exposure somehow leads to allergic diseases in adults. A related hypothesis is that of microbial dysbiosis in which a change in the composition and diversity of the microbiome associated with a Western lifestyle somehow contributes to EoE development. It’s also been proposed that environmental factors such as genetic modification or chemical treatment of crops, hormone and antibiotic treatment of livestock, changes in food additives and in the processing and packaging of foods, and air and water pollutants might contribute to the development of EoE. A declining frequency of Helicobacter pylori infection might contribute to the rising frequency in EoE because data suggest that H. pylori induces T regulatory cells that protect against allergy development. Alternatively, H. pylori infection might just be a marker of poor hygiene which may be protective against allergic diseases, as suggested by the hygiene hypothesis. An increase in the frequency of gastroesophageal reflux disease (GERD) might increase esophageal permeability allowing food allergens to enter the esophageal epithelium leading to EoE. The most fascinating hypothesis, however, has to do with the use of acid suppressant medications.

The steep rise in the frequency of EoE begins in the early 1990s, just when the therapeutic use of PPIs becomes widespread. As we discussed earlier, every day, we ingest a huge numbers of protein allergens that have the potential to evoke an immune response. When a protein allergen enters the stomach, it is digested by pepsin into small peptide fragments that may no longer by allergenic. However, PPIs raise the gastric pH to levels above 4.5 which, at these pH levels, the enzymatic activity of pepsin is no longer active. In addition, PPIs have been found to increase gastric mucosal permeability.¹³ As a result, allergenic peptides are not degraded in the stomach, and instead get absorbed intact through the gastric mucosa or through the small intestine where they might evoke an allergic response. Intriguingly, there is some experimental support for this hypothesis. Food-specific IgE antibodies can develop in patients taking PPIs or H2-receptor blockers for three months,¹⁴despite having negative histories for atopy or allergies. After three months of treatment with an acid reducing medication, however, 10% of patients boosted their pre-existing IgE levels, and 15% of patients with no detectable IgE at baseline developed new, food-specific IgE antibodies suggesting that acid suppressing medications might predispose to the development of food allergies.¹⁴ Moreover, a recent case-control study explored the association between prenatal, intrapartum, and postnatal factors and the risk of developing EoE later on in childhood.15 Several prenatal factors were significantly associated with EoE including maternal fever, pregnancy complications, and preterm labor. Cesarean delivery also was associated with later development of EoE. Postnatal, during infancy, the use of antibiotics was associated with EoE whereas having a dog or cat at home was protective. However, the single strongest risk factor (odd ratio >7) for the development of EoE later on in childhood was the use of acid suppressant medications during the first year of life.¹⁵

Why Do We Use Proton Pump Inhibitors to Treat EoE

It may seem paradoxical that PPIs are used to treat EoE after our previous discussion on how PPIs might cause the disease. So, let’s consider why PPIs are used for treatment. Esophageal symptoms, endoscopic findings, and esophageal eosinophilia are not specific for EoE as these features can also be seen in other esophageal conditions including GERD. Initially, a PPI trial was used as a diagnostic test for EoE because it was thought that a symptomatic response to PPIs meant that the patient has GERD since there was no way that an antigen-driven condition like EoE could respond to a PPI. In 2007, a subcommittee of the First International Gastrointestinal Eosinophil Research Symposium (FIGERS) composed of physicians and researchers with expertise in EoE put forth the first consensus recommendations based on a systematic review of the literature and expert opinion specially stating that, to make a diagnosis of EoE, a lack of response to high-dose PPI treatment was required.¹⁶ This approach sounded reasonable until investigators began to recognize patients with esophageal symptoms and histology typical of EoE, but who had no evidence of GERD either by endoscopy or pH monitoring, and who responded to PPIs nevertheless.¹⁷ At that time, however, our prevailing definition of EoE excluded patients who responded to PPIs, so investigators had to use another term to described such patients and coined the phrase “PPI-responsive esophageal eosinophilia” (PPI-REE). Since then, several studies have found histologic response rate of 30% to 50% among patients with esophageal eosinophilia treated with PPIs (Reviewed in ¹⁸).

In 2011, an interdisciplinary expert panel of EoE investigators was convened to update the 2007 consensus recommendations.¹ These updated recommendations removed the requirement for “lack of PPI responsiveness” from the diagnostic criterion and considered PPI-REE as a separate and distinct entity from EoE.¹ Around this same time, data were emerging about potential anti-inflammatory effects of PPIs that were entirely independent of their effects on gastric acid secretion.¹⁹ Indeed, Cheng et al. reported that PPIs block the secretion of eotaxin-3 by Th2 cytokine-simulated esophageal epithelial cells in culture (Figure 1).¹¹ Since these studies were performed in esophageal squamous cells in culture, this anti-inflammatory effect of the PPI clearly was entirely independent of effects on gastric acid secretion. Subsequently, Zhang et al. showed that PPIs causes chromatin remodeling in the eotaxin-3 promoter, resulting in decreased eotaxin-3 transcriptional activity in Th2 cytokine-stimulated esophageal squamous cells in culture.²⁰ Thus, these studies provided a molecular mechanism underlying PPI-REE. In addition, multiple clinical studies found that EoE that does not respond to PPIs cannot be distinguished from PPI-REE based on any clinical, endoscopic, or histological findings suggesting that they are the same disorder (Reviewed in ⁶). Indeed, studies using RNA microarrays found a similar esophageal transcriptome in patients with EoE and PPI-REE.^21,22 Finally, two reports described EoE patients treated with diet or topical steroids, who for various reasons did not want to continue those treatments, who also achieved remission on PPI therapy (Reviewed in ⁶). In 2017, guidelines published by a European task force composed of physicians and researchers with expertise in EoE formally put forth the notion that PPI-REE is part of an EoE continuum and not a separate entity.⁶ Moreover, they proposed that treatment with PPIs should be used as a first-line therapy and not as a diagnostic test. Most recently, the proceeding from the International AGREE Conference which included United States physicians and researchers with expertise in EoE also concluded that PPIs should be classified as a first-line treatment for EoE and not as a diagnostic criterion.⁷

Practical Management Considerations of Using Proton Pump Inhibitors in EoE

It should be noted that the United States Food and Drug Administration to date has not approved any medication to treat EoE, and all medications including PPIs are used off label. At our Center for Esophageal Diseases, for a patient with esophageal symptoms and an esophageal biopsy showing more than 15 eosinophils/HPF, we first exclude non-EoE disorders that can cause esophageal eosinophilia (i.e. vasculitis, eosinophilic gastroenteritis, Crohn’s disease, and connective tissue disease), to establish the diagnosis of EoE. Although most gastroenterologists are aware of the condition PPI-REE, they have been told for over 10 years that this condition is not EoE, and it will take some time before the practicing community accepts the notion that PPI-REE is really just EoE that responds to PPIs. Therefore, if your patient is scheduled for a diagnostic endoscopy in which EoE is a consideration, we recommend that you stop PPIs for 3-4 weeks before performing diagnostic endoscopy.²³ Once EoE is diagnosed, we usually begin treatment with PPIs because of the safety profile, ease of use, and high response rate. PPIs are given twice a day for 4-8 weeks and we perform a follow up endoscopy with biopsies while the patient is on PPIs to document histological remission of the esophageal eosinophilia. If patients respond to PPIs, then PPIs are continued. In a retrospective study, 75 patients with PPI-REE from a European and US cohort in remission with PPIs taken more than once daily, had their PPI dose tapered down to once daily with a follow up endoscopy performed 1 year later.²⁴ Fifty-five patients (73%) had fewer than 15 eosinophils/HPF and were in remission at 1 year. Another 9 patients (45%) regained histologic remission when their PPI dose was increased to omeprazole 40 mg twice daily. So it appears that PPI therapy works long term to maintain remission in most adults with PPI-REE.²⁴ For patients that are unresponsive to PPIs, a choice between topical steroids or diet therapy is then offered.

SUMMARY

EoE is a chronic, antigen-mediated esophageal disorder whose incidence has increased dramatically since the early 1990s for reasons that remain unclear. EoE should be suspected in patients with symptoms of esophageal dysfunction, ≥15 eosinophils/HPF on esophageal biopsies, and the absence of a non-EoE disorder that can cause esophageal eosinophilia. Esophageal eosinophilia that responds to PPIs is called PPI-REE, a term that initially arose from the need to distinguish EoE from GERD. Since 2007, multiple lines of evidence have supported the notion that PPI-REE is on the spectrum of an EoE continuum and not a separate, distinct entity. Although the term PPI-REE is still used, it is now a description of EoE and not a separate diagnosis. In vitro studies have provided plausible molecular mechanisms regarding how EoE may respond to treatment with PPIs. Finally, and most importantly, PPIs are now used as first-line treatment for EoE, and not used as a means to exclude this diagnosis.

Dispatches from the GUILD Conference 2019

Welcome to the third annual Dispatches from GUILD series! The GastrointestinalUpdates-Inflammatory Bowel Disease- Liver Disease (GUILD) Conference is an annual CME conference held in Maui, Hawaii every February (GUILD 2019: February 17-20). The intent of this meeting is to offer a cutting edge update by world class speakers in a setting conducive to Socratic learning and interaction with peers. Our topics this year include 2 days of IBD updates, a day of Hepatology and a day of advanced endoscopy, esophagus and pancreas. GUILD also recognizes the role played by nurse practitioners and physician assistants in the care of IBD patients and introduced an IBD boot camp in 2019 as well as mentoring and networking sessions. This is in addition to our established mentoring and research presentation by GI trainees.

To share our learning with the gastroenterology community at large, we are happy to continue our series beginning with the following article,“Eosinophilic Esophagitis: When to Suspect and Why to Treat with Proton Pump Inhibitors.”

We look forward to providing informative and educational articles covering IBD, Hepatology and special topics in GI in Practical Gastroenterology over the following months.

For more information on the GUILD Conference visit their website.

FROM THE PEDIATRIC LITERATURE

Infant Colic and Long-Term Outcomes

A Case Report

Long Standing Crohn’s Disease and Signet Ring Cell Carcinoma of the Ileum

David M. Schwartzberg,H. Tarik Kirat,Feza H. Remzi

David M. Schwartzberg MD, H. Tarik Kirat MD, Feza H. Remzi MD FACS FASCRS Department of Surgery, Inflammatory Bowel Disease Center, New York University Langone Health, New York, NY

INTRODUCTION

Chronic intestinal inflammation caused by Crohn’s disease (CD) has been associated with malignant transformation into aggressive forms of small bowel adenocarcinoma. The overall incidence of small bowel adenocarcinoma is less than 2%.^1,2 Signet ring cell carcinoma (SRCC) is an aggressive subtype and is associated with poor differentiation and a poor survival, often presenting as T4 lesions in Crohn’s patients.³ Mid-small bowel CD is difficult to survey and subtle symptomatology maybe the only clue in deciding between biologic therapy or surgical intervention. Before deciding on medical therapy, including a number of possible biologic therapies, malignancy must be ruled out, or surgical resection must be offered.⁴

We report a case of SRCC in a patient with long-standing Crohn’s disease who was suspected to have increasing symptoms secondary to Crohn’s ileitis. Escalation of medical therapy failed to control his symptoms and operative intervention was ultimately required. Pathology revealed a poorly differentiated, pT4aN2M1 SRCC adenocarcinoma in the setting of active Crohn’s disease. This case highlights the importance of considering malignant transformation of the small intestine in the setting of long-standing inflammatory bowel disease.

Case Report

A 63-year-old male with a 32-year history of Crohn’s disease presented with increasing abdominal pain, fatigue, weight loss and intolerance to solid food. Historically he had been treated with budesonide and mesalamine only requiring sporadic corticosteroid tapers. Recent colonoscopy revealed a scarred ileocecal valve, which prompted initiation of infliximab. Ileal thickening (to 16.9mm) was noted on computed tomography (CT) ordered for persistent symptoms despite two months of infliximab treatment (Image 1). Aggressive inpatient therapy failed to control his symptoms and surgical intervention was recommended. Peritoneal implants were noted on the anterior abdominal wall; frozen section was positive for mucinous adenocarcinoma. En bloc resection was performed (Image 2). His final pathology showed a poorly differentiated, pT4N2M1 signet ring cell carcinoma measuring 23 cm in length. Mismatch repair was stable. There was metastatic lymph node spread (12 of 15 lymph nodes), lymphovascular and perineural invasion, omental and peritoneal metastasis. CDX2, CK20 and CK7 stains were positive. The surrounding bowel was consistent with active Crohn’s disease.

Discussion

This case describes malignant transformation of the ileum to an aggressive form of small bowel adenocarcinoma, signet ring cell carcinoma, in a patient with long-standing Crohn’s disease. The subtype of SRCC is rare with only one other case arising in the presence of Crohn’s disease.8 SRCC originate from undifferentiated stem cells and are mucin secreting tumors with an abundance of intracellular mucin that peripherally displaces the nucleus.2 SRCC is most commonly found in the stomach and colon, with small bowel SRCC only occurring in 1.1% of reported cases. It is generally associated with poor-differentiation and T4 lesions with a reported 5-year overall survival of 16.1%.^2,3

Overall, small bowel adenocarcinoma is uncommon, and its symptoms non-specific. Its association with Crohn’s disease, however, increases the risk 40 to 60-fold relative to the general population.^1,6 Though adenocarcinoma is rare, and the exact mechanism of malignant degeneration unknown, malignancy must be ruled out prior to escalating medical therapy, especially in patients with long-standing CD.⁶

Surveillance of CD is possible in upper and lower gastrointestinal disease. Small bowel disease is often difficult to access endoscopically, thus location of disease must factor into the treatment algorithm. The aggressive nature of small bowel adenocarcinoma, specifically SRCC, should be considered when small bowel CD fails to improve with escalating medical therapy, or long-standing disease becomes increasingly worrisome. Surgical resection may be the only opportunity for cure, and it must be considered to be diagnosed.¹¹.

A Case Report

An Uncommon Complication of a Motor Vehicle Accident, Diagnosed via ERCP

David T. Chao,Victoria O’Connor,Karl K. Kwok

Cholecystocolonic fistulas are a rare complication of gallstone disease that are typically incidentally discovered intraoperatively while patients are undergoing cholecystectomy. We present a case of an incidental finding of a cholecystocolonic fistula diagnosed unequivocally while undergoing endoscopic retrograde cholangiopancreaticography to evaluate a biliary stricture that developed after a motor vehicle accident.

David T. Chao, MD¹ Victoria O’Connor, MD² Karl K. Kwok, MD¹ ¹Department of Gastroenterology ²Department of Surgical Oncology Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA

INTRODUCTION

Cholecystoenteric and cholecystocolonic fistulas are uncommon complications of gallstone disease. Symptoms are often absent or subtle and nonspecific, and abdominal imaging may fail to identify the presence of the fistula. Consequently, the majority of patients are diagnosed intraoperatively creating a difficult dilemma for the surgeon.

Case Report

A 61-year-old woman with no significant medical history was a restrained passenger in a motor vehicle accident with rollover approximately one year prior to presentation. She was discharged from the emergency room in stable condition after evaluation did not reveal any evidence of blunt force trauma.

Approximately eight months after the motor vehicle accident, the patient presented to an outside hospital with painless jaundice. She was otherwise asymptomatic, denying diarrhea, abdominal pain, nausea, and vomiting. Emphysematous cholecystitis was diagnosed on computed tomography (CT) scan of her abdomen with pericholecystic inflammatory changes, gallbladder wall thickening, air within the gallbladder lumen, and intrahepatic pneumobilia. No gallstones were noted. The patient underwent an endoscopic retrograde cholangiopancreatography (ERCP) which revealed a common bile duct stricture, that was brushed and stented. Bile duct brushings revealed atypical cells.

Re-evaluation of her common bile duct stricture with endoscopic ultrasound (EUS) and repeat ERCP was recommended. During EUS, the gallbladder was identified with some difficulty, after repeated imaging of the expected area of the gallbladder based on anatomical landmarks. Additionally, the distal bile duct appeared to have a discrete hypoechoic mass lesion, which was sampled with fine needle aspiration.

On cholangiogram, abnormal pooling of contrast into a tubular structure not obviously representative of the diseased gallbladder was noted (Figure 1). Although there were initial concerns of a spontaneous perforation, the contrast disappeared in less than 30 seconds, and could not be located. Repeat cholangiogram demonstrated antegrade contrast flow first into the gallbladder, then into the descending colon, sigmoid colon, and rectum (Figure 2), which was consistent with a cholecystocolonic fistula.

The patient underwent combined surgical repair of the cholecystocolonic fistula, as well as pancreaticoduodenectomy. Final pathologic diagnosis revealed no evidence of malignancy.

DISCUSSION

Cholecystocolonic fistula is a communication which originates from the gallbladder and extends typically to the proximal transverse colon at the hepatic flexure. It is the second most common cholecystoenteric fistula after cholecystoduodenal fistulas.¹ Women appear to be more affected than men in a 2.47:1 ratio with the majority of patients diagnosed when they are 60 to 70 years old.² However, cases have been described in patients younger than 40 years old and thus the diagnosis should be considered in all age groups.

Often considered a late sequelae of gallstone disease, cholecystocolonic fistulas complicate approximately 1 in 1000 cases of acute cholecystitis.³ They are thought to develop secondary to chronic inflammation involving the gallbladder wall from cholelithiasis that cause pressure necrosis, erosion, and eventual fistulization. Cholecystocolonic fistulas have also been associated with peptic ulcer disease, malignancy, and abdominal trauma.⁴ A review of 231 published cases of cholecystocolonic fistulas found an increased association with gallbladder cancer.²

The diagnosis is typically made incidentally, since patients with cholecystocolonic fistulas are either asymptomatic or develop symptoms insidiously. If symptoms are present, patients will most commonly complain of chronic watery diarrhea secondary to bile salt malabsorption.² Diversion of bile salts directly into the colon bypasses the terminal ileum, which disrupts enterohepatic circulation of bile salts and reduces absorption of vitamin K. Other nonspecific symptoms may include abdominal pain, nausea, vomiting, jaundice, and fevers. When symptoms develop more acutely, cholecystocolonic fistulas may present with large bowel obstruction (secondary to gallstones >2.5cm causing luminal obstruction in the distal or sigmoid colon).^5,6,2 Laboratory testing may reveal cholestatic liver chemistry elevations or coagulopathy that corrects with parenteral vitamin K administration. Standard diagnostic imaging including CT, magnetic resonance imaging (MRI), and ultrasound have poor sensitivity may not reveal presence of a cholecystocolonic fistula 50% of patients.⁷ The presence of pneumobilia in conjunction with an elevated protime in a patient presenting with diarrhea should raise suspicion for the presence of a cholecystocolonic fistula.⁷

Treatment is surgical and typically consists of a cholecystectomy en bloc with partial colectomy followed by either primary repair of the colonic wall defect or primary anastomosis of the colon. Formation of a diverting end ileostomy may be needed, but is generally not required in patients with good nutritional status who undergo tension-free anastomosis without serious intra-operative deviations from the planned operation. As cases of cholecystocolonic fistula are often times not detected pre-operatively in patients undergoing cholecystectomy, incidental discovery of a cholecystocolonic fistula presents surgeons with the intraoperative challenge of performing a much more complex operation than initially planned.

In conclusion, cholecystocolonic fistula is a rare complication of gallstone disease that should be considered in the differential diagnosis of unexplained chronic watery diarrhea, particularly in patients with known cholelithiasis. In this case, a pre-operative cholangiogram helped definitively define the disease process that was otherwise rather subtle on cross sectional imaging. Without evidence of gallstone disease on abdominal imaging, we suspect the patient may have developed her biliary stricture and cholecystocolonic fistula from abdominal trauma sustained during the motor vehicle accident.

Frontiers In Endoscopy, Series #48

Hemospray for Gastrointestinal Bleeding: Technology Status Update

Babatunde Olaiya,

Douglas G. Adler

A simple to use hemostatic agent such as a hemostatic powder may potentially impact the endoscopic management of gastrointestinal bleeding, especially in lesions less amenable to conventional endoscopy. This paper aims to describe the efficacy and safety of Hemospray (Cook Medical, Winston Salem NC) in the management of gastrointestinal bleeding.

Babatunde Olaiya MD, MPH, MPP¹ Douglas G. Adler MD, FACG, AGAF, FASGE² ¹Marshfield Clinic, Marshfield, Wisconsin ²University of Utah School of Medicine, Salt Lake City, UT

INTRODUCTION

Mortality due to upper gastrointestinal bleeding (UGIB) has declined significantly in the last two decades, largely attributable to improved endoscopic practices.¹ A similar downward trend has been observed in lower gastrointestinal bleeding (LGIB).² Nonetheless, gastrointestinal bleeding (GIB) is still a major cause of morbidity and mortality in the United States with significant associated healthcare costs. UGIB accounts for about 300,000 hospital admissions yearly with a case fatality rate of 2-3%.^1,2 Case fatality rate in LGIB is 1.47% with a two fold increase in patients greater than 75 years old.²

Endoscopic hemostasis remains first line treatment for GIB. While conventional endoscopic methods including injectable agents, thermal treatments, argon plasma coagulation (APC), hemostatic clips and other therapies are effective, they often require high level of endoscopic expertise which may not be readily available. Furthermore, these modalities often require precise localization of the bleeding source and may be less effective in patients experiencing large mucosal bleeds, difficult to access lesions or in severe bleeding. Even with high level of endoscopic expertise, rebleeding risk with conventional endoscopic methods is about 5%.³

Overview of Hemospray

Hemospray is a hemostatic powder developed for endoscopic therapy of GI bleeding. (Figure 1) Unlike conventional endoscopic methods, Hemospray is non-contact, non-thermal and non-traumatic. It also doesn’t require specific lesion targeting to secure hemostasis, although if possible direct spraying of the compound on the lesion is preferable.

According to the manufacturer, Hemospray is metabolically inert, presumably nontoxic and doesn’t contain any human or animal allergens. On contact with blood, Hemospray induces hemostasis by absorbing water and forming a mechanical and adhesive barrier over the bleeding site. It causes a dose dependent reduction in median recalcification and clotting time of whole blood, rapidly producing hemostasis.^{^43-45} Hemospray is not absorbed by the body and no long-term effects due to ingestion have been documented to date.

Hemospray was first studied in porcine models to control surgically created high-pressure spurting arterial bleeds.⁷ Hemostasis was achieved successfully in all study animals as compared to none in control animals. A pilot study of 20 people with peptic ulcer bleeding closely followed and hemostasis was achieved in 95% of cases.⁸ These initial results have prompted the evaluation of Hemospray for endoscopic hemostasis in a wide array of bleeding disorders in the upper and lower gastrointestinal tract.^8-16

Primary Hemostasis
Peptic Ulcer Disease

Gastrointestinal bleeding is common in peptic ulcer disease (PUD), accounting for more than 7 in 10 hospitalizations amongst PUD patients annually.¹⁷ (Figure 2 and Figure 3) About a tenth of those with severe bleeding die, a higher risk of death observed in patients with high risk stigmata (active bleeding, non-bleeding visible vessel) and/or duodenal ulcers.^4,17-19 While conventional endoscopic methods are often highly effective, some lesions are not easily amenable to conventional therapy due to difficulties in endoscope positioning, surrounding tissue friability or fibrosis, or other factors. This was evident in a recent large national study that observed that 7% of PUD patients with high risk stigmata did not receive any endoscopic therapy, with lesions deemed to be too large for endoscopic approaches being a frequently cited reason.²⁰

Hemospray has been used successfully both as monotherapy and in conjunction with conventional methods in controlling bleeding due to PUD.^8,9,21,22 Sung et al. used Hemospray monotherapy on 20 patients with Forrest 1a and 1b ulcers and reported immediate hemostasis in 95% of patients.⁸ Hemostasis was not secured in one patient who had a psuedoaneurysm and eventually required arterial embolization. Rebleeding occurred in 2 patients within 72 hours but there was no active bleeding on repeat endoscopy.

In a small study by Kwek et al. comparing the effectiveness of Hemospray monotherapy to conventional modalities, initial hemostasis was achieved in 90% (9/10) and 100% (10/10) of cases respectively.⁹ In the Hemospray group, 7 of 10 patients had duodenal ulcers and initial hemostasis was achieved in 6 of these. Of note, case of Hemospray failure involved a patient with a Forrest 1b posterior duodenal wall ulcer. Hemostasis was eventually achieved with conventional endoscopy. Cahyadi et al. recorded immediate hemostasis with Hemospray in 18 patients with PUD related bleeding whose lesions were deemed not amenable to endoscopy (due to difficult anatomical situation or diffuse bleeding without definite source.) or after conventional endoscopic failure.²² Similarly, Smith et al. reported success in a report of 5 patients who were treated with Hemospray as second line after the failure of conventional endoscopy.²¹

Hemospray has been used as an adjunct to conventional endoscopic methods to control PUD bleeding. Sinha et al. used Hemospray in addition to Adrenaline (8 cases) and Hemospray in addition to Adrenaline with clips or thermal devices (12 cases).²³ Immediate hemostasis was achieved 95% (19/20) of cases. The failure case occurred in the group that had Hemospray, Adrenaline with clips/thermal devices and hemostasis was secured by embolization to the gastroduodenal artery.

Tumor Bleeding

Gastrointestinal tumor bleeding accounts for 2.6 – 5% of UGIB.24-27 Bleeding is the initial symptom of gastrointestinal tumor in about half of cases making late stage presentation a common phenomenon.²⁴ Compared to other causes of UGIB, mortality in gastrointestinal tumor is quite high regardless of endoscopic therapy likely reflecting the severity of the underlying disease.^24,28 However, endoscopic hemostasis is pivotal to managing tumor bleeding and has been shown to reduce the need for blood transfusions or emergent surgery, often acting as a therapeutic bridge to palliative surgery, radiation or chemotherapy.^29-31 Rebleeding after endoscopic treatment is however very high in tumor bleeding.

Bleeding due to gastrointestinal tumor may be diffuse and lack a specific target for endoscopic hemostasis. Furthermore, tumor bleeding often arises from ulcerated or friable mucosa, potentially limiting the use of mechanical or contact hemostatic methods. As such, a non-contact, non-thermal option like Hemospray may be a good option for providing at least short-term hemostasis. Pittayanon et al. evaluated the effectiveness of Hemospray in 88 patients with tumor bleeding in a large multicenter study.³² Over 70% were stage 4 tumors and 50 were located in the upper gastrointestinal tract. Hemostasis was achieved with Hemospray in 98% of cases. Definite hemostatic treatment i.e. embolization, chemotherapy, radiotherapy and surgery was associated with improved survival after Hemospray treatment. In smaller studies, immediate hemostasis with Hemospray on bleeding due to upper gastrointestinal tumor ranged from 93 to 100%.^22,33-35

Variceal Upper Gastrointestinal Bleeding

Acute variceal bleeding (AVB) is a leading cause of death in cirrhotic patients, with mortality rates as high as 24% at 6 weeks.^36,37 While gastroduodenal ulcers coexist in a quarter of patients, variceal bleeding accounts for over 50% of UGIB in cirrhotic patients.^38,39 Per conventional endoscopy, sclerotherapy and variceal band ligation (VBL) are frequently utilized to treat bleeding esophageal varices, the latter having superior effects on reducing rebleeding, mortality and fewer esophageal strictures.⁴⁰ The combination of VBL with pharmacologic agents demonstrates even better effects on achieving hemostasis and reducing rebleeding than VBL alone.⁴¹ Nonetheless, failure to control bleeding occurs in up to 10% of patients with acute variceal bleeds.⁴²

There is emerging evidence on the efficacy of Hemospray in controlling acute variceal bleeding. In a single arm prospective trial, Ibrahim et al. used Hemospray monotherapy in 30 patients with confirmed AVB. Over 80% of varices were in the esophagus and more than half were actively bleeding.⁴³ With the exception of one patient who required the use of two Hemospray devices due to continued bleeding, others required just one application and immediate hemostasis was achieved in all patients at initial endoscopy.⁴³ In another study by Ibrahim et al., 100% hemostasis was achieved in all nine patients with AVB treated with Hemospray monotherapy.⁴⁴ Ibrahim et al. also studied 86 cirrhotic patients with AVB in a multicenter randomized trial. The study observed that patients who had immediate treatment with Hemospray within 2 hours of admission followed by elective endoscopy treatment at 24 hours had significantly better survival rates at 6 weeks compared to those who had elective endoscopy alone. These patients also had lower rates of rebleeding and need for rescue endoscopy.⁴⁵

Lower Gastrointestinal Bleeding

Lower gastrointestinal bleeding (LGIB) is about a fifth as common as UGIB and more prevalent in patients older than 65 years.⁴⁶ While acute LGIB often resolves spontaneously with supportive care, about 25- 40% of cases warrant direct endoscopic therapeutic intervention.^47,48 Conventional endoscopic treatment modalities are often effective at achieving hemostasis. However, in a few cases, bleeding persists warranting the need for other hemostatic options.⁴⁹

Hemospray use in LGIB has been less frequently reported; however some studies have reported on its efficacy in achieving initial hemostasis. (Figure 4) Ivekovic et al. reported the successful use of Hemospray in a patient with spurting post polypectomy bleeding that did not respond to clipping.⁵⁰ Similarly, Soulellis et al. also achieved hemostasis with Hemospray in two patients with post-polypectomy bleeding after failure of thermal and mechanical therapy.⁵¹ In a case series, Granata et al. treated four patients with severe LGIB due to ischemic colitis with Hemospray.⁵² All four patients were hypotensive and on antithrombotic therapy at presentation. Mean ulcer diameter was quite large at 32 mm. Hemostasis was achieved in all four patients. Less common causes of LGIB in which hemostasis was successfully achieved with Hemospray includes stercoral ulceration, cytomegalovirus induced bleeding, post proctocolectomy bleeding and diclofenac-induced lower GI bleed.^13-16

Rebleeding

Rebleeding after endoscopic hemostasis is an independent predictor of mortality in both UGIB and LGIB.^3,4,53 Endoscopic findings that are predictive of rebleeding include active bleeding at the time of endoscopy, large ulcer size, posterior duodenal location and lesser gastric curve location.⁵⁴ Various strategies have been proposed to reduce the risk of rebleeding including avoiding epinephrine monotherapy and the use of dual conventional therapy. Rebleeding occurs in 10 -20% of cases despite use of dual therapy.⁵⁵

Studies show rebleeding rates after Hemospray to be highly variable, typically ranging between 15 and 49%.^{9,21-23,35,56-58} This variability may be explained by heterogeneity of study populations, studies with small sample size and different modalities of Hemospray use. Certain factors are associated with an increased risk of rebleeding when Hemospray is used for endoscopic hemostasis. When Hemospray was used as a treatment modality for patients whose ulcers were deemed not amenable to conventional methods i.e. large ulcers or lesions at historically difficult locations to treat, rebleeding rates after initial hemostasis was as high as 49% after 7 days.²² Rebleeding also appears to be higher when Hemospray is used as salvage therapy i.e. after failure of conventional therapy as compared to primary hemostatic method.²² Similar to conventional modalities, rebleeding rates are much higher when Hemospray is used to treat spurting arterial bleeding (Forrest 1a ulcers).^9,21,23 However, when treating actively bleeding ulcers, Hemospray may have a higher risk of rebleeding as compared to conventional methods.⁹ In fact, at least one study suggests that Hemospray not be used as monotherapy for spurting arterial bleeds due to high risk of rebleeding.⁵⁶

Safety Issues/Adverse Effects

Despite the benefits of Hemospray or hemostatic powders, there are potential safety issues and reports of adverse events. When Hemospray is used before other hemostatic modalities, there is a risk of obscuring the boundaries of a lesion making it more difficult to implement other hemostatic options if they are needed.⁵⁹ Furthermore, there is a risk of catheter obstruction if the delivery device comes into contact with blood. Per the manufacturer, no more than 3 devices (60g) of Hemospray are to be used in a single patient. Hemospray is not absorbed by the gastrointestinal tract so there is a risk of colonic impaction at higher doses. Up to 150g of Hemospray was utilized in the study by Sung et al., without any report of colonic obstruction.⁸ Biliary obstruction after treatment of a post sphincterectomy bleed treated by Hemospray use has been documented.⁶⁰ Patency was restored by irrigation and prodding the orifice open with a sphincterotome tip.

Due to its pressurized contents, Hemospray is associated with a risk of bowel perforation and embolization. Hagel et al. documented an 8cm gastric wall perforation after Hemospray was used for a patient with ischemic colitis who presented with melena and generalized peritonitis after total colectomy.⁶¹ Similarly, visceral perforation after Hemospray application has been documented in two other studies although it was unclear if this was directly related to Hemospray use.^62,63 Hemospray is not currently recommended for primary treatment of variceal bleeding due to the theoretical risk of embolization, although this can be performed in an off-label manner. It is thought that the pressurized contents of Hemospray may overcome the low pressure venous system. However, this adverse event has not been recorded in studies where Hemospray was used for variceal bleeding.^43-45

CONCLUSION

Hemospray has potential advantages over conventional methods in the control of gastrointestinal bleeding. It has high primary hemostasis rates in both variceal and non-variceal upper gastrointestinal bleeding. Limited studies also demonstrate high primary hemostasis rates in LGIB. Beyond this, it is simple to use and does not require a high level of endoscopist expertise. It also appears to have a good safety profile, only very few studies documenting serious adverse effects. Hemospray also has some limitations. Despite high primary hemostasis rates, it appears to have higher rates of rebleeding if used to treat spurting arterial bleeding or large, difficult to reach ulcers. It is a single use product and cannot be reused in the same patient if rebleeding occurs at a later date. Furthermore, if the device becomes clogged during endoscopy, further use is impossible and another device needs to be used. Going forward, there is need for larger studies to define the optimal role and cost effectiveness of Hemospray in the management of gastrointestinal bleeding.

Inflammatory Bowel Disease: A Practical Approach, Series #105

Vaccinations for Patients with Inflammatory Bowel Disease: An Updated Review

Manisha Apte,

Jason Reich,

Francis A. Farraye

Patients with Inflammatory Bowel Disease (IBD) are at an increased risk for infectious complications due to the immune disturbance inherent with disease pathophysiology and immunosuppressive therapies. This review highlights vaccinations for patients with IBD, suggestions for increasing vaccination rates in your practice and new changes in practice guidelines.

INTRODUCTION

Patients with Inflammatory Bowel Disease (IBD) are a patient population where a focus on increasing preventative health care measures is needed.¹ The pathophysiology of IBD involves the activation of a systemic inflammatory process with release of cytokines and other inflammatory mediators.² As a result, patients with IBD are at an increased risk of infections due to their altered immune system; further complicating this is the fact that many patients with IBD are treated medically with immunosuppressive therapies, increasing risk of infection.³ For instance, a retrospective cohort study demonstrated patients with IBD are at increased risk for pneumonia, a risk further increased with steroids and opioids.⁴ Immunosuppressive therapies for IBD includes agents such as 6-mercaptopurine (6-MP), azathioprine, methotrexate and tofacitinib. In addition, biologic agents including infliximab, adalimumab, certolizumab, golimumab, vedolizumab and ustekinumab are being used more frequently, while corticosteroids continue to be used in acute flare management.⁵ Infectious complications are an important cause for hospitalization in IBD patients.⁶ With these heightened risks, it is important to understand the best practices in vaccinating patients with IBD, both before and after therapy is initiated. This article will discuss current guidelines for vaccination recommendations in patients with IBD and review how to implement a vaccination process in your practice.

Vaccination and Disease Activity

A growing body of literature has served as the basis of current expert recommendations on how and when to vaccinate patients with IBD, and has concluded that vaccinating IBD patients is not associated with a flare in disease activity.^7,8

Defining Immunosuppression in Patients with IBD

Patients with IBD on immunosuppressive agents are considered to have either low or high levels of immunosuppression depending on their medications. High levels of immunosuppression include those on treatment of daily steroid therapy with doses equivalent or greater than 20 mg of prednisone for 14 days or more, treatment with anti-TNF agents, ustekinumab, tofacitinib as well as patients with severe protein calorie malnutrition. Patients receiving 20 mg of prednisone or less for less than 14 days, those receiving methotrexate less than or equal to 0.4 mg/kg per week, and those on azathioprine less than or equal to 3 mg/kg per day or 6-mercaptopurine less than or equal to 1.5 mg/kg per day are considered to have low levels of immunosuppression.^9,10

Vaccination Recommendations
Live Vaccines
Varicella

In general, IBD patients should be immunized with live attenuated vaccines at a minimum of 6 weeks before starting immunosuppressant therapy.1 Before initiating immunosuppressive therapy for IBD, the Advisory Committee on Immunization Practices (ACIP)¹¹ recommends confirming immunity for varicella. If a history of vaccination cannot be confirmed or if they are not shown to be immune serologically, the 2013 Infectious Diseases Society of America (IDSA guidelines) recommend administration of the live varicella vaccine prior to immunosuppression.⁹

Measles, Mumps and Rubella

Vaccinating for measles, mumps and rubella (MMR) is typically accomplished in early childhood so a majority of patients with IBD are already immune. If patients have not been vaccinated or have negative serologies, MMR should be administered prior to initiating immunosuppressant therapies.¹² ACIP guidelines give attention to growing outbreaks of these preventable illnesses in the United States, including mumps.¹³ Patients determined to be at increased risk are recommended to receive an additional, third dose through the MMR vaccination.¹¹

Herpes Zoster

The incidence of herpes zoster virus reactivation is roughly 3 to 13/1000 person years and increases in patients who are receiving combination therapy, including anti-tumor necrosis factor alpha (TNF-a) with azathioprine and/or steroids.^14,15 Two retrospective studies demonstrated that patients on thiopurines or a combination of thiopurines and TNF antagonists had an increased risk of developing herpes zoster.¹⁶ Previous ACIP guidelines recommended all immunocompetent patients receive the live-attenuated vaccine Zostavax at age 60. IBD patients aged 60 or older should receive this vaccine before initiating immunosuppressant therapies given the risks of administering live vaccines to immunosuppressed patients.¹¹ However, patients with IBD considered to have a low level of immunosuppression fit a safety profile that still allow for vaccination.⁸

Recent data suggests that vaccinating patients with Zostavax while on anti-TNF therapy is relatively safe, as the use of these medications alone was not associated with increased incidence of vaccine related infection.18 Additionally, administration of the live zoster vaccine was associated with a significant reduction in the risk of developing shingles.¹⁷ Therefore, expert opinion recommends shared decision making with patients on anti-TNF agents, as well as an individual case review before offering the live vaccine.⁸ Potential barriers to vaccinating IBD patients against herpes zoster have recently been reduced with the new inactivated vaccine for herpes zoster, Shingrix (reviewed below). The recent Food and Drug Administration (FDA) approval of Shingrix has allowed for a review of vaccination guidelines.¹⁹

Inactivated Vaccines Herpes Zoster

Shingrix, a two-dose, inactivated vaccine against herpes zoster, was approved by the FDA in 2017 for adults aged 50 years or older (Table 2). Phase I and Phase II trials of Shingrix suggested that the effectiveness of the vaccines would wane a full 19 years after administration.17 The ACIP and CDC now recommend this vaccine to all immunocompetent adults aged 50 years or older instead of the live Zostavax vaccine, and also approving it for immunocompetent adults irrespective of prior Zostavax administration.¹⁸ With the prospect of a safe inactivated vaccine for healthy individuals against herpes zoster, additional studies are needed in immunosuppressed patients, including those with IBD. Studies demonstrating the efficacy and safety of Shingrix in hematologic malignancies and renal transplant patients offer the impetus to complete studies in immunocompromised patients with IBD.²⁰

Hepatitis A Virus

Patients in developed nations, including the United States, are at a lower risk of contracting hepatitis A virus (HAV) infection, but patients with IBD should still be vaccinated with the HAV vaccine if they are not immune.

Patients on anti-TNFs have a statistically significant decreased response to HAV vaccine compared to those not treated (p=0.001); however, the rate of seroconversion was still notably high in the anti-TNF group with a rate of 92.4% (85/92) compared to 99.1% (324/327) in the non-treatment group.²¹

Patients diagnosed with IBD should be tested for HAV immunity and should receive the routine two-dose series administered at 0 and 6 months if they are not immune. ⁵ The 2018 ACIP guidelines does not address immunosuppressed patients in its HAV guidelines, although prior ACIP recommendations noted this inactivated vaccine is safe to administer such populations.¹

Hepatitis B Virus

The prevalence of hepatitis B virus (HBV) is similar in patients with IBD and the general population.²² The ACIP recommends that patients with IBD who are not immune to HBV receive the vaccination series, even after initiating immunosuppressant therapy. The most commonly administered vaccine for HBV is a recombinant formulation that consists of the HBV surface antigen (HBsAg) administered in three doses. A newer vaccine, Heplisav-B, a single-antigen HepB vaccine with a immunostimulatory adjuvant, was approved by the FDA in 2018 for use in adults ≥18 years old.²³ This vaccine generates a strong serologic response in adults (95%), although long-term implications on safety have yet to be studied.²⁴ The ability to generate antibodies depends on a robust T-cell response and for B cells to proliferate and differentiate into anti-HBs-secreting plasma cells.²⁵ While these immune system components are fully functional in healthy individuals, patients with IBD have immune alterations and further suppression when on therapy. A lower antibody titer response may be seen in older age adults and the use of anti-TNF treatments.^26,27 When vaccinating patients on anti-TNF therapy, we ideally recommend vaccinating prior to initiation of therapy.²⁸

Influenza

The ACIP recommends patients receive the inactivated or recombinant influenza vaccination (available in trivalent or quadrivalent forms) annually to target the evolving viral strain.²⁹ Patients with IBD have a lower serologic response to this inactivated vaccine and this response is worse in those on immunosuppressant therapy.^30,31 There are no recommendations for an additional booster.³² Current ACIP guidelines allow for vaccinating IBD patients already on immunosuppressant therapies. There is improved serologic response to a higher-dose trivalent or quadrivalent dose, a reliable option for the elderly.¹¹

Pneumococcal Pneumonia

Two vaccines are available for pneumococcal pneumonia (Table 3), the 23-valent polysaccharide (Pneumovax; PPSV23) and the 13-valent conjugate vaccine (Prevnar; PCV13). The ACIP recommends immunosuppressed patients receive a two-dose vaccination series.

PPSV23 is a polysaccharide vaccine that depends on B-cell immune response. This humoral immune response creates specific antibodies (IgM and IgG) that target 23 pneumococcal bacterial strains. IgM memory cells are primarily responsible for targeting the bacteria.³⁴ Since IBD patients have lower circulating levels of IgM B cells due to their altered immune function, and deficient spleen function, their response to the vaccine may be suboptimal.³⁵

Patients with IBD had lower circulating antibodies after receiving PPSV23, with patients on combination therapy having a decreased immune response.³⁶ Per the 2018 ACIP guidelines, adults aged ≥19 years with anatomical or functional asplenia, cerebrospinal fluid leak, or cochlear implant or who are immunocompromised should receive PCV13 and then PPSV23 at least 8 weeks after.¹¹ We recommend that patients with IBD receive these vaccines at initial diagnosis of IBD.³⁷ They should then receive an additional PPSV23 booster at least five years after their first dose as long as they received their initial PPSV23 before they turn 65 years of age. If a patient has already received PPSV23, PCV13 should be administered 1 year later.

Tetanus and Diphtheria

The tetanus and diphtheria vaccine (Tdap) should be administered to all patients with IBD every 10 years, as per ACIP recommendations.¹ A meta-analysis assessing IBD patient response to this vaccine has revealed no conclusive results on immune response and seroconversion.³⁸ Patients receiving combination therapies or single biologics were found to have significantly decreased response, and, should therefore ideally receive Tdap before starting immunomodulators, particularly when used in combination with anti-tumor necrosis factor alpha agents.^39,40

Meningococcal

Neisseria meningitides infection poses a risk of meningitis; young adults are especially vulnerable due to their proximity to other individuals in colleges and the military. The 2018 ACIP guidelines recommends young adults aged 16-23 should be vaccinated. Given the vaccine is inactivated, patients with IBD in this age group are also recommended to receive the vaccine even if they are on immunosuppressive therapies. This however remains a conditional recommendation, as there have been few evidence-based studies to support this action.^8,39 There are multiple vaccine options against Neisseria, which cover different serotypes. The conjugate Menactra, Menveo and polysaccharide Menomune act against serogroups A, C, W, and Y, while Bexero and Trumenba only cover serogroup B (MenB) with a two-dose or three-dose series, respectively.⁸ As MenB is the prevalent serogroup observed in meningitis cases in the United States, the vaccine series targeting it is recommended for adolescents.⁴⁰

HPV

The human papillomavirus (HPV) is the strongest risk factor for cervical cancer, which is the second most common cause of cancer in women worldwide.⁴² Additionally, it is also associated with penile, vulvar, vaginal, anal and oropharnygeal cancers. Specific HPV genotypes are associated with both low and high-grade cervical dysplasia on cytology.⁴³ There are two vaccines available that protect against HPV types 6, 11, 16 and 18-the former two genotypes are associated with low grade dysplasia and the latter two are associated with cervical cancer.⁴⁴ The bivalent vaccination protects against types 16 and 18 while the quadrivalent targets all four types.

As an inactivated vaccine, the quadrivalent form (Gardasil) is given in three doses at 0, 2 and 6 months, respectively for males and females aged 16-26.¹¹ Additional recommendations from 201811 guidelines now also include children aged 9-15, who can instead receive two doses 6 months apart. On October 5, 2018 the FDA approved Gardasil for adults aged 27 through 45. We await updated recommendations from the ACIP.⁴⁵ In measuring serologic response to this vaccine, 94% of IBD patients who received three doses, seroconverted to all four types of the virus, which was a similar response to rates previously documented in healthy individuals.⁴⁶

Implementation

It is important to note that despite vaccination schedule guidelines, there is no current consensus on who is responsible for coordinating and administering vaccinations. Surveys of gastroenterologists and family practitioners revealed that the majority of physicians believe the responsibility to ensure vaccine completion lies with the patient [41.7%] and the family physician [32.3%]. Furthermore, this survey revealed that significant predictors of vaccine completion were annual vaccination review by family physician (odds ratio [OR] = 1.82) or gastroenterologist [OR = 1.72], current steroid use [OR = 1.28], and current or prior treatment with biologics [OR = 1.42].⁴⁷ An understanding of how to implement a vaccination program is therefore necessary. New innovative approaches to aid clinicians and patients alike have been developed and introduced to improve vaccination rates amongst IBD patients. One example is the utilization of electronic medical records to create smart phrases, which can be auto-populated in notes or letters to patients to include completed and overdue vaccinations;¹ these templates can be used whenever a patient is seen in the office so that it is always updated. The Crohn’s and Colitis Foundation and Cornerstones have developed useful checklists for office use. If offices carry vaccines, it is efficient to use this template and administer the vaccine before a patient leaves the appointment. Utilizing nurses has also been demonstrated to increase vaccination rates.⁴⁸ For practices that do not stock vaccines, or have limited resources to administer vaccinations, an alternative approach is to prescribe vaccines for patients to receive at a local pharmacy. Pharmacy resources can prevent delays to vaccination and have the added benefit of offering more flexible hours and vaccine availability.⁴⁸ Finally, the success of implementing a vaccination program rests on shared decision-making with patients. Office visits should include educational components to emphasize the importance of vaccines and patients should be kept up to date on recommended scheduling. If patients are not seen regularly, then patient portals can be utilized with routine automated messages to remind patients of preventative health care tasks.¹

CONCLUSION

This review highlights current guidelines for vaccinating patients with IBD, including implications of the recent FDA approval of the new herpes zoster vaccine, the two-dose hepatitis B vaccine and new recommendations for the HPV vaccine. Vaccinating IBD patients is an important focus within the broader preventative care sphere, especially prior to initiating immune-modulating therapies. The optimal time to review vaccination schedules are when patients with IBD are seen for their initial gastroenterology visits. While live vaccines should generally be administered on these early visits if not already given, recommendations vary for inactivated vaccines and primarily differ on age; supporting data included here generally favor administration at any time, with minimal risk to patients on immunosuppressant therapy. The vaccinations discussed in this review article are imperative given the elevated risk patients with IBD are at for contracting infectious diseases. Further work to improve vaccinations rates in this population includes clarifying whether the gastroenterologist or primary care physician is primarily responsible for this task. Educating physicians in both fields will help spread knowledge on current guidelines and is an area for improvement in preventative care of IBD patients.

Liver Disorders, Series #10

Alcoholic Hepatitis: A Review

Navroop Nagra,

Robert Hu,

Gaurav Singhvi

Alcoholic Hepatitis (AH) is an acute clinical entity characterized by jaundice and coagulopathy occurring in individuals with a history of heavy alcohol use. It is associated with a high mortality rate, as treatment options available to date have been underwhelming. In this review we discuss AH with an emphasis on potential future treatment options.

Navroop Nagra MD, Peace Health Southwest Medical Center, Vancouver, WA Robert Hu, University of Pennsylvania, Philadelphia, PA Gaurav Singhvi, MD Olive View/UCLA Medical Center, Sylmar, CA

INTRODUCTION

Alcoholic Hepatitis (AH) is an acute clinical entity characterized by jaundice and coagulopathy occurring in individuals with a history of heavy alcohol use. It is associated with a high mortality rate, as treatment options available to date have been underwhelming.^1,2,3,4 In this review we discuss AH with an emphasis on potential future treatment options.

Epidemiology

The true incidence and prevalence of AH is difficult to define, as is the amount and duration of alcohol use needed to cause AH.⁵ Most individuals present between the age of 40 and 50. Typically, they have a history of using more than 100g/day over a time period of two decades.⁷ AH is more prevalent in men given their higher tendency to abuse alcohol. Binge drinking also increases the risk of AH.⁴ In patients with severe AH, the short-term mortality can be as high as 45%.^5,6

Pathophysiology

Oxidative stress and increased gut permeability are two major mechanisms triggering hepatic inflammation leading to AH.^6,8,9 By products of alcohol metabolism via the two major pathways lead to the formation of free radicals and increased oxidative stress. Alcohol is reduced to acetaldehyde and acetate by the enzymes alcohol dehydrogenase and acetaldehyde dehydrogenase, respectively. These enzymes convert NAD to NADH. An increased NADH/NAD ratio leads to the suppression of gluconeogenesis, increased fatty acid (FA) oxidation, and fatty infiltration.^10,11 Alcohol increases the activity of cytochrome P-4502E1, which also produces free radicals. Decreased levels of glutathione make the liver even more prone to oxidative stress.^11,12 The release of free radicals leads to the activation of inflammatory cytokines (TNF-α, IL-1 and IL-6 ), which in turn causes hepatic inflammation. Chronic alcohol use also leads to severe gut dysfunction due to intestinal bacterial overgrowth and the disruption of the tight junctions of the epithelial cells of the gut mucosa.^13,14,15 These changes increase the permeability of the gut and cause a leakage of bacteria and endotoxins into the blood stream. Increased levels of bacterial lipopolysaccharides (LPS) cause an activation of inflammatory cytokines, eventually leading to hepatic necrosis and inflammation.16 (Table 1.)

Clinical Presentation

Symptoms of AH tend to be nonspecific and variable.⁶ Elevated bilirubin is considered characteristic of AH.¹⁷ Other findings include fever, right upper quadrant abdominal pain, anorexia, and abdominal distension due to ascites. Severe cases may present with hepatic encephalopathy. Renal failure due to hepatorenal syndrome (HRS) and bleeding due to coagulopathy can also be seen.^18,19 Features of chronic liver disease such as spider angiomata, gynecomastia, and proximal muscle wasting are common. Alcohol withdrawal causing tremors, seizures, delirium, and coma can complicate matters. Lab abnormalities include elevated bilirubin, mild leukocytosis with neutrophilic predominance, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), anemia, thrombocytopenia, and elevated international normalized ratio (INR). AST/ALT levels are typically below 500 mg/dl with an AST/ALT ratio that is more than two being characteristic of AH. This is attributed to a deficiency of pyridoxal 5′-phosphate in alcoholics, which is required for the enzymatic activity of ALT.^17,21 Reversal of this ratio should lead to the workup for other etiologies of hepatitis.

DIAGNOSIS

The diagnosis of AH is a clinical one.⁶ A medical history should be obtained in detail with an emphasis on the amount and duration of alcohol intake. Some patients may not have been drinking for a few weeks prior to presentation but may still have AH. This history, in conjunction with lab findings, helps to make the diagnosis. Other etiologies of acute hepatitis need to be ruled out if the clinical features and labs are inconsistent with AH. Although liver biopsy is not routinely indicated, it is recommended if there is a doubt about the diagnosis and an alternate diagnosis is suspected. Pathology shows ballooning hepatocytes, Mallory-Denk bodies, severe fibrosis (usually micronodular, but sometimes mixed macro- and micronodular) starting from the central vein and extending into the portal triad, and neutrophilic infiltration.²⁰

Scoring Systems in AH

Various scoring systems have been developed for AH in order to assist in determining the severity and prognosis, and to guide treatment. The Maddrey discriminant function (DF) score and model for end-stage liver disease (MELD) score are the most commonly utilized.^14,23,24 Other less commonly used ones are the Glasgow alcoholic hepatitis score (GAHS), alcoholic hepatitis histology score (AHHS), and Lille score. DF uses the prothrombin time (PT) and bilirubin levels with the equation to calculate the score being: 4.6 x [prothrombin time (sec) – control prothrombin time (sec)]) + (serum bilirubin). Patients with a DF ≥32 have an almost 50% short term mortality (severe AH) and may benefit from glucocorticoid treatment.²⁵ Individuals with a DF< 32 will not benefit from steroids. MELD score is typically used for prioritization of liver transplant and to predict mortality in cirrhotic patients, but it has also been used in predicting prognosis in AH. It takes the creatinine, total bilirubin, and INR into account. An increase in the MELD score of ≥2 points in the first week of hospitalization may independently predict mortality.22 MELD ≥ 21 has a 75% sensitivity and specificity in predicting 3 months mortality (20%).²⁸ GAHS uses age, serum bilirubin, blood urea nitrogen, prothrombin time, and peripheral white blood cell count. This multivariable scoring system also predicts mortality in AH. Patients with a DF ≥32 and GAH score ≥9 had higher survival rates after receiving steroids.²⁶ AHHS score requires a liver biopsy, which as previously mentioned is not performed routinely for AH. It also predicts severity and 90-day mortality in AH. The stage of fibrosis, degree of neutrophilic infiltration, and type of bilirubinostasis are the major variables predicting severity and prognosis.^27,28 A high stage of fibrosis and presence of bilirubinostasis favors a poor outcome. A higher degree of neutrophilic infiltration and the presence of megamitochondria represents an early stage of hepatocellular injury and represents a favorable prognosis.^29,30,31 The Lille score helps to identify the response to glucocorticoids. It uses the decrease in bilirubin after one week of glucocorticoid treatment as a marker of response. The score is calculated one week after steroid initiation. Scores of more than 0.45 predict a poor prognosis with 6-month survival rate of less than 25%.³² Glucocorticoids should be stopped in patients who are steroid non-responders (score ≥ 0.56).

Treatment

Treatment of AH with steroids and pentoxifylline has been the mainstay for many years. The importance of nutritional support cannot be understated. It is also vital that the virtues of abstinence be stressed to patients. Resources such as alcoholics anonymous should be utilized. The feasibility of early transplant, even in those who are actively drinking, continues to be studied and is advocated by some. There are also many other novel treatments being looked at. While none are ready for widespread usage at this time, they do provide for some potentially exciting opportunities in the future.

Nutrition

Most patients with AH have nutritional deficiencies and protein calorie malnutrition.³⁶ Randomized controlled trials have come to different conclusions in regards to the role and survival benefit of enteral nutrition, but poor nutritional status is associated with worse outcomes in AH. All patients should get a calorie count and should receive enough calorie supplementation to meet their needs. Protein intake does not need to be restricted.³³ The enteral route is preferred since it maintains gut mucosal integrity, decrease the risk of bacterial translocation, and is cost-effective.^34,35

Steroids

Treatment with glucocorticoids is indicated in severe AH (DF≥32) or hepatic encephalopathy.^43,44,45 Glucocorticoids decrease the levels of TNF and IL8, ultimately decreasing inflammation.^46,47 Prednisolone is the steroid of choice since it does not require conversion to any active metabolites in the liver,48 although it is contraindicated in renal failure, active gastrointestinal bleeding, uncontrolled hyperglycemia, acute pancreatitis, psychosis, and infection.^49,50 Prednisolone 40 mg/day orally is given for four weeks, followed by a gradual taper over the next two weeks in patients who are steroid responders.²⁵ Response to steroids is determined by the Lille score, calculated one week after the start of steroids.

Pentoxifylline

Pentoxifylline acts by inhibiting phosphodiesterase and decreasing the levels of TNF.^37,38 It is known to decrease the incidence of HRS in AH.^39,40,41 The studies and trials conducted to date, including the STOPAH study, have concluded that pentoxifylline has no impact on mortality in AH. It may be used as an alternative therapy in patients with severe AH in whom steroids are contraindicated or in patients with renal failure.⁴² It is not recommended in patients who are steroid non-responders. The combined use of pentoxifylline and steroids has not demonstrated a mortality benefit and is not recommended.⁴²

Liver Transplant

Liver transplant is considered in those with severe AH who have failed medical management. Studies have shown a significant long-term mortality benefit in patients who underwent liver transplantation. Six month and two-year survival were significantly higher in patients who received early liver transplant despite being active drinkers upon presentation.⁵² Most transplant centers require a minimum of six months of abstinence before considering liver transplant. Given that severe AH carries a high mortality, many patients do not survive long enough to meet this criterion. Although early liver transplant in AH has good outcomes, patient selection is very difficult. Alcohol relapse after transplantation is a challenge, and it is therefore no surprise that ethical and sociocultural factors play a big role. More studies are needed in order to create better criteria for transplant eligibility.

Granulocyte Colony Stimulating Factor (G-CSF)

G-CSF acts by mobilizing the hematopoietic stem cells that cause liver regeneration.^53,54 It also increases the bactericidal activity of neutrophils.^57,58 Studies have shown that G-CSF leads to the production of CD34⁺ stem cells and induces proliferation of hepatic progenitor cells which can lead to liver regeneration.^55,56 This leads to decreased infections, improved DF score, and increased three month survival.⁵⁹ The studies conducted so far have only compared GCSF with pentoxifylline or with normal controls not receiving any pharmacological treatment. None of the studies have compared outcomes with patients on steroids. The treatment may improve survival in patients who are steroid ineligible or steroid refractory, but this needs to be further researched.

Extra Corporal Liver Support

Various biologic and non-biologic liver support systems are being developed and studied in AH. Extracorporeal cellular therapy (ELAD) is a biologic system that uses liver cells (C3Acells). These cells have anti-inflammatory and antioxidative properties that help regenerate the liver.^60,61,62 Non-biologic liver support devices use the concepts of plasma exchange and albumin dialysis. Some examples of such devices are single pass albumin dialysis (SPAD), molecular adsorbent recirculating system (MARS), and fractionated plasma separation and adsorption (PROMETHEUS). MARS therapy has been shown to decrease serum bilirubin and serum creatinine. It also leads to clearance of hepatic encephalopathy.⁶³ The favorable effects of albumin dialysis in patients with severe AH suggest that the procedure used alone or in combination with other pharmacological therapies may play a role in the future. However, prior to being used further it has to be proven to be effective in well-designed randomized controlled trials, especially in terms of improving both short- and long-term survival.⁶⁴ The outcome of ELAD depends on the severity of AH and organ dysfunction. Patients with acute renal failure, severe coagulopathy, age >50 and MELD >28 have worse outcomes with ELAD.⁶² ELAD can work as a bridge therapy for liver transplant in younger patients who do not have renal failure or severe coagulopathy.

N Acetyl Cysteine (NAC)

N Acetyl cysteine acts by replenishing glutathione levels, which tend to be depleted in AH. NAC alone is not an effective treatment for AH.^65,66,67 That being said, the combined use of NAC and steroids decreases the risk of infections and hepatorenal syndrome. Combination therapy also decreases short term mortality but has no long-term survival benefit.⁶⁸ Further studies are needed before making the combination therapy of NAC and steroids a standard of care in AH.

Stool Transplant / Fecal Microbiota Transplant (FMT)

Studies looking at healthy donor fecal microbiota transplant (FMT) have shown improved survival at one year in steroid ineligible patients.⁶⁹ In one trial, patients with severe alcoholic hepatitis were transplanted for seven continuous days with the goal of modulating patient gut bacteria. Microbiota analysis was subsequently performed, with similar profile found between donors and recipients at the one-year mark. Immune Modulation One potential therapy target is chemokines. These molecules, especially CCL20,⁷⁰ play an important role in alcoholic hepatitis due to upregulation. Targeting this molecule, along with IL8, is being studied in order to see if a safe and effective therapy may be developed. Secukinamab is an anti IL-17a monoclonal antibody, currently used for rheumatoid arthritis, that may play a role in AH.⁷ IL-10, anti-osteoponin, and anti-TNF agents are also being looked at to see if they might be effective against AH. Osteoponin is an extracellular protein matrix that is highly expressed in alcoholic hepatitis and may be a good potential target for treatment as well.⁷²

Granulacytapheresis

This is a technique in which granulocytes and monocytes are removed from patient blood. It is well tolerated, may be beneficial in steroid non-responders, and is under further study in AH patients.⁷³

CONCLUSION

Alcoholic hepatitis is a relatively common condition that can have deadly consequences for patients, and is burdensome for society at large given the loss of productivity and costs that are associated with it. Fortunately, research continues to elucidate the pathophysiology of the disease and this may potentially lead to new breakthroughs in treatment. Novel treatments such as FMT deserve further study, as does early transplantation. Despite these advances, nutrition and abstinence are two relatively simple interventions that need to be the cornerstone of any treatment regimen going forward.

Aspen Announces Publication of the Guidebook on Enteral Medication Administration