From the AGA Journals

Eleven operational taxonomic units (OTUs) of fecal bacteria were less abundant in children with celiac disease than in healthy children, according to the findings of a study published in Gastroenterology.

chameleonseye/Thinkstock

This microbial signature correctly identified approximately four out of five cases of celiac disease, regardless of whether children were newly diagnosed or had already modified their diet, reported Konstantina Zafeiropoulou and Ben Nichols, PhD, of the Glasgow Royal Infirmary. “It is not clear whether the microbes identified [in this study] contribute to the pathogenesis of celiac disease or are the result of it. Future research should explore the role of the disease-specific species identified here,” the researchers wrote in Gastroenterology.

Celiac disease is multifactorial. While up to 40% of people are genetically predisposed, only a small proportion develop it, suggesting that environmental factors are key to pathogenesis. Recent studies have linked celiac disease with alterations in the gut microbiome, but it is unclear whether dysbiosis is pathogenic or a secondary effect of disease processes such as nutrient malabsorption, or whether dysbiosis is present at disease onset or results from a gluten-free diet.

For the study, the researchers performed gas chromatography and 16S ribosomal RNA sequencing of fecal samples from 141 children, including 20 with newly biopsy-confirmed, previously untreated celiac disease, 45 who were previously diagnosed and on a gluten-free diet, 19 unaffected siblings, and 57 healthy children who were not on regular medications and had no history of chronic gastrointestinal symptoms. A single fecal sample was tested for all but the previously untreated children, who were tested at baseline and then after 6 and 12 months on a gluten-free diet.

Children with new-onset celiac disease showed no evidence of dysbiosis, while a gluten-free diet explained up to 2.8% of variation in microbiota between patients and controls. Microbial alpha diversity, a measure of species-level diversity, was generally similar among groups, but between 3% and 5% of all taxa differed. Irrespective of treatment, the decreased abundance of the 11 OTUs was diagnostic for celiac disease with an error rate of 21.5% (P < .001 vs. random classification). Notably, most of these 11 discrepant OTUs were associated with nutrient or food group intake and with biomarkers of gluten ingestion, the researchers said. Gas chromatography showed that, after patients started a gluten-free diet, fecal levels of butyrate and ammonia decreased.

“Even though we identified differences in the abundance of a few species between patients with untreated celiac disease and healthy controls, the profound microbial dysbiosis noted in Crohn’s disease was not observed, at least using crude diversity indices,” the investigators commented. “Although several alterations in the intestinal microbiota of children with established celiac disease appear to be effects of a gluten-free diet, there are specific bacteria that are distinct biomarkers of celiac disease.”

Future research might involve performing in vitro tests of “candidate” bacteria, coculturing these bacteria with human immune cells, and studying whether dietary interventions alter the relative abundance of these bacteria in the gut microbiome, the researchers said.

Nutricia Research Foundation, the Biotechnology and Biological Sciences Research Council, and The Catherine McEwan Foundation provided funding. Three coinvestigators disclosed ties to Nutricia, 4D Pharma, AbbVie, Celltrion, Janssen, Takeda, and several other pharmaceutical companies. One coinvestigator reported chairing the working group for ISLI Europe. The remaining investigators reported having no conflicts of interest.

SOURCE: Zafeiropoulou K et al. Gastroenterology. 2020 Aug 10;S0016-5085(20)35023-X. doi: 10.1053/j.gastro.2020.08.007.

Eleven operational taxonomic units (OTUs) of fecal bacteria were less abundant in children with celiac disease than in healthy children, according to the findings of a study published in Gastroenterology.

chameleonseye/Thinkstock

This microbial signature correctly identified approximately four out of five cases of celiac disease, regardless of whether children were newly diagnosed or had already modified their diet, reported Konstantina Zafeiropoulou and Ben Nichols, PhD, of the Glasgow Royal Infirmary. “It is not clear whether the microbes identified [in this study] contribute to the pathogenesis of celiac disease or are the result of it. Future research should explore the role of the disease-specific species identified here,” the researchers wrote in Gastroenterology.

Celiac disease is multifactorial. While up to 40% of people are genetically predisposed, only a small proportion develop it, suggesting that environmental factors are key to pathogenesis. Recent studies have linked celiac disease with alterations in the gut microbiome, but it is unclear whether dysbiosis is pathogenic or a secondary effect of disease processes such as nutrient malabsorption, or whether dysbiosis is present at disease onset or results from a gluten-free diet.

For the study, the researchers performed gas chromatography and 16S ribosomal RNA sequencing of fecal samples from 141 children, including 20 with newly biopsy-confirmed, previously untreated celiac disease, 45 who were previously diagnosed and on a gluten-free diet, 19 unaffected siblings, and 57 healthy children who were not on regular medications and had no history of chronic gastrointestinal symptoms. A single fecal sample was tested for all but the previously untreated children, who were tested at baseline and then after 6 and 12 months on a gluten-free diet.

Children with new-onset celiac disease showed no evidence of dysbiosis, while a gluten-free diet explained up to 2.8% of variation in microbiota between patients and controls. Microbial alpha diversity, a measure of species-level diversity, was generally similar among groups, but between 3% and 5% of all taxa differed. Irrespective of treatment, the decreased abundance of the 11 OTUs was diagnostic for celiac disease with an error rate of 21.5% (P < .001 vs. random classification). Notably, most of these 11 discrepant OTUs were associated with nutrient or food group intake and with biomarkers of gluten ingestion, the researchers said. Gas chromatography showed that, after patients started a gluten-free diet, fecal levels of butyrate and ammonia decreased.

“Even though we identified differences in the abundance of a few species between patients with untreated celiac disease and healthy controls, the profound microbial dysbiosis noted in Crohn’s disease was not observed, at least using crude diversity indices,” the investigators commented. “Although several alterations in the intestinal microbiota of children with established celiac disease appear to be effects of a gluten-free diet, there are specific bacteria that are distinct biomarkers of celiac disease.”

Future research might involve performing in vitro tests of “candidate” bacteria, coculturing these bacteria with human immune cells, and studying whether dietary interventions alter the relative abundance of these bacteria in the gut microbiome, the researchers said.

Nutricia Research Foundation, the Biotechnology and Biological Sciences Research Council, and The Catherine McEwan Foundation provided funding. Three coinvestigators disclosed ties to Nutricia, 4D Pharma, AbbVie, Celltrion, Janssen, Takeda, and several other pharmaceutical companies. One coinvestigator reported chairing the working group for ISLI Europe. The remaining investigators reported having no conflicts of interest.

SOURCE: Zafeiropoulou K et al. Gastroenterology. 2020 Aug 10;S0016-5085(20)35023-X. doi: 10.1053/j.gastro.2020.08.007.

Eleven operational taxonomic units (OTUs) of fecal bacteria were less abundant in children with celiac disease than in healthy children, according to the findings of a study published in Gastroenterology.

chameleonseye/Thinkstock

This microbial signature correctly identified approximately four out of five cases of celiac disease, regardless of whether children were newly diagnosed or had already modified their diet, reported Konstantina Zafeiropoulou and Ben Nichols, PhD, of the Glasgow Royal Infirmary. “It is not clear whether the microbes identified [in this study] contribute to the pathogenesis of celiac disease or are the result of it. Future research should explore the role of the disease-specific species identified here,” the researchers wrote in Gastroenterology.

Celiac disease is multifactorial. While up to 40% of people are genetically predisposed, only a small proportion develop it, suggesting that environmental factors are key to pathogenesis. Recent studies have linked celiac disease with alterations in the gut microbiome, but it is unclear whether dysbiosis is pathogenic or a secondary effect of disease processes such as nutrient malabsorption, or whether dysbiosis is present at disease onset or results from a gluten-free diet.

For the study, the researchers performed gas chromatography and 16S ribosomal RNA sequencing of fecal samples from 141 children, including 20 with newly biopsy-confirmed, previously untreated celiac disease, 45 who were previously diagnosed and on a gluten-free diet, 19 unaffected siblings, and 57 healthy children who were not on regular medications and had no history of chronic gastrointestinal symptoms. A single fecal sample was tested for all but the previously untreated children, who were tested at baseline and then after 6 and 12 months on a gluten-free diet.

Children with new-onset celiac disease showed no evidence of dysbiosis, while a gluten-free diet explained up to 2.8% of variation in microbiota between patients and controls. Microbial alpha diversity, a measure of species-level diversity, was generally similar among groups, but between 3% and 5% of all taxa differed. Irrespective of treatment, the decreased abundance of the 11 OTUs was diagnostic for celiac disease with an error rate of 21.5% (P < .001 vs. random classification). Notably, most of these 11 discrepant OTUs were associated with nutrient or food group intake and with biomarkers of gluten ingestion, the researchers said. Gas chromatography showed that, after patients started a gluten-free diet, fecal levels of butyrate and ammonia decreased.

“Even though we identified differences in the abundance of a few species between patients with untreated celiac disease and healthy controls, the profound microbial dysbiosis noted in Crohn’s disease was not observed, at least using crude diversity indices,” the investigators commented. “Although several alterations in the intestinal microbiota of children with established celiac disease appear to be effects of a gluten-free diet, there are specific bacteria that are distinct biomarkers of celiac disease.”

Future research might involve performing in vitro tests of “candidate” bacteria, coculturing these bacteria with human immune cells, and studying whether dietary interventions alter the relative abundance of these bacteria in the gut microbiome, the researchers said.

Nutricia Research Foundation, the Biotechnology and Biological Sciences Research Council, and The Catherine McEwan Foundation provided funding. Three coinvestigators disclosed ties to Nutricia, 4D Pharma, AbbVie, Celltrion, Janssen, Takeda, and several other pharmaceutical companies. One coinvestigator reported chairing the working group for ISLI Europe. The remaining investigators reported having no conflicts of interest.

SOURCE: Zafeiropoulou K et al. Gastroenterology. 2020 Aug 10;S0016-5085(20)35023-X. doi: 10.1053/j.gastro.2020.08.007.

Interleukin-23 optimizes antimicrobial macrophage activity, which is reduced among persons harboring an IL-23 receptor variant that helps protect against inflammatory bowel disease (IBD), recent research has found.

“These [findings] highlight that the susceptibility to infections with therapeutic blockade of the IL-23/IL-12 pathways may be owing in part to the essential role for IL-23 in mediating antimicrobial functions in macrophages. They further highlight that carriers of the IL-23R–Q381 variant, who are relatively protected from IBD and other immune-mediated diseases, may be at increased risk for bacterial infection,” Rui Sun and Clara Abraham, MD, of Yale University, New Haven, Conn., wrote in Cellular and Molecular Gastroenterology and Hepatology.

IL-23 is key to the pathogenesis of IBD and is being studied as a therapeutic target, both alone and in combination with IL-12 blocking. Although human macrophages express low levels of IL-23 receptor, recent research reveals that IL-23R is up-regulated “within minutes of exposure to IL-23,” which promotes signaling and cytokine secretion, the investigators wrote. However, the extent to which IL-23 supports macrophage antimicrobial activity was unknown. To characterize protein expression, signaling, and bacterial uptake and clearance of bacteria by human macrophages derived from monocytes, the investigators tested these cells with Western blot, flow cytometry, and gentamicin protection, which involved coculturing human macrophages with bacteria, adding gentamicin solution, and then lysing and plating the cells onto agar to assess the extent to which the macrophages had taken up the bacteria.

After 48 hours of exposure to IL-23 or IL-12, macrophages increased their intracellular clearance of clinically relevant bacteria, including Enterococcus faecalis, adherent invasive Escherichia coli, and Salmonella typhimurium. Notably, this did not occur when the investigators reduced (“knocked down”) macrophage expression of either IL-23R or IL-12 receptor alpha 2. Additional investigations showed that in macrophages, IL-23 promotes bacterial uptake, clearance, and autophagy by inducing a pyruvate dehydrogenase kinase 1 (PDK1)–dependent pathway mediated by Janus kinase 2/tyrosine kinase 2 and by inducing reactive oxygen species (ROS) and reactive nitrogen species (RNS) pathways. IL-23 also activates two key proteins involved in autophagy (ATG5 and ATG16L1), the researchers reported. “ROS, RNS, and autophagy cooperate to mediate IL-23-induced bacterial clearance. Reduction of each ROS, RNS, and autophagy pathway partially reversed the enhanced bacterial clearance observed with chronic IL-23 treatment.”

Further tests found that IL-23 mediates antimicrobial pathways through the Janus kinase 2, tyrosine kinase 2, and STAT3 pathways, which “cooperate to mediate optimal IL-23-induced intracellular bacterial clearance in human macrophages.” Importantly, human macrophages showed less antimicrobial activity when transfected with the IL-23R–Q381 variant than with IL-23R–R381. The IL-23R-Q381 variant, which reduces susceptibility to IBD, “decreased IL-23-induced and NOD2-induced antimicrobial pathways and intracellular bacterial clearance in monocyte-derived macrophages,” the researchers explained. Evaluating actual carriers of these variants showed the same results – macrophages harboring IBD-protective IL-23R–R381/Q381 exhibited lower antimicrobial activity and less intracellular bacterial clearance compared with macrophages from carriers of IL-23R–R381/R381.

“Taken together, IL-23 promotes increased bacterial uptake and then induces a more rapid and effective clearance of these intracellular bacteria in human monocyte-derived macrophages,” the researchers wrote. “The reduced inflammatory responses observed in IL-23R Q381 carriers are associated with protection from multiple immune-mediated diseases. This would imply that loss-of-function observed with the common IL-23R–R381Q variant may lead to a disadvantage in select infectious diseases, including through [this variant’s] now identified role in promoting antimicrobial pathways in macrophages.”

The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.

SOURCE: Sun R, Abraham C. Cell Molec Gastro Hepatol. 2020 May 28. doi.: 10.1016/j.jcmgh.2020.05.007.

Interleukin-23 optimizes antimicrobial macrophage activity, which is reduced among persons harboring an IL-23 receptor variant that helps protect against inflammatory bowel disease (IBD), recent research has found.

“These [findings] highlight that the susceptibility to infections with therapeutic blockade of the IL-23/IL-12 pathways may be owing in part to the essential role for IL-23 in mediating antimicrobial functions in macrophages. They further highlight that carriers of the IL-23R–Q381 variant, who are relatively protected from IBD and other immune-mediated diseases, may be at increased risk for bacterial infection,” Rui Sun and Clara Abraham, MD, of Yale University, New Haven, Conn., wrote in Cellular and Molecular Gastroenterology and Hepatology.

IL-23 is key to the pathogenesis of IBD and is being studied as a therapeutic target, both alone and in combination with IL-12 blocking. Although human macrophages express low levels of IL-23 receptor, recent research reveals that IL-23R is up-regulated “within minutes of exposure to IL-23,” which promotes signaling and cytokine secretion, the investigators wrote. However, the extent to which IL-23 supports macrophage antimicrobial activity was unknown. To characterize protein expression, signaling, and bacterial uptake and clearance of bacteria by human macrophages derived from monocytes, the investigators tested these cells with Western blot, flow cytometry, and gentamicin protection, which involved coculturing human macrophages with bacteria, adding gentamicin solution, and then lysing and plating the cells onto agar to assess the extent to which the macrophages had taken up the bacteria.

After 48 hours of exposure to IL-23 or IL-12, macrophages increased their intracellular clearance of clinically relevant bacteria, including Enterococcus faecalis, adherent invasive Escherichia coli, and Salmonella typhimurium. Notably, this did not occur when the investigators reduced (“knocked down”) macrophage expression of either IL-23R or IL-12 receptor alpha 2. Additional investigations showed that in macrophages, IL-23 promotes bacterial uptake, clearance, and autophagy by inducing a pyruvate dehydrogenase kinase 1 (PDK1)–dependent pathway mediated by Janus kinase 2/tyrosine kinase 2 and by inducing reactive oxygen species (ROS) and reactive nitrogen species (RNS) pathways. IL-23 also activates two key proteins involved in autophagy (ATG5 and ATG16L1), the researchers reported. “ROS, RNS, and autophagy cooperate to mediate IL-23-induced bacterial clearance. Reduction of each ROS, RNS, and autophagy pathway partially reversed the enhanced bacterial clearance observed with chronic IL-23 treatment.”

Further tests found that IL-23 mediates antimicrobial pathways through the Janus kinase 2, tyrosine kinase 2, and STAT3 pathways, which “cooperate to mediate optimal IL-23-induced intracellular bacterial clearance in human macrophages.” Importantly, human macrophages showed less antimicrobial activity when transfected with the IL-23R–Q381 variant than with IL-23R–R381. The IL-23R-Q381 variant, which reduces susceptibility to IBD, “decreased IL-23-induced and NOD2-induced antimicrobial pathways and intracellular bacterial clearance in monocyte-derived macrophages,” the researchers explained. Evaluating actual carriers of these variants showed the same results – macrophages harboring IBD-protective IL-23R–R381/Q381 exhibited lower antimicrobial activity and less intracellular bacterial clearance compared with macrophages from carriers of IL-23R–R381/R381.

“Taken together, IL-23 promotes increased bacterial uptake and then induces a more rapid and effective clearance of these intracellular bacteria in human monocyte-derived macrophages,” the researchers wrote. “The reduced inflammatory responses observed in IL-23R Q381 carriers are associated with protection from multiple immune-mediated diseases. This would imply that loss-of-function observed with the common IL-23R–R381Q variant may lead to a disadvantage in select infectious diseases, including through [this variant’s] now identified role in promoting antimicrobial pathways in macrophages.”

The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.

SOURCE: Sun R, Abraham C. Cell Molec Gastro Hepatol. 2020 May 28. doi.: 10.1016/j.jcmgh.2020.05.007.

Interleukin-23 optimizes antimicrobial macrophage activity, which is reduced among persons harboring an IL-23 receptor variant that helps protect against inflammatory bowel disease (IBD), recent research has found.

“These [findings] highlight that the susceptibility to infections with therapeutic blockade of the IL-23/IL-12 pathways may be owing in part to the essential role for IL-23 in mediating antimicrobial functions in macrophages. They further highlight that carriers of the IL-23R–Q381 variant, who are relatively protected from IBD and other immune-mediated diseases, may be at increased risk for bacterial infection,” Rui Sun and Clara Abraham, MD, of Yale University, New Haven, Conn., wrote in Cellular and Molecular Gastroenterology and Hepatology.

IL-23 is key to the pathogenesis of IBD and is being studied as a therapeutic target, both alone and in combination with IL-12 blocking. Although human macrophages express low levels of IL-23 receptor, recent research reveals that IL-23R is up-regulated “within minutes of exposure to IL-23,” which promotes signaling and cytokine secretion, the investigators wrote. However, the extent to which IL-23 supports macrophage antimicrobial activity was unknown. To characterize protein expression, signaling, and bacterial uptake and clearance of bacteria by human macrophages derived from monocytes, the investigators tested these cells with Western blot, flow cytometry, and gentamicin protection, which involved coculturing human macrophages with bacteria, adding gentamicin solution, and then lysing and plating the cells onto agar to assess the extent to which the macrophages had taken up the bacteria.

After 48 hours of exposure to IL-23 or IL-12, macrophages increased their intracellular clearance of clinically relevant bacteria, including Enterococcus faecalis, adherent invasive Escherichia coli, and Salmonella typhimurium. Notably, this did not occur when the investigators reduced (“knocked down”) macrophage expression of either IL-23R or IL-12 receptor alpha 2. Additional investigations showed that in macrophages, IL-23 promotes bacterial uptake, clearance, and autophagy by inducing a pyruvate dehydrogenase kinase 1 (PDK1)–dependent pathway mediated by Janus kinase 2/tyrosine kinase 2 and by inducing reactive oxygen species (ROS) and reactive nitrogen species (RNS) pathways. IL-23 also activates two key proteins involved in autophagy (ATG5 and ATG16L1), the researchers reported. “ROS, RNS, and autophagy cooperate to mediate IL-23-induced bacterial clearance. Reduction of each ROS, RNS, and autophagy pathway partially reversed the enhanced bacterial clearance observed with chronic IL-23 treatment.”

Further tests found that IL-23 mediates antimicrobial pathways through the Janus kinase 2, tyrosine kinase 2, and STAT3 pathways, which “cooperate to mediate optimal IL-23-induced intracellular bacterial clearance in human macrophages.” Importantly, human macrophages showed less antimicrobial activity when transfected with the IL-23R–Q381 variant than with IL-23R–R381. The IL-23R-Q381 variant, which reduces susceptibility to IBD, “decreased IL-23-induced and NOD2-induced antimicrobial pathways and intracellular bacterial clearance in monocyte-derived macrophages,” the researchers explained. Evaluating actual carriers of these variants showed the same results – macrophages harboring IBD-protective IL-23R–R381/Q381 exhibited lower antimicrobial activity and less intracellular bacterial clearance compared with macrophages from carriers of IL-23R–R381/R381.

“Taken together, IL-23 promotes increased bacterial uptake and then induces a more rapid and effective clearance of these intracellular bacteria in human monocyte-derived macrophages,” the researchers wrote. “The reduced inflammatory responses observed in IL-23R Q381 carriers are associated with protection from multiple immune-mediated diseases. This would imply that loss-of-function observed with the common IL-23R–R381Q variant may lead to a disadvantage in select infectious diseases, including through [this variant’s] now identified role in promoting antimicrobial pathways in macrophages.”

The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.

SOURCE: Sun R, Abraham C. Cell Molec Gastro Hepatol. 2020 May 28. doi.: 10.1016/j.jcmgh.2020.05.007.

Budesonide orodispersible tablets maintained remissions of eosinophilic esophagitis for 48 weeks in approximately 75% of patients and did not increase the risk for most adverse events, compared with placebo, according to the findings of a multicenter, randomized, double-blind trial.

While prior studies have shown that swallowed topical corticosteroids such as budesonide or fluticasone induce remission in EoE, this is the first multicenter phase 3 study of budesonide orodispersible tablets (BOTs) for maintaining remissions over the long term, wrote Alex Straumann, MD, of the Swiss EoE Research Group and University Hospital Zurich, and associates in Gastroenterology.

Eosinophilic esophagitis is the most common cause of esophageal dysphagia and food impaction. Swallowed topical corticosteroids improve symptoms and inflammation, but the off-label use of formulations developed for airway administration in asthma shows “suboptimal esophageal targeting and efficacy,” the researchers wrote. In the phase 3 EOS-2 trial, twice-daily treatment with 1.0 mg BOTs had induced clinicohistologic remissions in 58% of adults with EoE at 6 weeks and in 85% at 12 weeks.

To study long-term maintenance BOT therapy, the researchers randomly assigned 204 of the remitted patients to 48 weeks of twice-daily BOT 0.5 mg, BOT 1.0 mg, or placebo. There were 68 patients per group. A total of 141 patients completed this double-blind phase, but all 204 were evaluable for the primary analysis. The primary outcome was remission at week 48, defined as freedom from relapse (dysphagia or odynophagia rated as 4 or higher on a 10-point numeric rating scale), histologic relapse (≥48 eosinophils per mm² high-power field), food impaction requiring endoscopic intervention, and dilation.

After 48 weeks, 51 patients in the 1-mg group (75%) and 50 patients in the 0.5-mg group (73.5%) remained in remission, compared with only three patients in the placebo group (4.4%; both P less than .0001). Patients in the placebo group relapsed after a median of 87 days off BOTs. Overall, BOT therapy was similarly efficacious regardless of factors such as history of allergic diseases, location of inflammation at the start of induction, or concomitant use of proton pump inhibitors. However, patients with inflammation of all three esophageal segments achieved “clinically relevant” greater rates of remission with twice-daily 1.0-mg BOT, compared with twice-daily 0.5-mg BOT (80% vs. 68%). In secondary analyses, rates of histologic relapse were 13.2% with 0.5-mg BOT twice daily, 10.3% with 1.0-mg BOT twice daily, and 90% with placebo, and rates of clinical relapse were 10.3%, 7.4%, and 60.3%, respectively. “Histological remission in the BOT 0.5 and 1.0mg twice daily group was independently maintained in all esophageal segments,” the researchers reported.

Rates of most adverse events were similar across treatment groups, and no serious treatment-emergent adverse events were reported. Average morning serum cortisol levels were similar among groups and did not change after treatment ended, but four patients on BOT therapy developed asymptomatic subnormal levels of morning cortisol. “Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5mg group and in 11.8% of patients in the BOT 1.0mg group; all infections resolved with treatment,” the researchers wrote.

The study and editorial support were funded by Dr. Falk Pharma GmbH, a pharmaceutical company in Germany. Dr. Falk Pharma was involved in the study design and data collection, analysis, and interpretation. Dr. Straumann disclosed fees from several pharmaceutical companies, including Dr. Falk Pharma and AstraZeneca, which makes budesonide. Several other coinvestigators also disclosed ties to Dr. Falk Pharma, AstraZeneca, and other pharmaceutical companies.

SOURCE: Straumann A et al. Gastroenterology. 2020 July 25. doi: 10.1053/j.gastro.2020.07.039.

Budesonide orodispersible tablets maintained remissions of eosinophilic esophagitis for 48 weeks in approximately 75% of patients and did not increase the risk for most adverse events, compared with placebo, according to the findings of a multicenter, randomized, double-blind trial.

While prior studies have shown that swallowed topical corticosteroids such as budesonide or fluticasone induce remission in EoE, this is the first multicenter phase 3 study of budesonide orodispersible tablets (BOTs) for maintaining remissions over the long term, wrote Alex Straumann, MD, of the Swiss EoE Research Group and University Hospital Zurich, and associates in Gastroenterology.

Eosinophilic esophagitis is the most common cause of esophageal dysphagia and food impaction. Swallowed topical corticosteroids improve symptoms and inflammation, but the off-label use of formulations developed for airway administration in asthma shows “suboptimal esophageal targeting and efficacy,” the researchers wrote. In the phase 3 EOS-2 trial, twice-daily treatment with 1.0 mg BOTs had induced clinicohistologic remissions in 58% of adults with EoE at 6 weeks and in 85% at 12 weeks.

To study long-term maintenance BOT therapy, the researchers randomly assigned 204 of the remitted patients to 48 weeks of twice-daily BOT 0.5 mg, BOT 1.0 mg, or placebo. There were 68 patients per group. A total of 141 patients completed this double-blind phase, but all 204 were evaluable for the primary analysis. The primary outcome was remission at week 48, defined as freedom from relapse (dysphagia or odynophagia rated as 4 or higher on a 10-point numeric rating scale), histologic relapse (≥48 eosinophils per mm² high-power field), food impaction requiring endoscopic intervention, and dilation.

After 48 weeks, 51 patients in the 1-mg group (75%) and 50 patients in the 0.5-mg group (73.5%) remained in remission, compared with only three patients in the placebo group (4.4%; both P less than .0001). Patients in the placebo group relapsed after a median of 87 days off BOTs. Overall, BOT therapy was similarly efficacious regardless of factors such as history of allergic diseases, location of inflammation at the start of induction, or concomitant use of proton pump inhibitors. However, patients with inflammation of all three esophageal segments achieved “clinically relevant” greater rates of remission with twice-daily 1.0-mg BOT, compared with twice-daily 0.5-mg BOT (80% vs. 68%). In secondary analyses, rates of histologic relapse were 13.2% with 0.5-mg BOT twice daily, 10.3% with 1.0-mg BOT twice daily, and 90% with placebo, and rates of clinical relapse were 10.3%, 7.4%, and 60.3%, respectively. “Histological remission in the BOT 0.5 and 1.0mg twice daily group was independently maintained in all esophageal segments,” the researchers reported.

Rates of most adverse events were similar across treatment groups, and no serious treatment-emergent adverse events were reported. Average morning serum cortisol levels were similar among groups and did not change after treatment ended, but four patients on BOT therapy developed asymptomatic subnormal levels of morning cortisol. “Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5mg group and in 11.8% of patients in the BOT 1.0mg group; all infections resolved with treatment,” the researchers wrote.

The study and editorial support were funded by Dr. Falk Pharma GmbH, a pharmaceutical company in Germany. Dr. Falk Pharma was involved in the study design and data collection, analysis, and interpretation. Dr. Straumann disclosed fees from several pharmaceutical companies, including Dr. Falk Pharma and AstraZeneca, which makes budesonide. Several other coinvestigators also disclosed ties to Dr. Falk Pharma, AstraZeneca, and other pharmaceutical companies.

SOURCE: Straumann A et al. Gastroenterology. 2020 July 25. doi: 10.1053/j.gastro.2020.07.039.

Budesonide orodispersible tablets maintained remissions of eosinophilic esophagitis for 48 weeks in approximately 75% of patients and did not increase the risk for most adverse events, compared with placebo, according to the findings of a multicenter, randomized, double-blind trial.

While prior studies have shown that swallowed topical corticosteroids such as budesonide or fluticasone induce remission in EoE, this is the first multicenter phase 3 study of budesonide orodispersible tablets (BOTs) for maintaining remissions over the long term, wrote Alex Straumann, MD, of the Swiss EoE Research Group and University Hospital Zurich, and associates in Gastroenterology.

Eosinophilic esophagitis is the most common cause of esophageal dysphagia and food impaction. Swallowed topical corticosteroids improve symptoms and inflammation, but the off-label use of formulations developed for airway administration in asthma shows “suboptimal esophageal targeting and efficacy,” the researchers wrote. In the phase 3 EOS-2 trial, twice-daily treatment with 1.0 mg BOTs had induced clinicohistologic remissions in 58% of adults with EoE at 6 weeks and in 85% at 12 weeks.

To study long-term maintenance BOT therapy, the researchers randomly assigned 204 of the remitted patients to 48 weeks of twice-daily BOT 0.5 mg, BOT 1.0 mg, or placebo. There were 68 patients per group. A total of 141 patients completed this double-blind phase, but all 204 were evaluable for the primary analysis. The primary outcome was remission at week 48, defined as freedom from relapse (dysphagia or odynophagia rated as 4 or higher on a 10-point numeric rating scale), histologic relapse (≥48 eosinophils per mm² high-power field), food impaction requiring endoscopic intervention, and dilation.

After 48 weeks, 51 patients in the 1-mg group (75%) and 50 patients in the 0.5-mg group (73.5%) remained in remission, compared with only three patients in the placebo group (4.4%; both P less than .0001). Patients in the placebo group relapsed after a median of 87 days off BOTs. Overall, BOT therapy was similarly efficacious regardless of factors such as history of allergic diseases, location of inflammation at the start of induction, or concomitant use of proton pump inhibitors. However, patients with inflammation of all three esophageal segments achieved “clinically relevant” greater rates of remission with twice-daily 1.0-mg BOT, compared with twice-daily 0.5-mg BOT (80% vs. 68%). In secondary analyses, rates of histologic relapse were 13.2% with 0.5-mg BOT twice daily, 10.3% with 1.0-mg BOT twice daily, and 90% with placebo, and rates of clinical relapse were 10.3%, 7.4%, and 60.3%, respectively. “Histological remission in the BOT 0.5 and 1.0mg twice daily group was independently maintained in all esophageal segments,” the researchers reported.

Rates of most adverse events were similar across treatment groups, and no serious treatment-emergent adverse events were reported. Average morning serum cortisol levels were similar among groups and did not change after treatment ended, but four patients on BOT therapy developed asymptomatic subnormal levels of morning cortisol. “Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5mg group and in 11.8% of patients in the BOT 1.0mg group; all infections resolved with treatment,” the researchers wrote.

The study and editorial support were funded by Dr. Falk Pharma GmbH, a pharmaceutical company in Germany. Dr. Falk Pharma was involved in the study design and data collection, analysis, and interpretation. Dr. Straumann disclosed fees from several pharmaceutical companies, including Dr. Falk Pharma and AstraZeneca, which makes budesonide. Several other coinvestigators also disclosed ties to Dr. Falk Pharma, AstraZeneca, and other pharmaceutical companies.

SOURCE: Straumann A et al. Gastroenterology. 2020 July 25. doi: 10.1053/j.gastro.2020.07.039.

Diarrhea affected one in every five patients with inflammatory bowel disease (IBD) and COVID-19, compared with only 7%-10% of all patients with COVID-19 in prior studies, researchers reported in Clinical Gastroenterology and Hepatology.

In a systematic review and meta-analysis of 23 studies incorporating data from 449 patients with IBD and COVID-19, their most common symptoms were fever (affecting 48.3% of patients), cough (46.5%), and diarrhea (20.5%), and diarrhea was approximately twice as prevalent as dyspnea, nausea, abdominal pain, and fatigue, wrote Ferdinando D’Amico of Humanitas University in Milan and his associates. “[S]ymptoms experienced by IBD patients with COVID-19 are similar to those occurring in the general population, except for a higher percentage of diarrhea,” they wrote. This increased prevalence might result from IBD itself or from inflammatory effects of viral gut tropism, they noted. “Currently, the diagnostic–therapeutic approach does not differ between IBD and non-IBD patients, but further studies are needed to evaluate whether fecal research of viral RNA and treatment with IBD drugs may play a role in the management of COVID-19 patients.”

To characterize the clinical presentation and course of patients with IBD and COVID-19, the researchers searched PubMed, Embase, Web of Science, and MedRxiv through July 29, 2020, for keywords related to COVID-19, Crohn’s disease, ulcerative colitis, and IBD. They identified 23 studies presenting clinical data from adults or children with a confirmed IBD diagnosis and least one case of COVID-19. Among 243,760 patients with IBD, 1,028 patients had COVID-19 infection, including 509 patients with Crohn’s disease, 428 patients with ulcerative colitis, 49 patients with indeterminate colitis, and 42 patients for whom the IBD subtype was not recorded.

In all, 0.4% of patients with IBD had COVID-19. Nearly all had been diagnosed by polymerase chain reaction of nasopharyngeal swabs, and approximately 40% also had received chest CT scans. Most were male (56.5%), and 43.5% were older than 65 years. Patients were receiving a wide range of IBD therapies, most commonly anti–tumor necrosis factor (TNF) agents, mesalamine, thiopurine (alone or in combination with biologics), vedolizumab, ustekinumab, steroids, methotrexate, and tofacitinib. Results from six studies indicated that patients with IBD were significantly more likely to be diagnosed with COVID-19 if they were older than 66 years (odds ratio, 21.3) or had other comorbidities (OR, 1.24). The most commonly used drugs for managing COVID-19 were hydroxychloroquine, lopinavir/ritonavir, steroids, antibiotics, chloroquine, tofacitinib, and infliximab.

A total of 30.6% of patients with IBD and COVID-19 were hospitalized, 11.4% stayed in the ICU, 3.7% required mechanical ventilation, and 3.8% died from COVID-19. Significant risk factors for death from COVID-19 included older age, active IBD, and a Charlson Comorbidity Index score above 1. Similarly, risk factors for severe COVID-19 included older age, having two or more comorbidities, receiving systemic steroids, and receiving mesalamine/sulfasalazine. In one study, a recent (3-month) history of corticosteroid treatment was associated with a 60% increase in the risk for severe COVID-19. Other immune-mediated therapies did not show this association. Patients with ulcerative colitis were significantly more likely to be seen in the ED or hospitalized, compared with patients with other forms of IBD (adjusted OR, 12.7).

No funding sources were disclosed. Dr. D’Amico reported having no conflicts of interest. Two coinvestigators disclosed ties to AbbVie, MSD, Schering-Plough, UCB Pharma, and several other pharmaceutical companies.

SOURCE: D’Amico F et al. Clin Gastroenterol Hepatol. 2020 Aug 7. doi: 10.1016/j.cgh.2020.08.003.
 

Diarrhea affected one in every five patients with inflammatory bowel disease (IBD) and COVID-19, compared with only 7%-10% of all patients with COVID-19 in prior studies, researchers reported in Clinical Gastroenterology and Hepatology.

In a systematic review and meta-analysis of 23 studies incorporating data from 449 patients with IBD and COVID-19, their most common symptoms were fever (affecting 48.3% of patients), cough (46.5%), and diarrhea (20.5%), and diarrhea was approximately twice as prevalent as dyspnea, nausea, abdominal pain, and fatigue, wrote Ferdinando D’Amico of Humanitas University in Milan and his associates. “[S]ymptoms experienced by IBD patients with COVID-19 are similar to those occurring in the general population, except for a higher percentage of diarrhea,” they wrote. This increased prevalence might result from IBD itself or from inflammatory effects of viral gut tropism, they noted. “Currently, the diagnostic–therapeutic approach does not differ between IBD and non-IBD patients, but further studies are needed to evaluate whether fecal research of viral RNA and treatment with IBD drugs may play a role in the management of COVID-19 patients.”

To characterize the clinical presentation and course of patients with IBD and COVID-19, the researchers searched PubMed, Embase, Web of Science, and MedRxiv through July 29, 2020, for keywords related to COVID-19, Crohn’s disease, ulcerative colitis, and IBD. They identified 23 studies presenting clinical data from adults or children with a confirmed IBD diagnosis and least one case of COVID-19. Among 243,760 patients with IBD, 1,028 patients had COVID-19 infection, including 509 patients with Crohn’s disease, 428 patients with ulcerative colitis, 49 patients with indeterminate colitis, and 42 patients for whom the IBD subtype was not recorded.

In all, 0.4% of patients with IBD had COVID-19. Nearly all had been diagnosed by polymerase chain reaction of nasopharyngeal swabs, and approximately 40% also had received chest CT scans. Most were male (56.5%), and 43.5% were older than 65 years. Patients were receiving a wide range of IBD therapies, most commonly anti–tumor necrosis factor (TNF) agents, mesalamine, thiopurine (alone or in combination with biologics), vedolizumab, ustekinumab, steroids, methotrexate, and tofacitinib. Results from six studies indicated that patients with IBD were significantly more likely to be diagnosed with COVID-19 if they were older than 66 years (odds ratio, 21.3) or had other comorbidities (OR, 1.24). The most commonly used drugs for managing COVID-19 were hydroxychloroquine, lopinavir/ritonavir, steroids, antibiotics, chloroquine, tofacitinib, and infliximab.

A total of 30.6% of patients with IBD and COVID-19 were hospitalized, 11.4% stayed in the ICU, 3.7% required mechanical ventilation, and 3.8% died from COVID-19. Significant risk factors for death from COVID-19 included older age, active IBD, and a Charlson Comorbidity Index score above 1. Similarly, risk factors for severe COVID-19 included older age, having two or more comorbidities, receiving systemic steroids, and receiving mesalamine/sulfasalazine. In one study, a recent (3-month) history of corticosteroid treatment was associated with a 60% increase in the risk for severe COVID-19. Other immune-mediated therapies did not show this association. Patients with ulcerative colitis were significantly more likely to be seen in the ED or hospitalized, compared with patients with other forms of IBD (adjusted OR, 12.7).

No funding sources were disclosed. Dr. D’Amico reported having no conflicts of interest. Two coinvestigators disclosed ties to AbbVie, MSD, Schering-Plough, UCB Pharma, and several other pharmaceutical companies.

SOURCE: D’Amico F et al. Clin Gastroenterol Hepatol. 2020 Aug 7. doi: 10.1016/j.cgh.2020.08.003.
 

Diarrhea affected one in every five patients with inflammatory bowel disease (IBD) and COVID-19, compared with only 7%-10% of all patients with COVID-19 in prior studies, researchers reported in Clinical Gastroenterology and Hepatology.

In a systematic review and meta-analysis of 23 studies incorporating data from 449 patients with IBD and COVID-19, their most common symptoms were fever (affecting 48.3% of patients), cough (46.5%), and diarrhea (20.5%), and diarrhea was approximately twice as prevalent as dyspnea, nausea, abdominal pain, and fatigue, wrote Ferdinando D’Amico of Humanitas University in Milan and his associates. “[S]ymptoms experienced by IBD patients with COVID-19 are similar to those occurring in the general population, except for a higher percentage of diarrhea,” they wrote. This increased prevalence might result from IBD itself or from inflammatory effects of viral gut tropism, they noted. “Currently, the diagnostic–therapeutic approach does not differ between IBD and non-IBD patients, but further studies are needed to evaluate whether fecal research of viral RNA and treatment with IBD drugs may play a role in the management of COVID-19 patients.”

To characterize the clinical presentation and course of patients with IBD and COVID-19, the researchers searched PubMed, Embase, Web of Science, and MedRxiv through July 29, 2020, for keywords related to COVID-19, Crohn’s disease, ulcerative colitis, and IBD. They identified 23 studies presenting clinical data from adults or children with a confirmed IBD diagnosis and least one case of COVID-19. Among 243,760 patients with IBD, 1,028 patients had COVID-19 infection, including 509 patients with Crohn’s disease, 428 patients with ulcerative colitis, 49 patients with indeterminate colitis, and 42 patients for whom the IBD subtype was not recorded.

In all, 0.4% of patients with IBD had COVID-19. Nearly all had been diagnosed by polymerase chain reaction of nasopharyngeal swabs, and approximately 40% also had received chest CT scans. Most were male (56.5%), and 43.5% were older than 65 years. Patients were receiving a wide range of IBD therapies, most commonly anti–tumor necrosis factor (TNF) agents, mesalamine, thiopurine (alone or in combination with biologics), vedolizumab, ustekinumab, steroids, methotrexate, and tofacitinib. Results from six studies indicated that patients with IBD were significantly more likely to be diagnosed with COVID-19 if they were older than 66 years (odds ratio, 21.3) or had other comorbidities (OR, 1.24). The most commonly used drugs for managing COVID-19 were hydroxychloroquine, lopinavir/ritonavir, steroids, antibiotics, chloroquine, tofacitinib, and infliximab.

A total of 30.6% of patients with IBD and COVID-19 were hospitalized, 11.4% stayed in the ICU, 3.7% required mechanical ventilation, and 3.8% died from COVID-19. Significant risk factors for death from COVID-19 included older age, active IBD, and a Charlson Comorbidity Index score above 1. Similarly, risk factors for severe COVID-19 included older age, having two or more comorbidities, receiving systemic steroids, and receiving mesalamine/sulfasalazine. In one study, a recent (3-month) history of corticosteroid treatment was associated with a 60% increase in the risk for severe COVID-19. Other immune-mediated therapies did not show this association. Patients with ulcerative colitis were significantly more likely to be seen in the ED or hospitalized, compared with patients with other forms of IBD (adjusted OR, 12.7).

No funding sources were disclosed. Dr. D’Amico reported having no conflicts of interest. Two coinvestigators disclosed ties to AbbVie, MSD, Schering-Plough, UCB Pharma, and several other pharmaceutical companies.

SOURCE: D’Amico F et al. Clin Gastroenterol Hepatol. 2020 Aug 7. doi: 10.1016/j.cgh.2020.08.003.
 

A population-based cohort analysis of Barrett’s esophagus patients undergoing surveillance endoscopy suggests that the neoplasia detection rate (NDR) and the rate of missed dysplasia during the index endoscopy may be lower than previously reported in studies of referral-based cohorts. The new results suggest that NDR may be a useful quality control measure for Barrett’s esophagus surveillance.

The finding is welcome. “Just like we’ve done in colonoscopy with the adenoma detection rate, we need to have a quality metric to determine whether or not we’re adequately finding neoplasia while screening our patients with Barrett’s esophagus,” Jeffrey Mosko, MD, a gastroenterologist and interventional endoscopist at the University of Toronto’s St. Michael’s Hospital, said in an interview.

Societal guidelines recommend endoscopic screening in Barrett’s esophagus patients, with the goal of identifying dysplastic Barrett’s esophagus and eradicating it endoscopically before it can develop into esophageal adenocarcinoma (EAC). Despite this, 90% of patients with esophageal adenocarcinoma are diagnosed outside of a surveillance program.

Missed high-grade dysplasia or early EAC could become more invasive or metastasize, potentially leading to greater morbidity, mortality, and cost, although that relationship hasn’t been absolutely established yet the way it has with colonoscopy and colorectal cancer, according to Dr. Mosko.

Variation in endoscopy performance can be caused by the patchy and subtle appearance of dysplasia, and because procedural guidelines are not always closely followed. There is often a significant difference between procedures performed by specialists and nonspecialists. “Endoscopists in general don’t take enough time to examine the segment, they don’t wash appropriately, and when they do look, they may not be well enough trained to know what they’re looking at. The only way to improve on this aside from additional training is to have a metric that measures how you’re doing, and I think [the neoplasia detection rate] is as close as we get to doing that. I think the exact threshold for NDR is not as important as figuring out what your number is and then ways to improve it,” said Dr. Mosko.

A recent meta-analysis estimated NDR to be 7%, but the patient cohort used was derived from referrals to academic centers, where experienced gastroenterologists may register a higher than average NDR. The study also lacked data on patients, providers, or biopsy quality, which prevented assessment of the effects of NDR on subsequent missed dysplasia or predictors of high or low NDR.

To get a better estimate of NDR, researchers led by Lovekirat Dhaliwal, MD, at the Mayo Clinic in Rochester, Minn., analyzed data from the Rochester Epidemiology Project, including patients from 11 counties in Minnesota. They identified 1,066 patients with Barrett’s esophagus, 71.1% of whom were male, with a mean age of 63 years. 77% had surveillance endoscopies performed by gastroenterologists, the remainder by nongastroenterologists such as doctors, surgeons, or internal medicine physicians. About 60% of participants received adequate biopsies per Seattle protocol.

The NDR was 4.9% (95% CI, 3.8%-6.4%), including 3.1% high-grade dysplasia (HGD) and 1.8% EAC. One-quarter of EAC cases had metastatic lymphadenopathy at endoscopy or surgery, and 10.6% had low-grade dysplasia (LGD). Although high-definition monitors and high-resolution endoscopes were added to practices, particularly after 2000, the researchers found no evidence of increasing NDR over time on multivariate analysis. In a separate analysis of targeted biopsies in 54 patients with a visible lesion, 9 had LGD (7.96% of all LGD diagnoses) and 10 had EAC (50.0% of all EAC diagnoses). Visible lesions were more often reported by gastroenterologists than nongastroenterologists (odds ratio, 3.7; P = .0120). Gastroenterologists had a higher rate of NDR on univariate analysis (5.8% vs. 1.7%; P = .0098).

There were 391 Barrett’s esophagus patients with no diagnosis of HGD or EAC at the initial endoscopy underwent another endoscopy at 12 months. At the follow-up procedure, eight patients were found to have HGD/EAC, amounting to 13% of HGD/EAC cases being missed at the index endoscopy. There was no statistically significant association between a missed dysplasia or found dysplasia and segment length (4.7 cm vs. 3.7 cm; P = .4), Seattle protocol adherence (62% vs. 58.7%; P = .8), visibility of lesions (OR, 0.6; P = .55), age, smoking history, or practitioner specialty.

The study was funded by the National Cancer Institute and the National Institute of Aging. Dr. Mosko has no relevant financial disclosures.

SOURCE: Dhaliwal L et al. Clin Gastro Hepatol. 2020 Jul 21. doi: 10.1016/j.cgh.2020.07.034.

A population-based cohort analysis of Barrett’s esophagus patients undergoing surveillance endoscopy suggests that the neoplasia detection rate (NDR) and the rate of missed dysplasia during the index endoscopy may be lower than previously reported in studies of referral-based cohorts. The new results suggest that NDR may be a useful quality control measure for Barrett’s esophagus surveillance.

The finding is welcome. “Just like we’ve done in colonoscopy with the adenoma detection rate, we need to have a quality metric to determine whether or not we’re adequately finding neoplasia while screening our patients with Barrett’s esophagus,” Jeffrey Mosko, MD, a gastroenterologist and interventional endoscopist at the University of Toronto’s St. Michael’s Hospital, said in an interview.

Societal guidelines recommend endoscopic screening in Barrett’s esophagus patients, with the goal of identifying dysplastic Barrett’s esophagus and eradicating it endoscopically before it can develop into esophageal adenocarcinoma (EAC). Despite this, 90% of patients with esophageal adenocarcinoma are diagnosed outside of a surveillance program.

Missed high-grade dysplasia or early EAC could become more invasive or metastasize, potentially leading to greater morbidity, mortality, and cost, although that relationship hasn’t been absolutely established yet the way it has with colonoscopy and colorectal cancer, according to Dr. Mosko.

Variation in endoscopy performance can be caused by the patchy and subtle appearance of dysplasia, and because procedural guidelines are not always closely followed. There is often a significant difference between procedures performed by specialists and nonspecialists. “Endoscopists in general don’t take enough time to examine the segment, they don’t wash appropriately, and when they do look, they may not be well enough trained to know what they’re looking at. The only way to improve on this aside from additional training is to have a metric that measures how you’re doing, and I think [the neoplasia detection rate] is as close as we get to doing that. I think the exact threshold for NDR is not as important as figuring out what your number is and then ways to improve it,” said Dr. Mosko.

A recent meta-analysis estimated NDR to be 7%, but the patient cohort used was derived from referrals to academic centers, where experienced gastroenterologists may register a higher than average NDR. The study also lacked data on patients, providers, or biopsy quality, which prevented assessment of the effects of NDR on subsequent missed dysplasia or predictors of high or low NDR.

To get a better estimate of NDR, researchers led by Lovekirat Dhaliwal, MD, at the Mayo Clinic in Rochester, Minn., analyzed data from the Rochester Epidemiology Project, including patients from 11 counties in Minnesota. They identified 1,066 patients with Barrett’s esophagus, 71.1% of whom were male, with a mean age of 63 years. 77% had surveillance endoscopies performed by gastroenterologists, the remainder by nongastroenterologists such as doctors, surgeons, or internal medicine physicians. About 60% of participants received adequate biopsies per Seattle protocol.

The NDR was 4.9% (95% CI, 3.8%-6.4%), including 3.1% high-grade dysplasia (HGD) and 1.8% EAC. One-quarter of EAC cases had metastatic lymphadenopathy at endoscopy or surgery, and 10.6% had low-grade dysplasia (LGD). Although high-definition monitors and high-resolution endoscopes were added to practices, particularly after 2000, the researchers found no evidence of increasing NDR over time on multivariate analysis. In a separate analysis of targeted biopsies in 54 patients with a visible lesion, 9 had LGD (7.96% of all LGD diagnoses) and 10 had EAC (50.0% of all EAC diagnoses). Visible lesions were more often reported by gastroenterologists than nongastroenterologists (odds ratio, 3.7; P = .0120). Gastroenterologists had a higher rate of NDR on univariate analysis (5.8% vs. 1.7%; P = .0098).

There were 391 Barrett’s esophagus patients with no diagnosis of HGD or EAC at the initial endoscopy underwent another endoscopy at 12 months. At the follow-up procedure, eight patients were found to have HGD/EAC, amounting to 13% of HGD/EAC cases being missed at the index endoscopy. There was no statistically significant association between a missed dysplasia or found dysplasia and segment length (4.7 cm vs. 3.7 cm; P = .4), Seattle protocol adherence (62% vs. 58.7%; P = .8), visibility of lesions (OR, 0.6; P = .55), age, smoking history, or practitioner specialty.

The study was funded by the National Cancer Institute and the National Institute of Aging. Dr. Mosko has no relevant financial disclosures.

SOURCE: Dhaliwal L et al. Clin Gastro Hepatol. 2020 Jul 21. doi: 10.1016/j.cgh.2020.07.034.

A population-based cohort analysis of Barrett’s esophagus patients undergoing surveillance endoscopy suggests that the neoplasia detection rate (NDR) and the rate of missed dysplasia during the index endoscopy may be lower than previously reported in studies of referral-based cohorts. The new results suggest that NDR may be a useful quality control measure for Barrett’s esophagus surveillance.

The finding is welcome. “Just like we’ve done in colonoscopy with the adenoma detection rate, we need to have a quality metric to determine whether or not we’re adequately finding neoplasia while screening our patients with Barrett’s esophagus,” Jeffrey Mosko, MD, a gastroenterologist and interventional endoscopist at the University of Toronto’s St. Michael’s Hospital, said in an interview.

Societal guidelines recommend endoscopic screening in Barrett’s esophagus patients, with the goal of identifying dysplastic Barrett’s esophagus and eradicating it endoscopically before it can develop into esophageal adenocarcinoma (EAC). Despite this, 90% of patients with esophageal adenocarcinoma are diagnosed outside of a surveillance program.

Missed high-grade dysplasia or early EAC could become more invasive or metastasize, potentially leading to greater morbidity, mortality, and cost, although that relationship hasn’t been absolutely established yet the way it has with colonoscopy and colorectal cancer, according to Dr. Mosko.

Variation in endoscopy performance can be caused by the patchy and subtle appearance of dysplasia, and because procedural guidelines are not always closely followed. There is often a significant difference between procedures performed by specialists and nonspecialists. “Endoscopists in general don’t take enough time to examine the segment, they don’t wash appropriately, and when they do look, they may not be well enough trained to know what they’re looking at. The only way to improve on this aside from additional training is to have a metric that measures how you’re doing, and I think [the neoplasia detection rate] is as close as we get to doing that. I think the exact threshold for NDR is not as important as figuring out what your number is and then ways to improve it,” said Dr. Mosko.

A recent meta-analysis estimated NDR to be 7%, but the patient cohort used was derived from referrals to academic centers, where experienced gastroenterologists may register a higher than average NDR. The study also lacked data on patients, providers, or biopsy quality, which prevented assessment of the effects of NDR on subsequent missed dysplasia or predictors of high or low NDR.

To get a better estimate of NDR, researchers led by Lovekirat Dhaliwal, MD, at the Mayo Clinic in Rochester, Minn., analyzed data from the Rochester Epidemiology Project, including patients from 11 counties in Minnesota. They identified 1,066 patients with Barrett’s esophagus, 71.1% of whom were male, with a mean age of 63 years. 77% had surveillance endoscopies performed by gastroenterologists, the remainder by nongastroenterologists such as doctors, surgeons, or internal medicine physicians. About 60% of participants received adequate biopsies per Seattle protocol.

The NDR was 4.9% (95% CI, 3.8%-6.4%), including 3.1% high-grade dysplasia (HGD) and 1.8% EAC. One-quarter of EAC cases had metastatic lymphadenopathy at endoscopy or surgery, and 10.6% had low-grade dysplasia (LGD). Although high-definition monitors and high-resolution endoscopes were added to practices, particularly after 2000, the researchers found no evidence of increasing NDR over time on multivariate analysis. In a separate analysis of targeted biopsies in 54 patients with a visible lesion, 9 had LGD (7.96% of all LGD diagnoses) and 10 had EAC (50.0% of all EAC diagnoses). Visible lesions were more often reported by gastroenterologists than nongastroenterologists (odds ratio, 3.7; P = .0120). Gastroenterologists had a higher rate of NDR on univariate analysis (5.8% vs. 1.7%; P = .0098).

There were 391 Barrett’s esophagus patients with no diagnosis of HGD or EAC at the initial endoscopy underwent another endoscopy at 12 months. At the follow-up procedure, eight patients were found to have HGD/EAC, amounting to 13% of HGD/EAC cases being missed at the index endoscopy. There was no statistically significant association between a missed dysplasia or found dysplasia and segment length (4.7 cm vs. 3.7 cm; P = .4), Seattle protocol adherence (62% vs. 58.7%; P = .8), visibility of lesions (OR, 0.6; P = .55), age, smoking history, or practitioner specialty.

The study was funded by the National Cancer Institute and the National Institute of Aging. Dr. Mosko has no relevant financial disclosures.

SOURCE: Dhaliwal L et al. Clin Gastro Hepatol. 2020 Jul 21. doi: 10.1016/j.cgh.2020.07.034.

Fecal microbiota transplantation (FMT) appears safe and effective as a treatment for most Clostridioides difficile infections as it is currently being administered, researchers say.

“We actually didn’t see any infections that were definitely transmissible via fecal transplant,” Colleen Kelly, MD, an associate professor of medicine at Brown University, Providence, R.I., said in an interview.

The findings, published online Oct. 1 in the journal Gastroenterology, come from the American Gastroenterological Association (AGA) NIH-funded FMT National Registry and could allay concerns about a treatment that has yet to gain full approval by the Food and Drug Administration, despite successful clinical trials.

C. diff infections are common and increasing in the United States, often can’t be cured with conventional treatments such as antibiotics, and can be deadly.

Transplanting fecal matter from a donor to the patient appears to work by restoring beneficial microorganisms to the patient’s gut. The procedure is also under investigation for a wide range of other ailments, from irritable bowel syndrome to mood disorders.

But much remains unknown. Researchers have counted a thousand bacterial species along with viruses, bacteriophages, archaea, and fungi in the human gut that interact in complex ways, not all of them beneficial.

The FDA has not enforced regulations that would prohibit the procedure, but in March, it warned about infections with enteropathogenic Escherichia coli and Shiga toxin–producing E. coli following fecal transplants.

As a result of these reports, and the theoretical risk of spreading SARS-CoV-2, OpenBiome, the largest stool bank in the United States, has suspended shipments except for emergency orders, and asked clinicians to quarantine any of its products they already have on hand.

In the meantime, long-term effects of the treatment have not been well documented. And clinical trials have excluded patients who might benefit, such as those who have been immunocompromised or have inflammatory bowel disease.
 

National registry follows patients outside clinical trials

To better understand how patients fare outside these trials, AGA and other organizations developed a national registry, funded by a grant from the National Institute of Allergy and Infectious Diseases.

The current report summarizes results on 259 patients enrolled between Dec. 5, 2017, and Sept. 2, 2019 at 20 sites.

At baseline, 44% of these patients suffered moderate and 36% mild C. diff infections. The duration of the diagnosis ranged from less than 1 week to 9 years, with a median duration of 20 weeks. They ranged from 1 to 15 episodes with a mean of 3.5.

Almost all had received vancomycin, and 62% had at least two courses. About 40% had received metronidazole and 28% had received fidaxomicin.

Almost all participants received stool from an unknown donor, mostly from stool banks, with OpenBiome accounting for 67%. About 85% of the transplants were administered through colonoscopy and 6% by upper endoscopy.

Out of 222 patients who returned for a 1-month follow-up, 90% met the investigators’ definition of cure: resolution of diarrhea without need for further anti–C. diff therapy. About 98% received only one transplant. An intent to treat analysis produced a cure rate of 86%.

Results were good in patients with comorbidities, including 12% who had irritable bowel syndrome, 9% who had ulcerative colitis, and 7% who had Crohn’s disease, Dr. Kelly said. “I hope everybody sees the importance of it. In these patients that are more complicated, who may have underlying comorbidities, who may not have been in the clinical trials, it looks effective in that group, and also incredibly safe.”

She added that the risk of transmitting SARS-CoV-2 is minor. “I think it would be a very, very unlikely way for someone to get a respiratory pathogen.”

Of the 112 participants who were cured at 1 month and returned for follow-up after 6 months, 4 developed recurrent C. diff infection. Eleven patients who were not cured in the first month returned after 6 months. Of these, seven were reported cured at this later follow-up.

Three complications occurred as result of the procedure: one colonoscopic perforation and two episodes of gastrointestinal bleeding.

About 45% of participants reported at least one symptom, with diarrhea not related to C. difficile the most common, followed by abdominal pain, bloating, and constipation.

Eleven patients suffered infections, including two which the investigators thought might be related to the procedure: Bacteroides fragilis in one participant with severe diarrhea, and enteropathogenic E. coli in another with loose stools. Other infections included four urinary tract infections, three cases of pneumonia, one E. coli bacteremia and one tooth infection.

Within a month of the procedure, 27 patients were hospitalized, with 3 of these cases considered possibly related to the procedure.
 

Findings may not apply to all clinical settings

Vincent B. Young, MD, PhD, a professor of medicine and infectious diseases at the University of Michigan, Ann Arbor, pointed out that the findings might not apply to all clinical settings. The participating clinicians were almost all gastroenterologists working in academic centers.

“Most of them are not Joe Doctor at the doctor’s office,” said Dr. Young, who was not involved with the study. Clinicians in other specialties, such as infectious diseases, might be more inclined to administer fecal transplants through capsules rather than colonoscopies.

And he added that the study does not address effects of the transplant that might develop over years. “Some people talk about how changes in the microbiota lead to increased risk for long-term complications, things like cancer or heart disease. You’re not going to see those in 6 months.”

Also, the study didn’t yield any findings on indications other than C. diff. “In no way, shape, or form does it mean you can use it for autism, depression, heart disease, or [irritable bowel syndrome],” he said.

Still, he said, the study “confirms the fact that fecal cell transplantation is an effective treatment for recurrent C. diff infection when administered as they administered it.”

The National Institute of Allergy and Infectious Diseases funded the registry. Dr. Kelly reported a relationship with Finch Therapeutics. Dr. Young reports financial relationships with Vedanta Biosciences and Bio-K+.

This story was updated on Oct. 4, 2020.

A version of this article originally appeared on Medscape.com.

Fecal microbiota transplantation (FMT) appears safe and effective as a treatment for most Clostridioides difficile infections as it is currently being administered, researchers say.

“We actually didn’t see any infections that were definitely transmissible via fecal transplant,” Colleen Kelly, MD, an associate professor of medicine at Brown University, Providence, R.I., said in an interview.

The findings, published online Oct. 1 in the journal Gastroenterology, come from the American Gastroenterological Association (AGA) NIH-funded FMT National Registry and could allay concerns about a treatment that has yet to gain full approval by the Food and Drug Administration, despite successful clinical trials.

C. diff infections are common and increasing in the United States, often can’t be cured with conventional treatments such as antibiotics, and can be deadly.

Transplanting fecal matter from a donor to the patient appears to work by restoring beneficial microorganisms to the patient’s gut. The procedure is also under investigation for a wide range of other ailments, from irritable bowel syndrome to mood disorders.

But much remains unknown. Researchers have counted a thousand bacterial species along with viruses, bacteriophages, archaea, and fungi in the human gut that interact in complex ways, not all of them beneficial.

The FDA has not enforced regulations that would prohibit the procedure, but in March, it warned about infections with enteropathogenic Escherichia coli and Shiga toxin–producing E. coli following fecal transplants.

As a result of these reports, and the theoretical risk of spreading SARS-CoV-2, OpenBiome, the largest stool bank in the United States, has suspended shipments except for emergency orders, and asked clinicians to quarantine any of its products they already have on hand.

In the meantime, long-term effects of the treatment have not been well documented. And clinical trials have excluded patients who might benefit, such as those who have been immunocompromised or have inflammatory bowel disease.
 

National registry follows patients outside clinical trials

To better understand how patients fare outside these trials, AGA and other organizations developed a national registry, funded by a grant from the National Institute of Allergy and Infectious Diseases.

The current report summarizes results on 259 patients enrolled between Dec. 5, 2017, and Sept. 2, 2019 at 20 sites.

At baseline, 44% of these patients suffered moderate and 36% mild C. diff infections. The duration of the diagnosis ranged from less than 1 week to 9 years, with a median duration of 20 weeks. They ranged from 1 to 15 episodes with a mean of 3.5.

Almost all had received vancomycin, and 62% had at least two courses. About 40% had received metronidazole and 28% had received fidaxomicin.

Almost all participants received stool from an unknown donor, mostly from stool banks, with OpenBiome accounting for 67%. About 85% of the transplants were administered through colonoscopy and 6% by upper endoscopy.

Out of 222 patients who returned for a 1-month follow-up, 90% met the investigators’ definition of cure: resolution of diarrhea without need for further anti–C. diff therapy. About 98% received only one transplant. An intent to treat analysis produced a cure rate of 86%.

Results were good in patients with comorbidities, including 12% who had irritable bowel syndrome, 9% who had ulcerative colitis, and 7% who had Crohn’s disease, Dr. Kelly said. “I hope everybody sees the importance of it. In these patients that are more complicated, who may have underlying comorbidities, who may not have been in the clinical trials, it looks effective in that group, and also incredibly safe.”

She added that the risk of transmitting SARS-CoV-2 is minor. “I think it would be a very, very unlikely way for someone to get a respiratory pathogen.”

Of the 112 participants who were cured at 1 month and returned for follow-up after 6 months, 4 developed recurrent C. diff infection. Eleven patients who were not cured in the first month returned after 6 months. Of these, seven were reported cured at this later follow-up.

Three complications occurred as result of the procedure: one colonoscopic perforation and two episodes of gastrointestinal bleeding.

About 45% of participants reported at least one symptom, with diarrhea not related to C. difficile the most common, followed by abdominal pain, bloating, and constipation.

Eleven patients suffered infections, including two which the investigators thought might be related to the procedure: Bacteroides fragilis in one participant with severe diarrhea, and enteropathogenic E. coli in another with loose stools. Other infections included four urinary tract infections, three cases of pneumonia, one E. coli bacteremia and one tooth infection.

Within a month of the procedure, 27 patients were hospitalized, with 3 of these cases considered possibly related to the procedure.
 

Findings may not apply to all clinical settings

Vincent B. Young, MD, PhD, a professor of medicine and infectious diseases at the University of Michigan, Ann Arbor, pointed out that the findings might not apply to all clinical settings. The participating clinicians were almost all gastroenterologists working in academic centers.

“Most of them are not Joe Doctor at the doctor’s office,” said Dr. Young, who was not involved with the study. Clinicians in other specialties, such as infectious diseases, might be more inclined to administer fecal transplants through capsules rather than colonoscopies.

And he added that the study does not address effects of the transplant that might develop over years. “Some people talk about how changes in the microbiota lead to increased risk for long-term complications, things like cancer or heart disease. You’re not going to see those in 6 months.”

Also, the study didn’t yield any findings on indications other than C. diff. “In no way, shape, or form does it mean you can use it for autism, depression, heart disease, or [irritable bowel syndrome],” he said.

Still, he said, the study “confirms the fact that fecal cell transplantation is an effective treatment for recurrent C. diff infection when administered as they administered it.”

The National Institute of Allergy and Infectious Diseases funded the registry. Dr. Kelly reported a relationship with Finch Therapeutics. Dr. Young reports financial relationships with Vedanta Biosciences and Bio-K+.

This story was updated on Oct. 4, 2020.

A version of this article originally appeared on Medscape.com.

Fecal microbiota transplantation (FMT) appears safe and effective as a treatment for most Clostridioides difficile infections as it is currently being administered, researchers say.

“We actually didn’t see any infections that were definitely transmissible via fecal transplant,” Colleen Kelly, MD, an associate professor of medicine at Brown University, Providence, R.I., said in an interview.

The findings, published online Oct. 1 in the journal Gastroenterology, come from the American Gastroenterological Association (AGA) NIH-funded FMT National Registry and could allay concerns about a treatment that has yet to gain full approval by the Food and Drug Administration, despite successful clinical trials.

C. diff infections are common and increasing in the United States, often can’t be cured with conventional treatments such as antibiotics, and can be deadly.

Transplanting fecal matter from a donor to the patient appears to work by restoring beneficial microorganisms to the patient’s gut. The procedure is also under investigation for a wide range of other ailments, from irritable bowel syndrome to mood disorders.

But much remains unknown. Researchers have counted a thousand bacterial species along with viruses, bacteriophages, archaea, and fungi in the human gut that interact in complex ways, not all of them beneficial.

The FDA has not enforced regulations that would prohibit the procedure, but in March, it warned about infections with enteropathogenic Escherichia coli and Shiga toxin–producing E. coli following fecal transplants.

As a result of these reports, and the theoretical risk of spreading SARS-CoV-2, OpenBiome, the largest stool bank in the United States, has suspended shipments except for emergency orders, and asked clinicians to quarantine any of its products they already have on hand.

In the meantime, long-term effects of the treatment have not been well documented. And clinical trials have excluded patients who might benefit, such as those who have been immunocompromised or have inflammatory bowel disease.
 

National registry follows patients outside clinical trials

To better understand how patients fare outside these trials, AGA and other organizations developed a national registry, funded by a grant from the National Institute of Allergy and Infectious Diseases.

The current report summarizes results on 259 patients enrolled between Dec. 5, 2017, and Sept. 2, 2019 at 20 sites.

At baseline, 44% of these patients suffered moderate and 36% mild C. diff infections. The duration of the diagnosis ranged from less than 1 week to 9 years, with a median duration of 20 weeks. They ranged from 1 to 15 episodes with a mean of 3.5.

Almost all had received vancomycin, and 62% had at least two courses. About 40% had received metronidazole and 28% had received fidaxomicin.

Almost all participants received stool from an unknown donor, mostly from stool banks, with OpenBiome accounting for 67%. About 85% of the transplants were administered through colonoscopy and 6% by upper endoscopy.

Out of 222 patients who returned for a 1-month follow-up, 90% met the investigators’ definition of cure: resolution of diarrhea without need for further anti–C. diff therapy. About 98% received only one transplant. An intent to treat analysis produced a cure rate of 86%.

Results were good in patients with comorbidities, including 12% who had irritable bowel syndrome, 9% who had ulcerative colitis, and 7% who had Crohn’s disease, Dr. Kelly said. “I hope everybody sees the importance of it. In these patients that are more complicated, who may have underlying comorbidities, who may not have been in the clinical trials, it looks effective in that group, and also incredibly safe.”

She added that the risk of transmitting SARS-CoV-2 is minor. “I think it would be a very, very unlikely way for someone to get a respiratory pathogen.”

Of the 112 participants who were cured at 1 month and returned for follow-up after 6 months, 4 developed recurrent C. diff infection. Eleven patients who were not cured in the first month returned after 6 months. Of these, seven were reported cured at this later follow-up.

Three complications occurred as result of the procedure: one colonoscopic perforation and two episodes of gastrointestinal bleeding.

About 45% of participants reported at least one symptom, with diarrhea not related to C. difficile the most common, followed by abdominal pain, bloating, and constipation.

Eleven patients suffered infections, including two which the investigators thought might be related to the procedure: Bacteroides fragilis in one participant with severe diarrhea, and enteropathogenic E. coli in another with loose stools. Other infections included four urinary tract infections, three cases of pneumonia, one E. coli bacteremia and one tooth infection.

Within a month of the procedure, 27 patients were hospitalized, with 3 of these cases considered possibly related to the procedure.
 

Findings may not apply to all clinical settings

Vincent B. Young, MD, PhD, a professor of medicine and infectious diseases at the University of Michigan, Ann Arbor, pointed out that the findings might not apply to all clinical settings. The participating clinicians were almost all gastroenterologists working in academic centers.

“Most of them are not Joe Doctor at the doctor’s office,” said Dr. Young, who was not involved with the study. Clinicians in other specialties, such as infectious diseases, might be more inclined to administer fecal transplants through capsules rather than colonoscopies.

And he added that the study does not address effects of the transplant that might develop over years. “Some people talk about how changes in the microbiota lead to increased risk for long-term complications, things like cancer or heart disease. You’re not going to see those in 6 months.”

Also, the study didn’t yield any findings on indications other than C. diff. “In no way, shape, or form does it mean you can use it for autism, depression, heart disease, or [irritable bowel syndrome],” he said.

Still, he said, the study “confirms the fact that fecal cell transplantation is an effective treatment for recurrent C. diff infection when administered as they administered it.”

The National Institute of Allergy and Infectious Diseases funded the registry. Dr. Kelly reported a relationship with Finch Therapeutics. Dr. Young reports financial relationships with Vedanta Biosciences and Bio-K+.

This story was updated on Oct. 4, 2020.

A version of this article originally appeared on Medscape.com.

The American Gastroenterological Association (AGA) has issued guidance for pre-endoscopy coronavirus testing based on a review of existing literature and a survey of endoscopist risk tolerance.

While serologic antibody testing is not recommended for any patients, use of nucleic acid amplification testing (NAAT) for viral RNA should be informed by local prevalence of asymptomatic individuals, reported lead guideline panelist Shahnaz Sultan, MD, of the University of Minnesota in Minneapolis and colleagues.

“The two main concerns with a pretesting strategy are the false positives and false negatives,” the panelists wrote in Gastroenterology. When performing endoscopy in a false-negative patient, health care providers who wear a surgical mask instead of an N95/N99 respirator may have an increased risk of infection, and the patient undergoing the procedure may be falsely reassured that they are not contagious, the panelists wrote.

Among false-positive individuals, “implications for the patient include cancellation of the procedure, self-quarantine for 14 days, apprehension, and loss of work.”

Because of these concerns, the panelists concluded that pretesting strategies should be tailored to the local prevalence of asymptomatic infection because this rate is associated with likelihood of encountering false-positive and false-negative patients.

To determine appropriate prevalence thresholds, Dr. Sultan and colleagues first conducted a meta-analysis of 12 studies comparing the accuracy of various NAAT tests. This revealed a pooled sensitivity of 0.941 and a pooled specificity of 0.971. These figures remained consistent when only studies with low risk bias were considered; pooled sensitivity and specificity were 0.929 and 0.968, respectively.

“An important caveat of these studies is that tests were validated in samples from symptomatic individuals and it is likely that in asymptomatic individuals the tests may not perform as well and have lower sensitivity and specificity,” the panelists noted.

Next, Dr. Sultan and colleagues conducted an online survey of U.S. endoscopists to determine their tolerance for risk of coronavirus transmission, with proposed risk thresholds ranging from 1/40,000 to 1/1,000. Out of 74 respondents, 28 (37.8%) said that they would be willing to accept a risk level of 1/40,000, whereas 27 (36.5%) would accept risks between 1/10,000 and 1/2,500, and 19 (25.7%) would accept a risk level of 1/1,000. Among clinicians expressing the highest risk tolerance (1/1,000), almost two-thirds (63.2%) were private practitioners.

Drawing on these findings, the panelists issued three tiered recommendations for pretesting based on local prevalence of asymptomatic infection.

• Low prevalence (less than 0.5%): Pretesting is not recommended.
• Intermediate prevalence (0.5-2%): Pretesting is recommended.
• High prevalence (greater than 2%): Pretesting is not recommended.

The panelists recommended against pretesting in low and high prevalence settings because of the likelihood of false positives and false negatives, respectively. For “hotspot” areas, in which hospital capacity is acutely burdened, the panelists noted that “resumption of outpatient endoscopy may depend on availability of PPE.”

In areas of intermediate prevalence, the pretesting recommendation stands only if “testing is feasible and there is less perceived burden on patients, and when the benefits outweigh the downsides (e.g., false positives do not significantly outnumber the true positives).” According to the guidance, when performing upper and lower endoscopies on negative patients in areas of intermediate prevalence, surgical masks are appropriate for endoscopists and staff, with the caveat that those unwilling to accept any increased risk may still wear an N95/N99 respirator or a powered air-purifying respirator (PAPR).

Finally, the panelists made a recommendation against pretesting for antibodies in all areas, regardless of asymptomatic infection prevalence.

“Evidence supporting the role of seroconversion for return to work or hospital staffing policies is also lacking,” they added.

All recommendations were based on low or very low certainty evidence.

To help endoscopy centers determine an appropriate pretesting strategy, the AGA has created an online interactive tool that allows for input of diagnostic test accuracy and local prevalence rate.The investigators reported no conflicts of interest. 

Instructions for using the tool, along with additional COVID-19 guidance, can be found on the AGA website: www.gastro.org/COVID. 

The investigators reported no conflicts of interest.

This story was updated on 10/13/2020 and on 11/6/2020.

SOURCE: Sultan S et al. Gastroenterology. 2020 Jul 28. doi: 10.1053/j.gastro.2020.07.043.

The American Gastroenterological Association (AGA) has issued guidance for pre-endoscopy coronavirus testing based on a review of existing literature and a survey of endoscopist risk tolerance.

While serologic antibody testing is not recommended for any patients, use of nucleic acid amplification testing (NAAT) for viral RNA should be informed by local prevalence of asymptomatic individuals, reported lead guideline panelist Shahnaz Sultan, MD, of the University of Minnesota in Minneapolis and colleagues.

“The two main concerns with a pretesting strategy are the false positives and false negatives,” the panelists wrote in Gastroenterology. When performing endoscopy in a false-negative patient, health care providers who wear a surgical mask instead of an N95/N99 respirator may have an increased risk of infection, and the patient undergoing the procedure may be falsely reassured that they are not contagious, the panelists wrote.

Among false-positive individuals, “implications for the patient include cancellation of the procedure, self-quarantine for 14 days, apprehension, and loss of work.”

Because of these concerns, the panelists concluded that pretesting strategies should be tailored to the local prevalence of asymptomatic infection because this rate is associated with likelihood of encountering false-positive and false-negative patients.

To determine appropriate prevalence thresholds, Dr. Sultan and colleagues first conducted a meta-analysis of 12 studies comparing the accuracy of various NAAT tests. This revealed a pooled sensitivity of 0.941 and a pooled specificity of 0.971. These figures remained consistent when only studies with low risk bias were considered; pooled sensitivity and specificity were 0.929 and 0.968, respectively.

“An important caveat of these studies is that tests were validated in samples from symptomatic individuals and it is likely that in asymptomatic individuals the tests may not perform as well and have lower sensitivity and specificity,” the panelists noted.

Next, Dr. Sultan and colleagues conducted an online survey of U.S. endoscopists to determine their tolerance for risk of coronavirus transmission, with proposed risk thresholds ranging from 1/40,000 to 1/1,000. Out of 74 respondents, 28 (37.8%) said that they would be willing to accept a risk level of 1/40,000, whereas 27 (36.5%) would accept risks between 1/10,000 and 1/2,500, and 19 (25.7%) would accept a risk level of 1/1,000. Among clinicians expressing the highest risk tolerance (1/1,000), almost two-thirds (63.2%) were private practitioners.

Drawing on these findings, the panelists issued three tiered recommendations for pretesting based on local prevalence of asymptomatic infection.

• Low prevalence (less than 0.5%): Pretesting is not recommended.
• Intermediate prevalence (0.5-2%): Pretesting is recommended.
• High prevalence (greater than 2%): Pretesting is not recommended.

The panelists recommended against pretesting in low and high prevalence settings because of the likelihood of false positives and false negatives, respectively. For “hotspot” areas, in which hospital capacity is acutely burdened, the panelists noted that “resumption of outpatient endoscopy may depend on availability of PPE.”

In areas of intermediate prevalence, the pretesting recommendation stands only if “testing is feasible and there is less perceived burden on patients, and when the benefits outweigh the downsides (e.g., false positives do not significantly outnumber the true positives).” According to the guidance, when performing upper and lower endoscopies on negative patients in areas of intermediate prevalence, surgical masks are appropriate for endoscopists and staff, with the caveat that those unwilling to accept any increased risk may still wear an N95/N99 respirator or a powered air-purifying respirator (PAPR).

Finally, the panelists made a recommendation against pretesting for antibodies in all areas, regardless of asymptomatic infection prevalence.

“Evidence supporting the role of seroconversion for return to work or hospital staffing policies is also lacking,” they added.

All recommendations were based on low or very low certainty evidence.

To help endoscopy centers determine an appropriate pretesting strategy, the AGA has created an online interactive tool that allows for input of diagnostic test accuracy and local prevalence rate.The investigators reported no conflicts of interest. 

Instructions for using the tool, along with additional COVID-19 guidance, can be found on the AGA website: www.gastro.org/COVID. 

The investigators reported no conflicts of interest.

This story was updated on 10/13/2020 and on 11/6/2020.

SOURCE: Sultan S et al. Gastroenterology. 2020 Jul 28. doi: 10.1053/j.gastro.2020.07.043.

The American Gastroenterological Association (AGA) has issued guidance for pre-endoscopy coronavirus testing based on a review of existing literature and a survey of endoscopist risk tolerance.

While serologic antibody testing is not recommended for any patients, use of nucleic acid amplification testing (NAAT) for viral RNA should be informed by local prevalence of asymptomatic individuals, reported lead guideline panelist Shahnaz Sultan, MD, of the University of Minnesota in Minneapolis and colleagues.

“The two main concerns with a pretesting strategy are the false positives and false negatives,” the panelists wrote in Gastroenterology. When performing endoscopy in a false-negative patient, health care providers who wear a surgical mask instead of an N95/N99 respirator may have an increased risk of infection, and the patient undergoing the procedure may be falsely reassured that they are not contagious, the panelists wrote.

Among false-positive individuals, “implications for the patient include cancellation of the procedure, self-quarantine for 14 days, apprehension, and loss of work.”

Because of these concerns, the panelists concluded that pretesting strategies should be tailored to the local prevalence of asymptomatic infection because this rate is associated with likelihood of encountering false-positive and false-negative patients.

To determine appropriate prevalence thresholds, Dr. Sultan and colleagues first conducted a meta-analysis of 12 studies comparing the accuracy of various NAAT tests. This revealed a pooled sensitivity of 0.941 and a pooled specificity of 0.971. These figures remained consistent when only studies with low risk bias were considered; pooled sensitivity and specificity were 0.929 and 0.968, respectively.

“An important caveat of these studies is that tests were validated in samples from symptomatic individuals and it is likely that in asymptomatic individuals the tests may not perform as well and have lower sensitivity and specificity,” the panelists noted.

Next, Dr. Sultan and colleagues conducted an online survey of U.S. endoscopists to determine their tolerance for risk of coronavirus transmission, with proposed risk thresholds ranging from 1/40,000 to 1/1,000. Out of 74 respondents, 28 (37.8%) said that they would be willing to accept a risk level of 1/40,000, whereas 27 (36.5%) would accept risks between 1/10,000 and 1/2,500, and 19 (25.7%) would accept a risk level of 1/1,000. Among clinicians expressing the highest risk tolerance (1/1,000), almost two-thirds (63.2%) were private practitioners.

Drawing on these findings, the panelists issued three tiered recommendations for pretesting based on local prevalence of asymptomatic infection.

• Low prevalence (less than 0.5%): Pretesting is not recommended.
• Intermediate prevalence (0.5-2%): Pretesting is recommended.
• High prevalence (greater than 2%): Pretesting is not recommended.

The panelists recommended against pretesting in low and high prevalence settings because of the likelihood of false positives and false negatives, respectively. For “hotspot” areas, in which hospital capacity is acutely burdened, the panelists noted that “resumption of outpatient endoscopy may depend on availability of PPE.”

In areas of intermediate prevalence, the pretesting recommendation stands only if “testing is feasible and there is less perceived burden on patients, and when the benefits outweigh the downsides (e.g., false positives do not significantly outnumber the true positives).” According to the guidance, when performing upper and lower endoscopies on negative patients in areas of intermediate prevalence, surgical masks are appropriate for endoscopists and staff, with the caveat that those unwilling to accept any increased risk may still wear an N95/N99 respirator or a powered air-purifying respirator (PAPR).

Finally, the panelists made a recommendation against pretesting for antibodies in all areas, regardless of asymptomatic infection prevalence.

“Evidence supporting the role of seroconversion for return to work or hospital staffing policies is also lacking,” they added.

All recommendations were based on low or very low certainty evidence.

To help endoscopy centers determine an appropriate pretesting strategy, the AGA has created an online interactive tool that allows for input of diagnostic test accuracy and local prevalence rate.The investigators reported no conflicts of interest. 

Instructions for using the tool, along with additional COVID-19 guidance, can be found on the AGA website: www.gastro.org/COVID. 

The investigators reported no conflicts of interest.

This story was updated on 10/13/2020 and on 11/6/2020.

SOURCE: Sultan S et al. Gastroenterology. 2020 Jul 28. doi: 10.1053/j.gastro.2020.07.043.

The American Gastroenterological Association has published a clinical practice update that characterizes postendoscopy esophageal adenocarcinoma (EAC) and offers recommendations to improve endoscopic detection of dysplastic and neoplastic lesions in patients with Barrett’s esophagus.

While emerging technologies may improve detection rates in the future, short-term progress will depend on human expertise, reported lead author Sachin Wani, MD, of the University of Colorado at Denver, Aurora, and colleagues.

Writing in Gastroenterology, Dr. Wani and colleagues noted that EAC incidence has increased sevenfold over the past 4 decades, and 40% of patients with EAC have advanced disease at diagnosis, with a “dismal” 5-year survival rate.

Attempts to catch EAC earlier through Barrett’s esophagus surveillance endoscopy have been generally fallen short, the investigators added. They discussed a variety of obstacles to success, including divergence from recommended screening timelines, nonadherence to the Seattle biopsy protocol, sampling errors, and variability of dysplastic tissue interpretation between pathologists.

“Even in the face of suboptimal impact of current strategies on population-based EAC mortality, medical societies consistently recommend [Barrett’s esophagus] screening and surveillance,” the investigators wrote. “In this context, similar to postcolonoscopy colorectal cancer, the concept of missed EAC is gaining importance in endoscopic Barrett’s esophagus screening and surveillance.”

In the present update, the investigators first aimed to standardize definitions of postendoscopy and interval EAC.

“We propose that postendoscopy EAC be defined as EAC and/or [Barrett’s esophagus]–related high-grade dysplasia identified within a finite time period (typically 1 year) following a nondiagnostic endoscopy,” the investigators wrote. “Interval EAC may be defined as EAC or [Barrett’s esophagus]–related high-grade dysplasia diagnosed after a negative screening or surveillance endoscopy before the date of the next recommended test.”

The latter definition, the investigators noted, was written with acknowledgment of emerging, noninvasive, nonendoscopic screening tools.

Next, Dr. Wani and colleagues dove deeper into the incidence of postendoscopy EAC in the Barrett’s esophagus population. Across multiple cohort studies and meta-analyses, incidence within 1 year of screening endoscopy ranged widely, from 3% to 25%. Data from Barrett’s esophagus patients undergoing endoscopic eradication therapy suggest that incidence of postendoscopy EAC may be greatest within 1-2 years of complete eradication of intestinal metaplasia; one meta-analysis involving 22 studies reported that the risk of EAC was 92% higher within the first year of eradication, compared with subsequent years.

“These data support that high-grade dysplasia/EAC identified within 1 year after complete eradication of intestinal metaplasia likely represents missed and/or incompletely treated prevalent disease rather than recurrent or incident neoplasia,” the investigators wrote.

In support of this conclusion, Dr. Wani and colleagues drew upon data from colorectal cancer screening programs, which suggest that 89% of postcolonoscopy colorectal cancers “may be avoidable, attributable to technical endoscopic factors, compromised decision-making, and administrative factors.”

Regulatory agencies measure quality of colorectal cancer screening programs with adenoma detection rate, which has been shown to correlate inversely with colorectal cancer and mortality; but no analogous measure has been established for Barrett’s esophagus screening. Candidate quality markers include neoplasia detection rate and dysplasia detection rate, though more work is needed to confirm their reliability.

“While easier to measure, compared to postendoscopy EAC rates, neoplasia detection rate remains a surrogate endoscopy quality marker in Barrett’s esophagus surveillance, while postendoscopy EAC rates serve as a true outcome measure that matters clinically,” the investigators wrote.

Dr. Wani and colleagues proposed four clinical strategies that may immediately improve quality of Barrett’s esophagus screening.

• First, they recommended “assiduous identification and photo-documentation of esophageal landmarks” coupled with lesion descriptions that adhere to Prague and Paris classification schemes, along with resection or referral upon identification.
• Second, they called for consistent use of high-definition white-light endoscopy and virtual chromoendoscopy.
• Third, they suggested that endoscopists “spend adequate time for inspection,” with biopsies taken in accordance with the Seattle protocol.
• Fourth, Dr. Wani and colleagues suggested that all practices conducting Barrett’s esophagus screening and surveillance establish continuously active quality control programs.

The investigators concluded the clinical practice update with a discussion of future directions.

“Prospective trials are needed to evaluate the impact of better dissemination of guidelines and quality indicators, improved endoscopic dysplasia detection using interactive web-based educational tools, advanced imaging techniques with artificial intelligence, and improved sampling modalities that reduce sampling errors,” they wrote. “Finally, increased emphasis is needed on improving training in both the cognitive and procedural aspects of [Barrett’s esophagus] endoscopy through structured educational programs among trainees and practicing endoscopists.”

The study was supported by the University of Colorado department of medicine’s Outstanding Early Scholars Program. The investigators disclosed relationships with Medtronic, Boston Scientific, Ironwood, and others.

SOURCE: Wani S et al. Gastroenterology. 2020 Jul 13. doi: 10.1053/j.gastro.2020.06.089.

The American Gastroenterological Association has published a clinical practice update that characterizes postendoscopy esophageal adenocarcinoma (EAC) and offers recommendations to improve endoscopic detection of dysplastic and neoplastic lesions in patients with Barrett’s esophagus.

While emerging technologies may improve detection rates in the future, short-term progress will depend on human expertise, reported lead author Sachin Wani, MD, of the University of Colorado at Denver, Aurora, and colleagues.

Writing in Gastroenterology, Dr. Wani and colleagues noted that EAC incidence has increased sevenfold over the past 4 decades, and 40% of patients with EAC have advanced disease at diagnosis, with a “dismal” 5-year survival rate.

Attempts to catch EAC earlier through Barrett’s esophagus surveillance endoscopy have been generally fallen short, the investigators added. They discussed a variety of obstacles to success, including divergence from recommended screening timelines, nonadherence to the Seattle biopsy protocol, sampling errors, and variability of dysplastic tissue interpretation between pathologists.

“Even in the face of suboptimal impact of current strategies on population-based EAC mortality, medical societies consistently recommend [Barrett’s esophagus] screening and surveillance,” the investigators wrote. “In this context, similar to postcolonoscopy colorectal cancer, the concept of missed EAC is gaining importance in endoscopic Barrett’s esophagus screening and surveillance.”

In the present update, the investigators first aimed to standardize definitions of postendoscopy and interval EAC.

“We propose that postendoscopy EAC be defined as EAC and/or [Barrett’s esophagus]–related high-grade dysplasia identified within a finite time period (typically 1 year) following a nondiagnostic endoscopy,” the investigators wrote. “Interval EAC may be defined as EAC or [Barrett’s esophagus]–related high-grade dysplasia diagnosed after a negative screening or surveillance endoscopy before the date of the next recommended test.”

The latter definition, the investigators noted, was written with acknowledgment of emerging, noninvasive, nonendoscopic screening tools.

Next, Dr. Wani and colleagues dove deeper into the incidence of postendoscopy EAC in the Barrett’s esophagus population. Across multiple cohort studies and meta-analyses, incidence within 1 year of screening endoscopy ranged widely, from 3% to 25%. Data from Barrett’s esophagus patients undergoing endoscopic eradication therapy suggest that incidence of postendoscopy EAC may be greatest within 1-2 years of complete eradication of intestinal metaplasia; one meta-analysis involving 22 studies reported that the risk of EAC was 92% higher within the first year of eradication, compared with subsequent years.

“These data support that high-grade dysplasia/EAC identified within 1 year after complete eradication of intestinal metaplasia likely represents missed and/or incompletely treated prevalent disease rather than recurrent or incident neoplasia,” the investigators wrote.

In support of this conclusion, Dr. Wani and colleagues drew upon data from colorectal cancer screening programs, which suggest that 89% of postcolonoscopy colorectal cancers “may be avoidable, attributable to technical endoscopic factors, compromised decision-making, and administrative factors.”

Regulatory agencies measure quality of colorectal cancer screening programs with adenoma detection rate, which has been shown to correlate inversely with colorectal cancer and mortality; but no analogous measure has been established for Barrett’s esophagus screening. Candidate quality markers include neoplasia detection rate and dysplasia detection rate, though more work is needed to confirm their reliability.

“While easier to measure, compared to postendoscopy EAC rates, neoplasia detection rate remains a surrogate endoscopy quality marker in Barrett’s esophagus surveillance, while postendoscopy EAC rates serve as a true outcome measure that matters clinically,” the investigators wrote.

Dr. Wani and colleagues proposed four clinical strategies that may immediately improve quality of Barrett’s esophagus screening.

• First, they recommended “assiduous identification and photo-documentation of esophageal landmarks” coupled with lesion descriptions that adhere to Prague and Paris classification schemes, along with resection or referral upon identification.
• Second, they called for consistent use of high-definition white-light endoscopy and virtual chromoendoscopy.
• Third, they suggested that endoscopists “spend adequate time for inspection,” with biopsies taken in accordance with the Seattle protocol.
• Fourth, Dr. Wani and colleagues suggested that all practices conducting Barrett’s esophagus screening and surveillance establish continuously active quality control programs.

The investigators concluded the clinical practice update with a discussion of future directions.

“Prospective trials are needed to evaluate the impact of better dissemination of guidelines and quality indicators, improved endoscopic dysplasia detection using interactive web-based educational tools, advanced imaging techniques with artificial intelligence, and improved sampling modalities that reduce sampling errors,” they wrote. “Finally, increased emphasis is needed on improving training in both the cognitive and procedural aspects of [Barrett’s esophagus] endoscopy through structured educational programs among trainees and practicing endoscopists.”

The study was supported by the University of Colorado department of medicine’s Outstanding Early Scholars Program. The investigators disclosed relationships with Medtronic, Boston Scientific, Ironwood, and others.

SOURCE: Wani S et al. Gastroenterology. 2020 Jul 13. doi: 10.1053/j.gastro.2020.06.089.

The American Gastroenterological Association has published a clinical practice update that characterizes postendoscopy esophageal adenocarcinoma (EAC) and offers recommendations to improve endoscopic detection of dysplastic and neoplastic lesions in patients with Barrett’s esophagus.

While emerging technologies may improve detection rates in the future, short-term progress will depend on human expertise, reported lead author Sachin Wani, MD, of the University of Colorado at Denver, Aurora, and colleagues.

Writing in Gastroenterology, Dr. Wani and colleagues noted that EAC incidence has increased sevenfold over the past 4 decades, and 40% of patients with EAC have advanced disease at diagnosis, with a “dismal” 5-year survival rate.

Attempts to catch EAC earlier through Barrett’s esophagus surveillance endoscopy have been generally fallen short, the investigators added. They discussed a variety of obstacles to success, including divergence from recommended screening timelines, nonadherence to the Seattle biopsy protocol, sampling errors, and variability of dysplastic tissue interpretation between pathologists.

“Even in the face of suboptimal impact of current strategies on population-based EAC mortality, medical societies consistently recommend [Barrett’s esophagus] screening and surveillance,” the investigators wrote. “In this context, similar to postcolonoscopy colorectal cancer, the concept of missed EAC is gaining importance in endoscopic Barrett’s esophagus screening and surveillance.”

In the present update, the investigators first aimed to standardize definitions of postendoscopy and interval EAC.

“We propose that postendoscopy EAC be defined as EAC and/or [Barrett’s esophagus]–related high-grade dysplasia identified within a finite time period (typically 1 year) following a nondiagnostic endoscopy,” the investigators wrote. “Interval EAC may be defined as EAC or [Barrett’s esophagus]–related high-grade dysplasia diagnosed after a negative screening or surveillance endoscopy before the date of the next recommended test.”

The latter definition, the investigators noted, was written with acknowledgment of emerging, noninvasive, nonendoscopic screening tools.

Next, Dr. Wani and colleagues dove deeper into the incidence of postendoscopy EAC in the Barrett’s esophagus population. Across multiple cohort studies and meta-analyses, incidence within 1 year of screening endoscopy ranged widely, from 3% to 25%. Data from Barrett’s esophagus patients undergoing endoscopic eradication therapy suggest that incidence of postendoscopy EAC may be greatest within 1-2 years of complete eradication of intestinal metaplasia; one meta-analysis involving 22 studies reported that the risk of EAC was 92% higher within the first year of eradication, compared with subsequent years.

“These data support that high-grade dysplasia/EAC identified within 1 year after complete eradication of intestinal metaplasia likely represents missed and/or incompletely treated prevalent disease rather than recurrent or incident neoplasia,” the investigators wrote.

In support of this conclusion, Dr. Wani and colleagues drew upon data from colorectal cancer screening programs, which suggest that 89% of postcolonoscopy colorectal cancers “may be avoidable, attributable to technical endoscopic factors, compromised decision-making, and administrative factors.”

Regulatory agencies measure quality of colorectal cancer screening programs with adenoma detection rate, which has been shown to correlate inversely with colorectal cancer and mortality; but no analogous measure has been established for Barrett’s esophagus screening. Candidate quality markers include neoplasia detection rate and dysplasia detection rate, though more work is needed to confirm their reliability.

“While easier to measure, compared to postendoscopy EAC rates, neoplasia detection rate remains a surrogate endoscopy quality marker in Barrett’s esophagus surveillance, while postendoscopy EAC rates serve as a true outcome measure that matters clinically,” the investigators wrote.

Dr. Wani and colleagues proposed four clinical strategies that may immediately improve quality of Barrett’s esophagus screening.

• First, they recommended “assiduous identification and photo-documentation of esophageal landmarks” coupled with lesion descriptions that adhere to Prague and Paris classification schemes, along with resection or referral upon identification.
• Second, they called for consistent use of high-definition white-light endoscopy and virtual chromoendoscopy.
• Third, they suggested that endoscopists “spend adequate time for inspection,” with biopsies taken in accordance with the Seattle protocol.
• Fourth, Dr. Wani and colleagues suggested that all practices conducting Barrett’s esophagus screening and surveillance establish continuously active quality control programs.

The investigators concluded the clinical practice update with a discussion of future directions.

“Prospective trials are needed to evaluate the impact of better dissemination of guidelines and quality indicators, improved endoscopic dysplasia detection using interactive web-based educational tools, advanced imaging techniques with artificial intelligence, and improved sampling modalities that reduce sampling errors,” they wrote. “Finally, increased emphasis is needed on improving training in both the cognitive and procedural aspects of [Barrett’s esophagus] endoscopy through structured educational programs among trainees and practicing endoscopists.”

The study was supported by the University of Colorado department of medicine’s Outstanding Early Scholars Program. The investigators disclosed relationships with Medtronic, Boston Scientific, Ironwood, and others.

SOURCE: Wani S et al. Gastroenterology. 2020 Jul 13. doi: 10.1053/j.gastro.2020.06.089.

For patients with severe thrombocytopenia and chronic liver diseases, including hepatocellular carcinoma, treatment with lusutrombopag prior to invasive procedures significantly decreased the need for platelet transfusions without increasing the need for rescue treatment for bleeding or the rate of thromboembolic events.

In a post hoc analysis of data from 270 patients in two manufacturer-sponsored, multicenter, randomized, double-blind, placebo-controlled, phase 3 trials, significantly more lusutrombopag recipients met the primary efficacy endpoint, including patients with hepatocellular carcinoma (68.0% vs. 8.9% in the placebo group; P < .0001) and those without it (77.0% vs. 21.6%; P < .0001). Rates of treatment-emergent adverse events were similar between the lusutrombopag and placebo groups, and patients with hepatocellular carcinoma were not at increased risk for thrombosis, Naim Alkhouri, MD, of Texas Liver Institute in San Antonio, and associates wrote in Clinical Gastroenterology and Hepatology.

Platelet transfusion is the treatment mainstay for patients with thrombocytopenia related to cirrhosis who are undergoing invasive procedures, but its effects are short-lived, and at least one in five transfusions fails. Thrombopoietin agonists such as lusutrombopag are efficacious and approved in this setting, but they can be prothrombotic, particularly in patients with hepatocellular carcinoma, who already are at heightened risk for portal vein thrombosis.

Dr. Alkhouri and associates performed an integrated analysis of the PLUS 1 trial (Japan, October 2013–May 2014) and the L-PLUS 2 (global, June 2015–April 2017). Participants were adults with Child-Pugh Class A or B chronic liver disease and baseline platelet counts under 50 x 10⁹ per L who were scheduled for invasive procedures. Of the 270 patients, 95 had hepatocellular carcinoma. Patients were randomly assigned on a one-to-one basis to receive either lusutrombopag (3 mg) or placebo daily for up to 7 days before procedures. The primary endpoint was the percentage of patients in the per-protocol population who did not need a platelet transfusion before the invasive procedure or rescue therapy within 7 days afterward.

The treatment and placebo arms were similar except that patients with hepatocellular carcinoma were about 10 years older on average. In patients with hepatocellular carcinoma, 60.5% more lusutrombopag recipients than placebo recipients met the primary endpoint, and rates of bleeding-related adverse events were 9.1% and 15.7%, respectively. In patients with other chronic liver diseases, 52.6% more lusutrombopag recipients met the primary endpoint. Rates of bleeding-related adverse events were 5% and 10.6%.

“Approximately 88% of patients with hepatocellular carcinoma underwent a liver-related procedure, compared with approximately 10% of patients without hepatocellular carcinoma,” the investigators wrote. “This is significant because ablations or transcatheter arterial chemoembolizations can be associated with serious bleeding complications. It is clinically important that, given the greater number of liver-related procedures, the incidence of bleeding-related adverse events was lower in patients treated with lusutrombopag than placebo.”

Imaging after the procedures confirmed low rates of thromboses in both groups and subgroups. Four patients developed portal vein thromboses, including two lusutrombopag recipients (one of whom had hepatocellular carcinoma) and two placebo recipients without hepatocellular carcinoma.

These trials excluded patients undergoing major surgical procedures and those with decompensated cirrhosis; portal vein thrombosis; hematopoietic tumors; aplastic anemia; myelodysplastic syndrome; myelofibrosis; liver transplantation; splenectomy; and thrombocytopenia that was congenital, autoimmune, or drug induced. “A limitation of this study was the high rate of protocol violations related to platelet transfusions,” the researchers noted. “A number of patients [42 in all] were excluded from the per-protocol population owing to receipt of unnecessary platelet transfusions, or because they did not receive a needed platelet transfusion.”Shionogi makes lusutrombopag and sponsored the study. Dr. Alkhouri reported an advisory relationship with Shionogi and Dova Pharma. Two coinvestigators reported being employed by Shionogi. Three coinvestigators also disclosed ties to Shionogi and to several other pharmaceutical companies.

SOURCE: Alkhouri N et al. Clin Gastroenterol Hepatol. 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.032.

For patients with severe thrombocytopenia and chronic liver diseases, including hepatocellular carcinoma, treatment with lusutrombopag prior to invasive procedures significantly decreased the need for platelet transfusions without increasing the need for rescue treatment for bleeding or the rate of thromboembolic events.

In a post hoc analysis of data from 270 patients in two manufacturer-sponsored, multicenter, randomized, double-blind, placebo-controlled, phase 3 trials, significantly more lusutrombopag recipients met the primary efficacy endpoint, including patients with hepatocellular carcinoma (68.0% vs. 8.9% in the placebo group; P < .0001) and those without it (77.0% vs. 21.6%; P < .0001). Rates of treatment-emergent adverse events were similar between the lusutrombopag and placebo groups, and patients with hepatocellular carcinoma were not at increased risk for thrombosis, Naim Alkhouri, MD, of Texas Liver Institute in San Antonio, and associates wrote in Clinical Gastroenterology and Hepatology.

Platelet transfusion is the treatment mainstay for patients with thrombocytopenia related to cirrhosis who are undergoing invasive procedures, but its effects are short-lived, and at least one in five transfusions fails. Thrombopoietin agonists such as lusutrombopag are efficacious and approved in this setting, but they can be prothrombotic, particularly in patients with hepatocellular carcinoma, who already are at heightened risk for portal vein thrombosis.

Dr. Alkhouri and associates performed an integrated analysis of the PLUS 1 trial (Japan, October 2013–May 2014) and the L-PLUS 2 (global, June 2015–April 2017). Participants were adults with Child-Pugh Class A or B chronic liver disease and baseline platelet counts under 50 x 10⁹ per L who were scheduled for invasive procedures. Of the 270 patients, 95 had hepatocellular carcinoma. Patients were randomly assigned on a one-to-one basis to receive either lusutrombopag (3 mg) or placebo daily for up to 7 days before procedures. The primary endpoint was the percentage of patients in the per-protocol population who did not need a platelet transfusion before the invasive procedure or rescue therapy within 7 days afterward.

The treatment and placebo arms were similar except that patients with hepatocellular carcinoma were about 10 years older on average. In patients with hepatocellular carcinoma, 60.5% more lusutrombopag recipients than placebo recipients met the primary endpoint, and rates of bleeding-related adverse events were 9.1% and 15.7%, respectively. In patients with other chronic liver diseases, 52.6% more lusutrombopag recipients met the primary endpoint. Rates of bleeding-related adverse events were 5% and 10.6%.

“Approximately 88% of patients with hepatocellular carcinoma underwent a liver-related procedure, compared with approximately 10% of patients without hepatocellular carcinoma,” the investigators wrote. “This is significant because ablations or transcatheter arterial chemoembolizations can be associated with serious bleeding complications. It is clinically important that, given the greater number of liver-related procedures, the incidence of bleeding-related adverse events was lower in patients treated with lusutrombopag than placebo.”

Imaging after the procedures confirmed low rates of thromboses in both groups and subgroups. Four patients developed portal vein thromboses, including two lusutrombopag recipients (one of whom had hepatocellular carcinoma) and two placebo recipients without hepatocellular carcinoma.

These trials excluded patients undergoing major surgical procedures and those with decompensated cirrhosis; portal vein thrombosis; hematopoietic tumors; aplastic anemia; myelodysplastic syndrome; myelofibrosis; liver transplantation; splenectomy; and thrombocytopenia that was congenital, autoimmune, or drug induced. “A limitation of this study was the high rate of protocol violations related to platelet transfusions,” the researchers noted. “A number of patients [42 in all] were excluded from the per-protocol population owing to receipt of unnecessary platelet transfusions, or because they did not receive a needed platelet transfusion.”Shionogi makes lusutrombopag and sponsored the study. Dr. Alkhouri reported an advisory relationship with Shionogi and Dova Pharma. Two coinvestigators reported being employed by Shionogi. Three coinvestigators also disclosed ties to Shionogi and to several other pharmaceutical companies.

SOURCE: Alkhouri N et al. Clin Gastroenterol Hepatol. 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.032.

For patients with severe thrombocytopenia and chronic liver diseases, including hepatocellular carcinoma, treatment with lusutrombopag prior to invasive procedures significantly decreased the need for platelet transfusions without increasing the need for rescue treatment for bleeding or the rate of thromboembolic events.

In a post hoc analysis of data from 270 patients in two manufacturer-sponsored, multicenter, randomized, double-blind, placebo-controlled, phase 3 trials, significantly more lusutrombopag recipients met the primary efficacy endpoint, including patients with hepatocellular carcinoma (68.0% vs. 8.9% in the placebo group; P < .0001) and those without it (77.0% vs. 21.6%; P < .0001). Rates of treatment-emergent adverse events were similar between the lusutrombopag and placebo groups, and patients with hepatocellular carcinoma were not at increased risk for thrombosis, Naim Alkhouri, MD, of Texas Liver Institute in San Antonio, and associates wrote in Clinical Gastroenterology and Hepatology.

Platelet transfusion is the treatment mainstay for patients with thrombocytopenia related to cirrhosis who are undergoing invasive procedures, but its effects are short-lived, and at least one in five transfusions fails. Thrombopoietin agonists such as lusutrombopag are efficacious and approved in this setting, but they can be prothrombotic, particularly in patients with hepatocellular carcinoma, who already are at heightened risk for portal vein thrombosis.

Dr. Alkhouri and associates performed an integrated analysis of the PLUS 1 trial (Japan, October 2013–May 2014) and the L-PLUS 2 (global, June 2015–April 2017). Participants were adults with Child-Pugh Class A or B chronic liver disease and baseline platelet counts under 50 x 10⁹ per L who were scheduled for invasive procedures. Of the 270 patients, 95 had hepatocellular carcinoma. Patients were randomly assigned on a one-to-one basis to receive either lusutrombopag (3 mg) or placebo daily for up to 7 days before procedures. The primary endpoint was the percentage of patients in the per-protocol population who did not need a platelet transfusion before the invasive procedure or rescue therapy within 7 days afterward.

The treatment and placebo arms were similar except that patients with hepatocellular carcinoma were about 10 years older on average. In patients with hepatocellular carcinoma, 60.5% more lusutrombopag recipients than placebo recipients met the primary endpoint, and rates of bleeding-related adverse events were 9.1% and 15.7%, respectively. In patients with other chronic liver diseases, 52.6% more lusutrombopag recipients met the primary endpoint. Rates of bleeding-related adverse events were 5% and 10.6%.

“Approximately 88% of patients with hepatocellular carcinoma underwent a liver-related procedure, compared with approximately 10% of patients without hepatocellular carcinoma,” the investigators wrote. “This is significant because ablations or transcatheter arterial chemoembolizations can be associated with serious bleeding complications. It is clinically important that, given the greater number of liver-related procedures, the incidence of bleeding-related adverse events was lower in patients treated with lusutrombopag than placebo.”

Imaging after the procedures confirmed low rates of thromboses in both groups and subgroups. Four patients developed portal vein thromboses, including two lusutrombopag recipients (one of whom had hepatocellular carcinoma) and two placebo recipients without hepatocellular carcinoma.

These trials excluded patients undergoing major surgical procedures and those with decompensated cirrhosis; portal vein thrombosis; hematopoietic tumors; aplastic anemia; myelodysplastic syndrome; myelofibrosis; liver transplantation; splenectomy; and thrombocytopenia that was congenital, autoimmune, or drug induced. “A limitation of this study was the high rate of protocol violations related to platelet transfusions,” the researchers noted. “A number of patients [42 in all] were excluded from the per-protocol population owing to receipt of unnecessary platelet transfusions, or because they did not receive a needed platelet transfusion.”Shionogi makes lusutrombopag and sponsored the study. Dr. Alkhouri reported an advisory relationship with Shionogi and Dova Pharma. Two coinvestigators reported being employed by Shionogi. Three coinvestigators also disclosed ties to Shionogi and to several other pharmaceutical companies.

SOURCE: Alkhouri N et al. Clin Gastroenterol Hepatol. 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.032.

Unexplained diarrhea may be the most reliable symptom of small intestinal bacterial overgrowth (SIBO) in at-risk patients, according to a new clinical practice update from the American Gastroenterological Association.

“In those predisposed to SIBO due to anatomical, pathological, pharmacological or other changes that promote stasis or recirculation of colonic contents and/or impaired resistance to bacteria, SIBO will lead to diarrhea and can progress to a full-blown malabsorption syndrome” marked by steatorrhea and vitamin deficiencies, wrote Eamonn M.M. Quigley, MD, of Houston Methodist Hospital and Weill Cornell Medical College in Houston together with his fellow experts in Gastroenterology. But malabsorption is uncommon in patients whose SIBO is not caused by structural abnormalities, and gastrointestinal symptoms are “weakly predictive at best” if patients lack clear risk factors for SIBO, the experts cautioned.

The growing availability of breath testing has fueled diagnoses of SIBO, which the lay press often implicates in various disorders even though SIBO has no clear clinical or laboratory definition. Recent progress in techniques to measure bacterial populations and their metabolic products “should provide much needed clarity,” but for now, a SIBO diagnosis simply means that a patient’s presenting symptoms or laboratory findings are attributed to bacterial changes in the small intestine, the experts wrote.

Detecting SIBO also remains challenging. Most patients have normal results on routine laboratory tests, and there is not enough evidence to support testing for inflammatory markers such as fecal calprotectin. Patients with SIBO may have increased folate levels because of bacterial production of folic acid. Vitamin B₁₂ and other nutrient deficiencies also occur but are less common. The preferred diagnostic method is culture of a duodenal aspirate, and recent research supports a cutoff value of greater than 10³ CFUs of coliform bacteria per mL. Breath testing is less invasive but “more complex than simply measuring hydrogen,” the experts stressed. Methane-producing microorganisms (methanogens) suppress hydrogen on a breath test (fortunately, standard breath tests measure methane). Furthermore, a positive methane breath test also has been linked to constipation-predominant irritable bowel syndrome (IBS). Recent studies also suggest that lactulose breath testing is more sensitive than glucose for identifying SIBO in patients with IBS.

Antibiotic therapy is the treatment mainstay but remains largely empiric. The goal is to improve SIBO symptoms, not eradicate bacteria from the small intestine. Ideally, the antimicrobial regimen should cover both aerobic and anaerobic bacteria, but clinicians should be mindful of the risks of chronic broad-spectrum antibiotic exposure. In studies, a single 7- to 10-day antibiotic course improved symptoms in approximately 45%-90% of patients with SIBO (rates of breath test response were lower). For patients with IBS and SIBO, rifaximin (which is poorly absorbed) produced encouraging results in two phase 3 studies, but most patients did not receive breath testing, the experts noted. Patients with recurrent SIBO symptoms may need multiple courses of antibiotics with specific regimens rotated to help prevent resistance. “Decisions on management should be individualized and also [should factor in] such risks as diarrhea, Clostridiodes difficile infection, intolerance, and cost,” the experts wrote. “It is not necessary to repeat diagnostic tests for SIBO following antibiotic therapy [if] gastrointestinal symptoms respond.”

Dr. Quigley disclosed financial ties to 4D Pharma, Alimentary Health, Allergan, Biocodex, Biomerica, Ironwood, Salix, Takeda, Vibrant, and Zealand. He also disclosed patents with and equity in Alimentary Health. Both of his coauthors also disclosed ties to various pharmaceutical companies.

SOURCE: Quigley EMM et al. Gastroenterology. 2020 Jun 1. doi: 10.1053/j.gastro.2020.06.090.
 

Unexplained diarrhea may be the most reliable symptom of small intestinal bacterial overgrowth (SIBO) in at-risk patients, according to a new clinical practice update from the American Gastroenterological Association.

“In those predisposed to SIBO due to anatomical, pathological, pharmacological or other changes that promote stasis or recirculation of colonic contents and/or impaired resistance to bacteria, SIBO will lead to diarrhea and can progress to a full-blown malabsorption syndrome” marked by steatorrhea and vitamin deficiencies, wrote Eamonn M.M. Quigley, MD, of Houston Methodist Hospital and Weill Cornell Medical College in Houston together with his fellow experts in Gastroenterology. But malabsorption is uncommon in patients whose SIBO is not caused by structural abnormalities, and gastrointestinal symptoms are “weakly predictive at best” if patients lack clear risk factors for SIBO, the experts cautioned.

The growing availability of breath testing has fueled diagnoses of SIBO, which the lay press often implicates in various disorders even though SIBO has no clear clinical or laboratory definition. Recent progress in techniques to measure bacterial populations and their metabolic products “should provide much needed clarity,” but for now, a SIBO diagnosis simply means that a patient’s presenting symptoms or laboratory findings are attributed to bacterial changes in the small intestine, the experts wrote.

Detecting SIBO also remains challenging. Most patients have normal results on routine laboratory tests, and there is not enough evidence to support testing for inflammatory markers such as fecal calprotectin. Patients with SIBO may have increased folate levels because of bacterial production of folic acid. Vitamin B₁₂ and other nutrient deficiencies also occur but are less common. The preferred diagnostic method is culture of a duodenal aspirate, and recent research supports a cutoff value of greater than 10³ CFUs of coliform bacteria per mL. Breath testing is less invasive but “more complex than simply measuring hydrogen,” the experts stressed. Methane-producing microorganisms (methanogens) suppress hydrogen on a breath test (fortunately, standard breath tests measure methane). Furthermore, a positive methane breath test also has been linked to constipation-predominant irritable bowel syndrome (IBS). Recent studies also suggest that lactulose breath testing is more sensitive than glucose for identifying SIBO in patients with IBS.

Antibiotic therapy is the treatment mainstay but remains largely empiric. The goal is to improve SIBO symptoms, not eradicate bacteria from the small intestine. Ideally, the antimicrobial regimen should cover both aerobic and anaerobic bacteria, but clinicians should be mindful of the risks of chronic broad-spectrum antibiotic exposure. In studies, a single 7- to 10-day antibiotic course improved symptoms in approximately 45%-90% of patients with SIBO (rates of breath test response were lower). For patients with IBS and SIBO, rifaximin (which is poorly absorbed) produced encouraging results in two phase 3 studies, but most patients did not receive breath testing, the experts noted. Patients with recurrent SIBO symptoms may need multiple courses of antibiotics with specific regimens rotated to help prevent resistance. “Decisions on management should be individualized and also [should factor in] such risks as diarrhea, Clostridiodes difficile infection, intolerance, and cost,” the experts wrote. “It is not necessary to repeat diagnostic tests for SIBO following antibiotic therapy [if] gastrointestinal symptoms respond.”

Dr. Quigley disclosed financial ties to 4D Pharma, Alimentary Health, Allergan, Biocodex, Biomerica, Ironwood, Salix, Takeda, Vibrant, and Zealand. He also disclosed patents with and equity in Alimentary Health. Both of his coauthors also disclosed ties to various pharmaceutical companies.

SOURCE: Quigley EMM et al. Gastroenterology. 2020 Jun 1. doi: 10.1053/j.gastro.2020.06.090.
 

Unexplained diarrhea may be the most reliable symptom of small intestinal bacterial overgrowth (SIBO) in at-risk patients, according to a new clinical practice update from the American Gastroenterological Association.

“In those predisposed to SIBO due to anatomical, pathological, pharmacological or other changes that promote stasis or recirculation of colonic contents and/or impaired resistance to bacteria, SIBO will lead to diarrhea and can progress to a full-blown malabsorption syndrome” marked by steatorrhea and vitamin deficiencies, wrote Eamonn M.M. Quigley, MD, of Houston Methodist Hospital and Weill Cornell Medical College in Houston together with his fellow experts in Gastroenterology. But malabsorption is uncommon in patients whose SIBO is not caused by structural abnormalities, and gastrointestinal symptoms are “weakly predictive at best” if patients lack clear risk factors for SIBO, the experts cautioned.

The growing availability of breath testing has fueled diagnoses of SIBO, which the lay press often implicates in various disorders even though SIBO has no clear clinical or laboratory definition. Recent progress in techniques to measure bacterial populations and their metabolic products “should provide much needed clarity,” but for now, a SIBO diagnosis simply means that a patient’s presenting symptoms or laboratory findings are attributed to bacterial changes in the small intestine, the experts wrote.

Detecting SIBO also remains challenging. Most patients have normal results on routine laboratory tests, and there is not enough evidence to support testing for inflammatory markers such as fecal calprotectin. Patients with SIBO may have increased folate levels because of bacterial production of folic acid. Vitamin B₁₂ and other nutrient deficiencies also occur but are less common. The preferred diagnostic method is culture of a duodenal aspirate, and recent research supports a cutoff value of greater than 10³ CFUs of coliform bacteria per mL. Breath testing is less invasive but “more complex than simply measuring hydrogen,” the experts stressed. Methane-producing microorganisms (methanogens) suppress hydrogen on a breath test (fortunately, standard breath tests measure methane). Furthermore, a positive methane breath test also has been linked to constipation-predominant irritable bowel syndrome (IBS). Recent studies also suggest that lactulose breath testing is more sensitive than glucose for identifying SIBO in patients with IBS.

Antibiotic therapy is the treatment mainstay but remains largely empiric. The goal is to improve SIBO symptoms, not eradicate bacteria from the small intestine. Ideally, the antimicrobial regimen should cover both aerobic and anaerobic bacteria, but clinicians should be mindful of the risks of chronic broad-spectrum antibiotic exposure. In studies, a single 7- to 10-day antibiotic course improved symptoms in approximately 45%-90% of patients with SIBO (rates of breath test response were lower). For patients with IBS and SIBO, rifaximin (which is poorly absorbed) produced encouraging results in two phase 3 studies, but most patients did not receive breath testing, the experts noted. Patients with recurrent SIBO symptoms may need multiple courses of antibiotics with specific regimens rotated to help prevent resistance. “Decisions on management should be individualized and also [should factor in] such risks as diarrhea, Clostridiodes difficile infection, intolerance, and cost,” the experts wrote. “It is not necessary to repeat diagnostic tests for SIBO following antibiotic therapy [if] gastrointestinal symptoms respond.”

Dr. Quigley disclosed financial ties to 4D Pharma, Alimentary Health, Allergan, Biocodex, Biomerica, Ironwood, Salix, Takeda, Vibrant, and Zealand. He also disclosed patents with and equity in Alimentary Health. Both of his coauthors also disclosed ties to various pharmaceutical companies.

SOURCE: Quigley EMM et al. Gastroenterology. 2020 Jun 1. doi: 10.1053/j.gastro.2020.06.090.