Will Pass

Clinicians frequently increase doses of anti–tumor necrosis factor (anti-TNF) agents for patients with inflammatory bowel disease (IBD) without objective evidence of active inflammation, based on a retrospective study.

This strategy may be ineffective and expensive, according to lead author Evan D. Elias, MD, of the University of Manitoba, Winnipeg, Canada, and colleagues, who noted that worsening symptoms may have noninflammatory causes, such as coexisting functional disorders.

“Objective evidence of active inflammation is a key part of [the dose escalation] process,” the investigators wrote in the Journal of Clinical Gastroenterology, “however, there are no data assessing whether an adequate evaluation of the cause of persistent gastrointestinal symptoms is routinely undertaken in clinical practice.”

To address this knowledge gap, Dr. Elias and colleagues conducted a retrospective study involving 23 physicians in Manitoba who initiated anti-TNF therapy in 838 patients with IBD during 2005-2016. The primary outcome was rate of dose escalation within 1 year. Secondarily, the investigators audited 11 out of 23 prescribers to determine how frequently patients receiving increased doses underwent objective assessment of inflammation, both in general and in the 90 days preceding dose escalation.

Of note, therapeutic drug monitoring, fecal calprotectin testing, and transabdominal ultrasound were not commonly available to prescribers during the study period.

Within 1 year, almost one-third of patients (32.9%) received increased doses of either adalimumab or infliximab, with no significant difference in escalation practices between the two agents. After approximately 2 years, increased doses were prescribed for almost half of the patients (49%), with a median time to dose increase of 17.4 months.

Patients with ulcerative colitis were 83% more likely to receive increased doses than were those with Crohn’s disease (P = .0001), and doses were typically escalated at an earlier date (7.1 vs. 11.1 months). In contrast, dose escalation was not associated with a variety of other patient factors, such as sex, age, or baseline laboratory values.

Comprehensive data from 11 prescribers showed that 70.8% of patients who received increased doses underwent some form of testing to assess inflammation, but only 24.7% of them had objective evidence of inflammatory activity that supported the dose increase.

Raymond K. Cross Jr., MD, MS, AGAF, FACG, director of the IBD program at the University of Maryland, Baltimore County, said that the findings were “not surprising.”

Dr. Cross said that patients with IBD should ideally undergo testing for drug levels and inflammatory activity prior to dose escalation, but this one-size-fits-all approach doesn’t always translate to real-world practice.

“There’s the science, and there’s the practical,” he said, noting that dose escalation may precede testing “in an effort to be efficient and decrease suffering.” This includes cases in which patients receive an earlier or increased dose to bridge the gap between worsening of symptoms and completion of diagnostics.

Dr. Cross also pointed out that patients with ulcerative colitis typically have a strong correlation between symptoms and level of inflammation.

“If [a patient with ulcerative colitis] has bloody diarrhea, it’s 90% or so that they’re going to have active inflammation in their colon, so I feel less obligated to do those checks in an ulcerative colitis patient who has classic symptoms,” he said.

Byron Vaughn, MD, codirector of the IBD program at the University of Minnesota, Minneapolis, suggested that the study by Elias and colleagues “serves as an important reminder to follow the tenets of a treat-to-target strategy, which include regular assessment of objective markers of inflammation specific to IBD before and after a dose adjustment.”

Still, like Dr. Cross, Dr. Vaughn noted that dose escalation without additional testing “may be reasonable” in certain scenarios, such as when patients with ulcerative colitis have bloody diarrhea and tenesmus or for patients with perianal Crohn’s disease.

“A key limitation of this study is the lack of drug concentration monitoring,” Dr. Vaughn said. “Due to the immunogenicity of anti-TNF medications there is a strong rationale for proactive dose adjustments to avoid low or undetectable concentrations and subsequent antibody formation. However, as the authors point out, this is unlikely to be a major factor in this particular study as drug concentration measurement was not routinely available over the study period.”

The investigators disclosed relationships with AbbVie, Ferring, Janssen, and others. Dr. Vaughn disclosed relationships with AbbVie, Celgene, Genentech, Takeda, and others. Dr. Cross disclosed relationships with AbbVie, Janssen, and Samsung Bioepis.

SOURCE: Elias ED et al. J Clin Gastroenterol. 2020 Jul 17. doi: 10.1097/MCG.0000000000001391.

Clinicians frequently increase doses of anti–tumor necrosis factor (anti-TNF) agents for patients with inflammatory bowel disease (IBD) without objective evidence of active inflammation, based on a retrospective study.

This strategy may be ineffective and expensive, according to lead author Evan D. Elias, MD, of the University of Manitoba, Winnipeg, Canada, and colleagues, who noted that worsening symptoms may have noninflammatory causes, such as coexisting functional disorders.

“Objective evidence of active inflammation is a key part of [the dose escalation] process,” the investigators wrote in the Journal of Clinical Gastroenterology, “however, there are no data assessing whether an adequate evaluation of the cause of persistent gastrointestinal symptoms is routinely undertaken in clinical practice.”

To address this knowledge gap, Dr. Elias and colleagues conducted a retrospective study involving 23 physicians in Manitoba who initiated anti-TNF therapy in 838 patients with IBD during 2005-2016. The primary outcome was rate of dose escalation within 1 year. Secondarily, the investigators audited 11 out of 23 prescribers to determine how frequently patients receiving increased doses underwent objective assessment of inflammation, both in general and in the 90 days preceding dose escalation.

Of note, therapeutic drug monitoring, fecal calprotectin testing, and transabdominal ultrasound were not commonly available to prescribers during the study period.

Within 1 year, almost one-third of patients (32.9%) received increased doses of either adalimumab or infliximab, with no significant difference in escalation practices between the two agents. After approximately 2 years, increased doses were prescribed for almost half of the patients (49%), with a median time to dose increase of 17.4 months.

Patients with ulcerative colitis were 83% more likely to receive increased doses than were those with Crohn’s disease (P = .0001), and doses were typically escalated at an earlier date (7.1 vs. 11.1 months). In contrast, dose escalation was not associated with a variety of other patient factors, such as sex, age, or baseline laboratory values.

Comprehensive data from 11 prescribers showed that 70.8% of patients who received increased doses underwent some form of testing to assess inflammation, but only 24.7% of them had objective evidence of inflammatory activity that supported the dose increase.

Raymond K. Cross Jr., MD, MS, AGAF, FACG, director of the IBD program at the University of Maryland, Baltimore County, said that the findings were “not surprising.”

Dr. Cross said that patients with IBD should ideally undergo testing for drug levels and inflammatory activity prior to dose escalation, but this one-size-fits-all approach doesn’t always translate to real-world practice.

“There’s the science, and there’s the practical,” he said, noting that dose escalation may precede testing “in an effort to be efficient and decrease suffering.” This includes cases in which patients receive an earlier or increased dose to bridge the gap between worsening of symptoms and completion of diagnostics.

Dr. Cross also pointed out that patients with ulcerative colitis typically have a strong correlation between symptoms and level of inflammation.

“If [a patient with ulcerative colitis] has bloody diarrhea, it’s 90% or so that they’re going to have active inflammation in their colon, so I feel less obligated to do those checks in an ulcerative colitis patient who has classic symptoms,” he said.

Byron Vaughn, MD, codirector of the IBD program at the University of Minnesota, Minneapolis, suggested that the study by Elias and colleagues “serves as an important reminder to follow the tenets of a treat-to-target strategy, which include regular assessment of objective markers of inflammation specific to IBD before and after a dose adjustment.”

Still, like Dr. Cross, Dr. Vaughn noted that dose escalation without additional testing “may be reasonable” in certain scenarios, such as when patients with ulcerative colitis have bloody diarrhea and tenesmus or for patients with perianal Crohn’s disease.

“A key limitation of this study is the lack of drug concentration monitoring,” Dr. Vaughn said. “Due to the immunogenicity of anti-TNF medications there is a strong rationale for proactive dose adjustments to avoid low or undetectable concentrations and subsequent antibody formation. However, as the authors point out, this is unlikely to be a major factor in this particular study as drug concentration measurement was not routinely available over the study period.”

The investigators disclosed relationships with AbbVie, Ferring, Janssen, and others. Dr. Vaughn disclosed relationships with AbbVie, Celgene, Genentech, Takeda, and others. Dr. Cross disclosed relationships with AbbVie, Janssen, and Samsung Bioepis.

SOURCE: Elias ED et al. J Clin Gastroenterol. 2020 Jul 17. doi: 10.1097/MCG.0000000000001391.

Clinicians frequently increase doses of anti–tumor necrosis factor (anti-TNF) agents for patients with inflammatory bowel disease (IBD) without objective evidence of active inflammation, based on a retrospective study.

This strategy may be ineffective and expensive, according to lead author Evan D. Elias, MD, of the University of Manitoba, Winnipeg, Canada, and colleagues, who noted that worsening symptoms may have noninflammatory causes, such as coexisting functional disorders.

“Objective evidence of active inflammation is a key part of [the dose escalation] process,” the investigators wrote in the Journal of Clinical Gastroenterology, “however, there are no data assessing whether an adequate evaluation of the cause of persistent gastrointestinal symptoms is routinely undertaken in clinical practice.”

To address this knowledge gap, Dr. Elias and colleagues conducted a retrospective study involving 23 physicians in Manitoba who initiated anti-TNF therapy in 838 patients with IBD during 2005-2016. The primary outcome was rate of dose escalation within 1 year. Secondarily, the investigators audited 11 out of 23 prescribers to determine how frequently patients receiving increased doses underwent objective assessment of inflammation, both in general and in the 90 days preceding dose escalation.

Of note, therapeutic drug monitoring, fecal calprotectin testing, and transabdominal ultrasound were not commonly available to prescribers during the study period.

Within 1 year, almost one-third of patients (32.9%) received increased doses of either adalimumab or infliximab, with no significant difference in escalation practices between the two agents. After approximately 2 years, increased doses were prescribed for almost half of the patients (49%), with a median time to dose increase of 17.4 months.

Patients with ulcerative colitis were 83% more likely to receive increased doses than were those with Crohn’s disease (P = .0001), and doses were typically escalated at an earlier date (7.1 vs. 11.1 months). In contrast, dose escalation was not associated with a variety of other patient factors, such as sex, age, or baseline laboratory values.

Comprehensive data from 11 prescribers showed that 70.8% of patients who received increased doses underwent some form of testing to assess inflammation, but only 24.7% of them had objective evidence of inflammatory activity that supported the dose increase.

Raymond K. Cross Jr., MD, MS, AGAF, FACG, director of the IBD program at the University of Maryland, Baltimore County, said that the findings were “not surprising.”

Dr. Cross said that patients with IBD should ideally undergo testing for drug levels and inflammatory activity prior to dose escalation, but this one-size-fits-all approach doesn’t always translate to real-world practice.

“There’s the science, and there’s the practical,” he said, noting that dose escalation may precede testing “in an effort to be efficient and decrease suffering.” This includes cases in which patients receive an earlier or increased dose to bridge the gap between worsening of symptoms and completion of diagnostics.

Dr. Cross also pointed out that patients with ulcerative colitis typically have a strong correlation between symptoms and level of inflammation.

“If [a patient with ulcerative colitis] has bloody diarrhea, it’s 90% or so that they’re going to have active inflammation in their colon, so I feel less obligated to do those checks in an ulcerative colitis patient who has classic symptoms,” he said.

Byron Vaughn, MD, codirector of the IBD program at the University of Minnesota, Minneapolis, suggested that the study by Elias and colleagues “serves as an important reminder to follow the tenets of a treat-to-target strategy, which include regular assessment of objective markers of inflammation specific to IBD before and after a dose adjustment.”

Still, like Dr. Cross, Dr. Vaughn noted that dose escalation without additional testing “may be reasonable” in certain scenarios, such as when patients with ulcerative colitis have bloody diarrhea and tenesmus or for patients with perianal Crohn’s disease.

“A key limitation of this study is the lack of drug concentration monitoring,” Dr. Vaughn said. “Due to the immunogenicity of anti-TNF medications there is a strong rationale for proactive dose adjustments to avoid low or undetectable concentrations and subsequent antibody formation. However, as the authors point out, this is unlikely to be a major factor in this particular study as drug concentration measurement was not routinely available over the study period.”

The investigators disclosed relationships with AbbVie, Ferring, Janssen, and others. Dr. Vaughn disclosed relationships with AbbVie, Celgene, Genentech, Takeda, and others. Dr. Cross disclosed relationships with AbbVie, Janssen, and Samsung Bioepis.

SOURCE: Elias ED et al. J Clin Gastroenterol. 2020 Jul 17. doi: 10.1097/MCG.0000000000001391.

Mailing fecal immunochemical testing (FIT) kits with colorectal cancer (CRC) screening reminders appears cost effective and may boost screening rates across a variety of payers and providers, according to investigators.

Cost savings, when compared with mailing reminders alone, would be greatest from a Medicaid and state government perspective, reported lead author Stephanie B. Wheeler, PhD, MPH, of the University of North Carolina at Chapel Hill and colleagues.

“As payers and providers endeavor to increase the proportion of age-eligible adults who are up to date with CRC screening, according to the National Colorectal Cancer Roundtable target of 80% screened, understanding the comparative value of mailed FIT-based programs in low-income populations is urgently needed,” the investigators wrote in Cancer.

To address this need, Dr. Wheeler and colleagues coupled a randomized clinical trial with a cost-effectiveness analysis.

The trial involved 2,144 North Carolina Medicaid enrollees between 52 and 64 years of age who were overdue for CRC screening. Participants were randomly assigned to receive either a mailed reminder with an FIT kit or a mailed reminder alone. Those who received the reminder alone were provided with information about how to get an FIT kit or undergo screening colonoscopy.

The screening rate was significantly higher in the combination mailer group than it was the reminder-only group, at 21.1% versus 12.3% (P less than .01). Based on data from previous research, the investigators estimated that a number of participants also underwent colonoscopy screenings because of the reminders; this resulted in an estimated 23.3% screening rate among those who received an FIT kit, compared with 15.8% among those who received a reminder alone.

For cost analysis, these rates were entered into a model involving 35,000 Medicaid enrollees. Annual costs were compared from two perspectives: Medicaid/state and health clinic/facility, the latter of which included primary care providers, integrated health care systems, county health departments, and federally qualified health centers. The model incorporated a number of costs, such as those associated with equipment, mailing supplies, FIT kits, colonoscopy screenings, and personnel.

From a Medicaid/state perspective, the estimated total population screening cost of mailing both an FIT kit and reminder was $1.40 million, compared with $1.45 million for a reminder alone. This translated to a total cost per person screened of $172 for the combination mailer versus $262 for the reminder alone.

“Notably, compared with the reminder-only alternative, the reminder + FIT alternative was cost-saving or dominant from this perspective because it yielded more screenings at lower cost,” the investigators wrote.

The cost analysis from a health clinic/facility perspective was more nuanced.

While the estimated total population screening cost of a combination mailer was more than the reminder alone ($927,000 vs. $624,000), sending test kits led to screening of 2,598 additional individuals (8,131 vs. 5,533). The incremental cost-effectiveness ratio (ICER) for the combination mailer was $116 per person screened.

“This ICER fell within the range of what decision makers typically would be willing to pay for an additional person screened for CRC, previously shown to include ICERs as high as several hundred dollars or more,” the investigators noted.

According to Beverly B. Green, MD, MPH, of Kaiser Permanente Washington, Seattle, and Richard T. Meenan, PhD, MPH, of Kaiser Permanente Northwest, Portland, Oregon, who wrote a simultaneously published editorial, the study “suggests that direct FIT mailing can be highly cost effective if not cost saving within the Medicaid population, similar to tobacco-cessation programs or diabetes prevention programs in the same context of a Medicaid population.”

Still, practical details need to be resolved prior to real-world application, they added.

“[T]he analysis by Wheeler et al. raises an important question: Who should pay for mailed FIT screening programs?”

The answer, they suggested, may be health plans, since prevention of CRC could mitigate greater costs of care down the line. Further motivation could come from a program such as the Medicare 5-star program, which rewards higher screening rates with bonuses such as longer enrollment periods and higher payments, according to Dr. Green and Dr. Meenan.

“Unsurprisingly, Medicare CRC screening rates have been steadily increasing and now are approaching 80%,” they noted, “whereas Medicaid CRC screening rates remain low.”

The study was supported by the University of North Carolina, the Cancer Prevention and Control Research Network, the Centers for Disease Control and Prevention, and the National Cancer Institute. Dr. Wheeler reported grant funding from Pfizer.

SOURCE: Wheeler SB et al. Cancer. 2020 Jul 20. doi: 10.1002/cncr.32992.

Mailing fecal immunochemical testing (FIT) kits with colorectal cancer (CRC) screening reminders appears cost effective and may boost screening rates across a variety of payers and providers, according to investigators.

Cost savings, when compared with mailing reminders alone, would be greatest from a Medicaid and state government perspective, reported lead author Stephanie B. Wheeler, PhD, MPH, of the University of North Carolina at Chapel Hill and colleagues.

“As payers and providers endeavor to increase the proportion of age-eligible adults who are up to date with CRC screening, according to the National Colorectal Cancer Roundtable target of 80% screened, understanding the comparative value of mailed FIT-based programs in low-income populations is urgently needed,” the investigators wrote in Cancer.

To address this need, Dr. Wheeler and colleagues coupled a randomized clinical trial with a cost-effectiveness analysis.

The trial involved 2,144 North Carolina Medicaid enrollees between 52 and 64 years of age who were overdue for CRC screening. Participants were randomly assigned to receive either a mailed reminder with an FIT kit or a mailed reminder alone. Those who received the reminder alone were provided with information about how to get an FIT kit or undergo screening colonoscopy.

The screening rate was significantly higher in the combination mailer group than it was the reminder-only group, at 21.1% versus 12.3% (P less than .01). Based on data from previous research, the investigators estimated that a number of participants also underwent colonoscopy screenings because of the reminders; this resulted in an estimated 23.3% screening rate among those who received an FIT kit, compared with 15.8% among those who received a reminder alone.

For cost analysis, these rates were entered into a model involving 35,000 Medicaid enrollees. Annual costs were compared from two perspectives: Medicaid/state and health clinic/facility, the latter of which included primary care providers, integrated health care systems, county health departments, and federally qualified health centers. The model incorporated a number of costs, such as those associated with equipment, mailing supplies, FIT kits, colonoscopy screenings, and personnel.

From a Medicaid/state perspective, the estimated total population screening cost of mailing both an FIT kit and reminder was $1.40 million, compared with $1.45 million for a reminder alone. This translated to a total cost per person screened of $172 for the combination mailer versus $262 for the reminder alone.

“Notably, compared with the reminder-only alternative, the reminder + FIT alternative was cost-saving or dominant from this perspective because it yielded more screenings at lower cost,” the investigators wrote.

The cost analysis from a health clinic/facility perspective was more nuanced.

While the estimated total population screening cost of a combination mailer was more than the reminder alone ($927,000 vs. $624,000), sending test kits led to screening of 2,598 additional individuals (8,131 vs. 5,533). The incremental cost-effectiveness ratio (ICER) for the combination mailer was $116 per person screened.

“This ICER fell within the range of what decision makers typically would be willing to pay for an additional person screened for CRC, previously shown to include ICERs as high as several hundred dollars or more,” the investigators noted.

According to Beverly B. Green, MD, MPH, of Kaiser Permanente Washington, Seattle, and Richard T. Meenan, PhD, MPH, of Kaiser Permanente Northwest, Portland, Oregon, who wrote a simultaneously published editorial, the study “suggests that direct FIT mailing can be highly cost effective if not cost saving within the Medicaid population, similar to tobacco-cessation programs or diabetes prevention programs in the same context of a Medicaid population.”

Still, practical details need to be resolved prior to real-world application, they added.

“[T]he analysis by Wheeler et al. raises an important question: Who should pay for mailed FIT screening programs?”

The answer, they suggested, may be health plans, since prevention of CRC could mitigate greater costs of care down the line. Further motivation could come from a program such as the Medicare 5-star program, which rewards higher screening rates with bonuses such as longer enrollment periods and higher payments, according to Dr. Green and Dr. Meenan.

“Unsurprisingly, Medicare CRC screening rates have been steadily increasing and now are approaching 80%,” they noted, “whereas Medicaid CRC screening rates remain low.”

The study was supported by the University of North Carolina, the Cancer Prevention and Control Research Network, the Centers for Disease Control and Prevention, and the National Cancer Institute. Dr. Wheeler reported grant funding from Pfizer.

SOURCE: Wheeler SB et al. Cancer. 2020 Jul 20. doi: 10.1002/cncr.32992.

Mailing fecal immunochemical testing (FIT) kits with colorectal cancer (CRC) screening reminders appears cost effective and may boost screening rates across a variety of payers and providers, according to investigators.

Cost savings, when compared with mailing reminders alone, would be greatest from a Medicaid and state government perspective, reported lead author Stephanie B. Wheeler, PhD, MPH, of the University of North Carolina at Chapel Hill and colleagues.

“As payers and providers endeavor to increase the proportion of age-eligible adults who are up to date with CRC screening, according to the National Colorectal Cancer Roundtable target of 80% screened, understanding the comparative value of mailed FIT-based programs in low-income populations is urgently needed,” the investigators wrote in Cancer.

To address this need, Dr. Wheeler and colleagues coupled a randomized clinical trial with a cost-effectiveness analysis.

The trial involved 2,144 North Carolina Medicaid enrollees between 52 and 64 years of age who were overdue for CRC screening. Participants were randomly assigned to receive either a mailed reminder with an FIT kit or a mailed reminder alone. Those who received the reminder alone were provided with information about how to get an FIT kit or undergo screening colonoscopy.

The screening rate was significantly higher in the combination mailer group than it was the reminder-only group, at 21.1% versus 12.3% (P less than .01). Based on data from previous research, the investigators estimated that a number of participants also underwent colonoscopy screenings because of the reminders; this resulted in an estimated 23.3% screening rate among those who received an FIT kit, compared with 15.8% among those who received a reminder alone.

For cost analysis, these rates were entered into a model involving 35,000 Medicaid enrollees. Annual costs were compared from two perspectives: Medicaid/state and health clinic/facility, the latter of which included primary care providers, integrated health care systems, county health departments, and federally qualified health centers. The model incorporated a number of costs, such as those associated with equipment, mailing supplies, FIT kits, colonoscopy screenings, and personnel.

From a Medicaid/state perspective, the estimated total population screening cost of mailing both an FIT kit and reminder was $1.40 million, compared with $1.45 million for a reminder alone. This translated to a total cost per person screened of $172 for the combination mailer versus $262 for the reminder alone.

“Notably, compared with the reminder-only alternative, the reminder + FIT alternative was cost-saving or dominant from this perspective because it yielded more screenings at lower cost,” the investigators wrote.

The cost analysis from a health clinic/facility perspective was more nuanced.

While the estimated total population screening cost of a combination mailer was more than the reminder alone ($927,000 vs. $624,000), sending test kits led to screening of 2,598 additional individuals (8,131 vs. 5,533). The incremental cost-effectiveness ratio (ICER) for the combination mailer was $116 per person screened.

“This ICER fell within the range of what decision makers typically would be willing to pay for an additional person screened for CRC, previously shown to include ICERs as high as several hundred dollars or more,” the investigators noted.

According to Beverly B. Green, MD, MPH, of Kaiser Permanente Washington, Seattle, and Richard T. Meenan, PhD, MPH, of Kaiser Permanente Northwest, Portland, Oregon, who wrote a simultaneously published editorial, the study “suggests that direct FIT mailing can be highly cost effective if not cost saving within the Medicaid population, similar to tobacco-cessation programs or diabetes prevention programs in the same context of a Medicaid population.”

Still, practical details need to be resolved prior to real-world application, they added.

“[T]he analysis by Wheeler et al. raises an important question: Who should pay for mailed FIT screening programs?”

The answer, they suggested, may be health plans, since prevention of CRC could mitigate greater costs of care down the line. Further motivation could come from a program such as the Medicare 5-star program, which rewards higher screening rates with bonuses such as longer enrollment periods and higher payments, according to Dr. Green and Dr. Meenan.

“Unsurprisingly, Medicare CRC screening rates have been steadily increasing and now are approaching 80%,” they noted, “whereas Medicaid CRC screening rates remain low.”

The study was supported by the University of North Carolina, the Cancer Prevention and Control Research Network, the Centers for Disease Control and Prevention, and the National Cancer Institute. Dr. Wheeler reported grant funding from Pfizer.

SOURCE: Wheeler SB et al. Cancer. 2020 Jul 20. doi: 10.1002/cncr.32992.

Hemospray is highly effective for initial gastrointestinal hemostasis, but not long-term therapy, based on a recent meta-analysis.

Among 814 patients with GI bleeding who were treated with Hemospray, respective rates of clinical success and early rebleeding were 92% and 20%, reported lead author Andrew Ofosu, MD, of the Brooklyn Hospital Center, New York, and colleagues.

“Since its introduction, multiple studies have evaluated the efficacy of Hemospray for endoscopic hemostasis in a wide array of bleeding disorders in either the upper and/or lower GI tract,” the investigators wrote. Their report is in the Journal of Clinical Gastroenterology.

The present review and meta-analysis included 19 of those studies, including randomized controlled trials, case series, and case-control studies.

Of 814 adult patients, 212 were treated with Hemospray as monotherapy, while 602 were treated with Hemospray combined with conventional hemostatic techniques.

“Unlike conventional endoscopic methods currently in use to achieve immediate hemostasis in GI bleeding, Hemospray is noncontact, nonthermal, and nontraumatic,” the investigators noted.

Clinical success, defined by endoscopically observed initial hemostasis, was achieved in 91% of patients who were treated with Hemospray as monotherapy, a rate that did not significantly differ from the 93% success rate achieved by a combination approach.

Early rebleeding, defined by rebleeding within 7 days, was comparable between monotherapy (21%) and combination therapy (20%), a finding that was maintained in subgroup analysis. Similarly, no statistical difference was found between rates of rebleeding within 30 days, which were 22% and 24%, for monotherapy and combination therapy, respectively.

“Our study showed the rate of rebleeding increased with time after the application of Hemospray, likely due to the limited duration of action of the hemostatic powder at the site of bleeding,” wrote Dr. Ofosu and colleagues. “Second-look endoscopy performed in some studies has shown Hemospray is eliminated from the GI tract in as few as 24 hours after use, which potentially increases the risk of recurrent bleeding.”

The investigators suggested that Hemospray is best suited for short-term use because of the rebleeding risk.

“The use of Hemospray offers the potential to control bleeding initially and to optimize positioning or application of other modalities if needed in a more controlled setting,” concluded Dr. Ofosu and colleagues, who noted that this stance aligns with the views of other investigators.

Daljeet Chahal, MD and Fergal Donnellan, MD, of the University of British Columbia, Vancouver, are two such investigators, having just published a retrospective cohort study that involved 86 applications of Hemospray. Their study, which was not included in the present meta-analysis because of recency of publication, revealed that “Hemospray is effective in achieving immediate hemostasis but is plagued by high rates of rebleeding.”

According to Dr. Chahal and Dr. Donnellan, who provided a written comment, the findings of Dr. Ofosu and colleagues are comparable to their own, thereby supporting a similar conclusion.

“Hemospray appears more suited to emergent situations, where it should be used as a last resort; as a bridge therapy to more definitive measures such as embolization or surgery,” they wrote.

Dr. Chahal and Dr. Donnellan also suggested that more work is needed to develop a comprehensive picture of Hemospray outcomes, which could guide usage.

“The meta-analysis does not comment specifically on rates of embolization or surgery after Hemospray use, or whether these rates differ by type of lesion,” they wrote. “These would be interesting measures to explore in future studies to more concretely define appropriate indications for Hemospray use.”

Bilal Toka, MD, of Sakarya University in Serdivan, Turkey, who has previously published research comparing conventional hemostatic techniques, also provided a written comment, in which he advised clinicians to be ready for a combination approach, particularly among high-risk patients.

“This meta-analysis shows that Hemospray is very useful in providing initial hemostasis in patients with GI bleeding,” Dr. Toka wrote. “[However], due to its high early and delayed rebleeding rates, additional mechanical or thermal endoscopic treatment should be applied in high-risk lesions such as actively bleeding peptic ulcers.”

The investigators reported no conflicts of interest.

SOURCE: Ofosu A et al. J Clin Gastroenterol. 2020 Jul 3. doi: 10.1097/MCG.0000000000001379.

Hemospray is highly effective for initial gastrointestinal hemostasis, but not long-term therapy, based on a recent meta-analysis.

Among 814 patients with GI bleeding who were treated with Hemospray, respective rates of clinical success and early rebleeding were 92% and 20%, reported lead author Andrew Ofosu, MD, of the Brooklyn Hospital Center, New York, and colleagues.

“Since its introduction, multiple studies have evaluated the efficacy of Hemospray for endoscopic hemostasis in a wide array of bleeding disorders in either the upper and/or lower GI tract,” the investigators wrote. Their report is in the Journal of Clinical Gastroenterology.

The present review and meta-analysis included 19 of those studies, including randomized controlled trials, case series, and case-control studies.

Of 814 adult patients, 212 were treated with Hemospray as monotherapy, while 602 were treated with Hemospray combined with conventional hemostatic techniques.

“Unlike conventional endoscopic methods currently in use to achieve immediate hemostasis in GI bleeding, Hemospray is noncontact, nonthermal, and nontraumatic,” the investigators noted.

Clinical success, defined by endoscopically observed initial hemostasis, was achieved in 91% of patients who were treated with Hemospray as monotherapy, a rate that did not significantly differ from the 93% success rate achieved by a combination approach.

Early rebleeding, defined by rebleeding within 7 days, was comparable between monotherapy (21%) and combination therapy (20%), a finding that was maintained in subgroup analysis. Similarly, no statistical difference was found between rates of rebleeding within 30 days, which were 22% and 24%, for monotherapy and combination therapy, respectively.

“Our study showed the rate of rebleeding increased with time after the application of Hemospray, likely due to the limited duration of action of the hemostatic powder at the site of bleeding,” wrote Dr. Ofosu and colleagues. “Second-look endoscopy performed in some studies has shown Hemospray is eliminated from the GI tract in as few as 24 hours after use, which potentially increases the risk of recurrent bleeding.”

The investigators suggested that Hemospray is best suited for short-term use because of the rebleeding risk.

“The use of Hemospray offers the potential to control bleeding initially and to optimize positioning or application of other modalities if needed in a more controlled setting,” concluded Dr. Ofosu and colleagues, who noted that this stance aligns with the views of other investigators.

Daljeet Chahal, MD and Fergal Donnellan, MD, of the University of British Columbia, Vancouver, are two such investigators, having just published a retrospective cohort study that involved 86 applications of Hemospray. Their study, which was not included in the present meta-analysis because of recency of publication, revealed that “Hemospray is effective in achieving immediate hemostasis but is plagued by high rates of rebleeding.”

According to Dr. Chahal and Dr. Donnellan, who provided a written comment, the findings of Dr. Ofosu and colleagues are comparable to their own, thereby supporting a similar conclusion.

“Hemospray appears more suited to emergent situations, where it should be used as a last resort; as a bridge therapy to more definitive measures such as embolization or surgery,” they wrote.

Dr. Chahal and Dr. Donnellan also suggested that more work is needed to develop a comprehensive picture of Hemospray outcomes, which could guide usage.

“The meta-analysis does not comment specifically on rates of embolization or surgery after Hemospray use, or whether these rates differ by type of lesion,” they wrote. “These would be interesting measures to explore in future studies to more concretely define appropriate indications for Hemospray use.”

Bilal Toka, MD, of Sakarya University in Serdivan, Turkey, who has previously published research comparing conventional hemostatic techniques, also provided a written comment, in which he advised clinicians to be ready for a combination approach, particularly among high-risk patients.

“This meta-analysis shows that Hemospray is very useful in providing initial hemostasis in patients with GI bleeding,” Dr. Toka wrote. “[However], due to its high early and delayed rebleeding rates, additional mechanical or thermal endoscopic treatment should be applied in high-risk lesions such as actively bleeding peptic ulcers.”

The investigators reported no conflicts of interest.

SOURCE: Ofosu A et al. J Clin Gastroenterol. 2020 Jul 3. doi: 10.1097/MCG.0000000000001379.

Hemospray is highly effective for initial gastrointestinal hemostasis, but not long-term therapy, based on a recent meta-analysis.

Among 814 patients with GI bleeding who were treated with Hemospray, respective rates of clinical success and early rebleeding were 92% and 20%, reported lead author Andrew Ofosu, MD, of the Brooklyn Hospital Center, New York, and colleagues.

“Since its introduction, multiple studies have evaluated the efficacy of Hemospray for endoscopic hemostasis in a wide array of bleeding disorders in either the upper and/or lower GI tract,” the investigators wrote. Their report is in the Journal of Clinical Gastroenterology.

The present review and meta-analysis included 19 of those studies, including randomized controlled trials, case series, and case-control studies.

Of 814 adult patients, 212 were treated with Hemospray as monotherapy, while 602 were treated with Hemospray combined with conventional hemostatic techniques.

“Unlike conventional endoscopic methods currently in use to achieve immediate hemostasis in GI bleeding, Hemospray is noncontact, nonthermal, and nontraumatic,” the investigators noted.

Clinical success, defined by endoscopically observed initial hemostasis, was achieved in 91% of patients who were treated with Hemospray as monotherapy, a rate that did not significantly differ from the 93% success rate achieved by a combination approach.

Early rebleeding, defined by rebleeding within 7 days, was comparable between monotherapy (21%) and combination therapy (20%), a finding that was maintained in subgroup analysis. Similarly, no statistical difference was found between rates of rebleeding within 30 days, which were 22% and 24%, for monotherapy and combination therapy, respectively.

“Our study showed the rate of rebleeding increased with time after the application of Hemospray, likely due to the limited duration of action of the hemostatic powder at the site of bleeding,” wrote Dr. Ofosu and colleagues. “Second-look endoscopy performed in some studies has shown Hemospray is eliminated from the GI tract in as few as 24 hours after use, which potentially increases the risk of recurrent bleeding.”

The investigators suggested that Hemospray is best suited for short-term use because of the rebleeding risk.

“The use of Hemospray offers the potential to control bleeding initially and to optimize positioning or application of other modalities if needed in a more controlled setting,” concluded Dr. Ofosu and colleagues, who noted that this stance aligns with the views of other investigators.

Daljeet Chahal, MD and Fergal Donnellan, MD, of the University of British Columbia, Vancouver, are two such investigators, having just published a retrospective cohort study that involved 86 applications of Hemospray. Their study, which was not included in the present meta-analysis because of recency of publication, revealed that “Hemospray is effective in achieving immediate hemostasis but is plagued by high rates of rebleeding.”

According to Dr. Chahal and Dr. Donnellan, who provided a written comment, the findings of Dr. Ofosu and colleagues are comparable to their own, thereby supporting a similar conclusion.

“Hemospray appears more suited to emergent situations, where it should be used as a last resort; as a bridge therapy to more definitive measures such as embolization or surgery,” they wrote.

Dr. Chahal and Dr. Donnellan also suggested that more work is needed to develop a comprehensive picture of Hemospray outcomes, which could guide usage.

“The meta-analysis does not comment specifically on rates of embolization or surgery after Hemospray use, or whether these rates differ by type of lesion,” they wrote. “These would be interesting measures to explore in future studies to more concretely define appropriate indications for Hemospray use.”

Bilal Toka, MD, of Sakarya University in Serdivan, Turkey, who has previously published research comparing conventional hemostatic techniques, also provided a written comment, in which he advised clinicians to be ready for a combination approach, particularly among high-risk patients.

“This meta-analysis shows that Hemospray is very useful in providing initial hemostasis in patients with GI bleeding,” Dr. Toka wrote. “[However], due to its high early and delayed rebleeding rates, additional mechanical or thermal endoscopic treatment should be applied in high-risk lesions such as actively bleeding peptic ulcers.”

The investigators reported no conflicts of interest.

SOURCE: Ofosu A et al. J Clin Gastroenterol. 2020 Jul 3. doi: 10.1097/MCG.0000000000001379.

BRCA carrier status alone should not influence screening recommendations for colorectal cancer or pancreatic ductal adenocarcinoma, according to an American Gastroenterological Association clinical practice update.

Relationships between BRCA carrier status and risks of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) remain unclear, reported lead author Sonia S. Kupfer, MD, AGAF, of the University of Chicago, and colleagues.

“Pathogenic variants in BRCA1 and BRCA2 have ... been associated with variable risk of GI cancer, including CRC, PDAC, biliary, and gastric cancers,” the investigators wrote in Gastroenterology. “However, the magnitude of GI cancer risks is not well established and there is minimal evidence or guidance on screening for GI cancers among BRCA1 and BRCA2 carriers.”

According to the investigators, personalized screening for CRC is well supported by evidence, as higher-risk individuals, such as those with a family history of CRC, have been shown to benefit from earlier and more frequent colonoscopies. Although the value of risk-based screening is less clear for other types of GI cancer, the investigators cited a growing body of evidence that supports screening individuals at high risk of PDAC.

Still, data illuminating the role of BRCA carrier status are relatively scarce, which has led to variability in clinical practice.

“Lack of accurate CRC and PDAC risk estimates in BRCA1 and BRCA2 leave physicians and patients without guidance, and result in a range of screening recommendations and practices in this population,” wrote Dr. Kupfer and colleagues.

To offer some clarity, they drafted the present clinical practice update on behalf of the AGA. The recommendations are framed within a discussion of relevant publications.

Data from multiple studies, for instance, suggest that BRCA pathogenic variants are found in 1.3% of patients with early-onset CRC, 0.2% of those with high-risk CRC, and 1.0% of those with any type of CRC, all of which are higher rates “than would be expected by chance.

“However,” the investigators added, “this association is not proof that the observed BRCA1 and BRCA2 pathogenic variants play a causative role in CRC.”

The investigators went on to discuss a 2018 meta-analysis by Oho et al., which included 14 studies evaluating risk of CRC among BRCA carriers. The analysis found that BRCA carriers had a 24% increased risk of CRC, which Dr. Kupfer and colleagues described as “small but statistically significant.” Subgroup analysis suggested that BRCA1 carriers drove this association, with a 49% increased risk of CRC, whereas no significant link was found with BRCA2.

Dr. Kupfer and colleagues described the 49% increase as “very modest,” and therefore insufficient to warrant more intensive screening, particularly when considered in the context of other risk factors, such as Lynch syndrome, which may entail a 1,600% increased risk of CRC. For PDAC, no such meta-analysis has been conducted; however, multiple studies have pointed to associations between BRCA and risk of PDAC.

For example, a 2018 case-control study by Hu et al. showed that BRCA1 and BRCA2 had relative prevalence rates of 0.59% and 1.95% among patients with PDAC. These rates translated to a 158% increased risk of PDAC for BRCA1, and a 520% increase risk for BRCA2; but Dr. Kupfer and colleagues noted that the BRCA2 carriers were from high-risk families, so the findings may not extend to the general population.

In light of these findings, the update recommends PDAC screening for BRCA carriers only if they have a family history of PDAC, with the caveat that the association between risk and degree of family involvement remains unknown.

Ultimately, for both CRC and PDAC, the investigators called for further BRCA research, based on the conclusion that “results from published studies provide inconsistent levels of evidence.”

The investigators reported no conflicts of interest.

SOURCE: Kupfer SS et al. Gastroenterology. 2020 Apr 23. doi: 10.1053/j.gastro.2020.03.086.

BRCA carrier status alone should not influence screening recommendations for colorectal cancer or pancreatic ductal adenocarcinoma, according to an American Gastroenterological Association clinical practice update.

Relationships between BRCA carrier status and risks of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) remain unclear, reported lead author Sonia S. Kupfer, MD, AGAF, of the University of Chicago, and colleagues.

“Pathogenic variants in BRCA1 and BRCA2 have ... been associated with variable risk of GI cancer, including CRC, PDAC, biliary, and gastric cancers,” the investigators wrote in Gastroenterology. “However, the magnitude of GI cancer risks is not well established and there is minimal evidence or guidance on screening for GI cancers among BRCA1 and BRCA2 carriers.”

According to the investigators, personalized screening for CRC is well supported by evidence, as higher-risk individuals, such as those with a family history of CRC, have been shown to benefit from earlier and more frequent colonoscopies. Although the value of risk-based screening is less clear for other types of GI cancer, the investigators cited a growing body of evidence that supports screening individuals at high risk of PDAC.

Still, data illuminating the role of BRCA carrier status are relatively scarce, which has led to variability in clinical practice.

“Lack of accurate CRC and PDAC risk estimates in BRCA1 and BRCA2 leave physicians and patients without guidance, and result in a range of screening recommendations and practices in this population,” wrote Dr. Kupfer and colleagues.

To offer some clarity, they drafted the present clinical practice update on behalf of the AGA. The recommendations are framed within a discussion of relevant publications.

Data from multiple studies, for instance, suggest that BRCA pathogenic variants are found in 1.3% of patients with early-onset CRC, 0.2% of those with high-risk CRC, and 1.0% of those with any type of CRC, all of which are higher rates “than would be expected by chance.

“However,” the investigators added, “this association is not proof that the observed BRCA1 and BRCA2 pathogenic variants play a causative role in CRC.”

The investigators went on to discuss a 2018 meta-analysis by Oho et al., which included 14 studies evaluating risk of CRC among BRCA carriers. The analysis found that BRCA carriers had a 24% increased risk of CRC, which Dr. Kupfer and colleagues described as “small but statistically significant.” Subgroup analysis suggested that BRCA1 carriers drove this association, with a 49% increased risk of CRC, whereas no significant link was found with BRCA2.

Dr. Kupfer and colleagues described the 49% increase as “very modest,” and therefore insufficient to warrant more intensive screening, particularly when considered in the context of other risk factors, such as Lynch syndrome, which may entail a 1,600% increased risk of CRC. For PDAC, no such meta-analysis has been conducted; however, multiple studies have pointed to associations between BRCA and risk of PDAC.

For example, a 2018 case-control study by Hu et al. showed that BRCA1 and BRCA2 had relative prevalence rates of 0.59% and 1.95% among patients with PDAC. These rates translated to a 158% increased risk of PDAC for BRCA1, and a 520% increase risk for BRCA2; but Dr. Kupfer and colleagues noted that the BRCA2 carriers were from high-risk families, so the findings may not extend to the general population.

In light of these findings, the update recommends PDAC screening for BRCA carriers only if they have a family history of PDAC, with the caveat that the association between risk and degree of family involvement remains unknown.

Ultimately, for both CRC and PDAC, the investigators called for further BRCA research, based on the conclusion that “results from published studies provide inconsistent levels of evidence.”

The investigators reported no conflicts of interest.

SOURCE: Kupfer SS et al. Gastroenterology. 2020 Apr 23. doi: 10.1053/j.gastro.2020.03.086.

BRCA carrier status alone should not influence screening recommendations for colorectal cancer or pancreatic ductal adenocarcinoma, according to an American Gastroenterological Association clinical practice update.

Relationships between BRCA carrier status and risks of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) remain unclear, reported lead author Sonia S. Kupfer, MD, AGAF, of the University of Chicago, and colleagues.

“Pathogenic variants in BRCA1 and BRCA2 have ... been associated with variable risk of GI cancer, including CRC, PDAC, biliary, and gastric cancers,” the investigators wrote in Gastroenterology. “However, the magnitude of GI cancer risks is not well established and there is minimal evidence or guidance on screening for GI cancers among BRCA1 and BRCA2 carriers.”

According to the investigators, personalized screening for CRC is well supported by evidence, as higher-risk individuals, such as those with a family history of CRC, have been shown to benefit from earlier and more frequent colonoscopies. Although the value of risk-based screening is less clear for other types of GI cancer, the investigators cited a growing body of evidence that supports screening individuals at high risk of PDAC.

Still, data illuminating the role of BRCA carrier status are relatively scarce, which has led to variability in clinical practice.

“Lack of accurate CRC and PDAC risk estimates in BRCA1 and BRCA2 leave physicians and patients without guidance, and result in a range of screening recommendations and practices in this population,” wrote Dr. Kupfer and colleagues.

To offer some clarity, they drafted the present clinical practice update on behalf of the AGA. The recommendations are framed within a discussion of relevant publications.

Data from multiple studies, for instance, suggest that BRCA pathogenic variants are found in 1.3% of patients with early-onset CRC, 0.2% of those with high-risk CRC, and 1.0% of those with any type of CRC, all of which are higher rates “than would be expected by chance.

“However,” the investigators added, “this association is not proof that the observed BRCA1 and BRCA2 pathogenic variants play a causative role in CRC.”

The investigators went on to discuss a 2018 meta-analysis by Oho et al., which included 14 studies evaluating risk of CRC among BRCA carriers. The analysis found that BRCA carriers had a 24% increased risk of CRC, which Dr. Kupfer and colleagues described as “small but statistically significant.” Subgroup analysis suggested that BRCA1 carriers drove this association, with a 49% increased risk of CRC, whereas no significant link was found with BRCA2.

Dr. Kupfer and colleagues described the 49% increase as “very modest,” and therefore insufficient to warrant more intensive screening, particularly when considered in the context of other risk factors, such as Lynch syndrome, which may entail a 1,600% increased risk of CRC. For PDAC, no such meta-analysis has been conducted; however, multiple studies have pointed to associations between BRCA and risk of PDAC.

For example, a 2018 case-control study by Hu et al. showed that BRCA1 and BRCA2 had relative prevalence rates of 0.59% and 1.95% among patients with PDAC. These rates translated to a 158% increased risk of PDAC for BRCA1, and a 520% increase risk for BRCA2; but Dr. Kupfer and colleagues noted that the BRCA2 carriers were from high-risk families, so the findings may not extend to the general population.

In light of these findings, the update recommends PDAC screening for BRCA carriers only if they have a family history of PDAC, with the caveat that the association between risk and degree of family involvement remains unknown.

Ultimately, for both CRC and PDAC, the investigators called for further BRCA research, based on the conclusion that “results from published studies provide inconsistent levels of evidence.”

The investigators reported no conflicts of interest.

SOURCE: Kupfer SS et al. Gastroenterology. 2020 Apr 23. doi: 10.1053/j.gastro.2020.03.086.

The role of probiotics in the management of gastrointestinal disorders remains largely unclear, according to a clinical practice guideline published by the American Gastroenterological Association (AGA).

Out of eight disorders reviewed by the guideline panel, four had enough relevant data to support conditional recommendations, while the other four were associated with knowledge gaps that precluded guidance, reported lead author Grace L. Su, MD, AGAF, of the University of Michigan, Ann Arbor, and colleagues.

“It is estimated that 3.9 million American adults used some form of probiotics or prebiotics ... in 2015, an amount which is four times that in 2007,” the guideline panelists wrote. Their report is in Gastroenterology. “Given widespread use and often biased sources of information, it is essential that clinicians have objective guidance for their patients about the appropriate use of and indications for probiotics.”

The creation of such guidance, however, proved a challenging task for the panel, who faced an “extremely varied” evidence base.

Dr. Su and colleagues, who were selected by the AGA Governing Board and Clinical Guidelines Committee, encountered “differences in the strain of microbe(s) used, dose, and route of administration.”

They noted that such differences can significantly affect clinical outcomes.

“Within species, different strains can have widely different activities and biologic effects,” they wrote. “Many immunologic, neurologic, and biochemical effects of gut microbiota are likely not only to be strain specific, but also dose specific. Furthermore, combinations of different microbial strains may also have widely different activity as some microbial activities are dependent on interactions between different strains.”

Beyond differences in treatments, the investigators also reported wide variability in endpoints and outcomes, as well as relatively small study populations compared with pharmacological trials.

Still, data were sufficient to provide some conditional recommendations.

The guideline supports probiotics for patients with pouchitis, those receiving antibiotic therapy, and preterm/low-birthweight infants. In contrast, the panel recommended against probiotics for children with acute infectious gastroenteritis, noting that this recommendation differs from those made by other medical organizations.

“While other society guidelines have previously recommended the use of probiotics in [children with acute infectious gastroenteritis], these guidelines were developed without utilizing GRADE methodology and also relied on data outside of North America which became available after the recommendations were made,” wrote Dr. Su and colleagues. They described a moderate quality of evidence relevant to this indication.

In comparison, the quality of evidence was very low for patients with pouchitis, low for those receiving antibiotics, and moderate/high for preterm/low-birthweight infants.

For Clostridioides difficile infection, Crohn’s disease, ulcerative colitis, and irritable bowel syndrome, the panel recommended probiotics only in the context of a clinical trial, citing knowledge gaps in these areas.

They also noted that probiotics may not be suitable for those at high risk of infection.

“[F]or patients who place a high value on avoidance of potential harms, particularly those with severe illnesses or immunosuppression, it would be reasonable to select not to use probiotics,” the panelists wrote.

Concluding their discussion, Dr. Su and colleagues called for more high-quality research.

“We identified that significant knowledge gaps exist in this very promising and important area of research due to the significant heterogeneity between studies and variability in the probiotic strains studied,” they wrote. “The lack of consistent harms reporting makes it difficult to assess true harms. The lack of product manufacturing details prohibits true comparisons and decreases the feasibility of obtaining certain products by patients. Future high-quality studies are urgently needed which address these pitfalls.”

According to the panelists, the probiotic guideline will be updated in 3-5 years, or possibly earlier if practice-altering findings are published.

The investigators disclosed relationships with Nestex, AbbVie, Takeda, and others.

The role of probiotics in the management of gastrointestinal disorders remains largely unclear, according to a clinical practice guideline published by the American Gastroenterological Association (AGA).

Out of eight disorders reviewed by the guideline panel, four had enough relevant data to support conditional recommendations, while the other four were associated with knowledge gaps that precluded guidance, reported lead author Grace L. Su, MD, AGAF, of the University of Michigan, Ann Arbor, and colleagues.

“It is estimated that 3.9 million American adults used some form of probiotics or prebiotics ... in 2015, an amount which is four times that in 2007,” the guideline panelists wrote. Their report is in Gastroenterology. “Given widespread use and often biased sources of information, it is essential that clinicians have objective guidance for their patients about the appropriate use of and indications for probiotics.”

The creation of such guidance, however, proved a challenging task for the panel, who faced an “extremely varied” evidence base.

Dr. Su and colleagues, who were selected by the AGA Governing Board and Clinical Guidelines Committee, encountered “differences in the strain of microbe(s) used, dose, and route of administration.”

They noted that such differences can significantly affect clinical outcomes.

“Within species, different strains can have widely different activities and biologic effects,” they wrote. “Many immunologic, neurologic, and biochemical effects of gut microbiota are likely not only to be strain specific, but also dose specific. Furthermore, combinations of different microbial strains may also have widely different activity as some microbial activities are dependent on interactions between different strains.”

Beyond differences in treatments, the investigators also reported wide variability in endpoints and outcomes, as well as relatively small study populations compared with pharmacological trials.

Still, data were sufficient to provide some conditional recommendations.

The guideline supports probiotics for patients with pouchitis, those receiving antibiotic therapy, and preterm/low-birthweight infants. In contrast, the panel recommended against probiotics for children with acute infectious gastroenteritis, noting that this recommendation differs from those made by other medical organizations.

“While other society guidelines have previously recommended the use of probiotics in [children with acute infectious gastroenteritis], these guidelines were developed without utilizing GRADE methodology and also relied on data outside of North America which became available after the recommendations were made,” wrote Dr. Su and colleagues. They described a moderate quality of evidence relevant to this indication.

In comparison, the quality of evidence was very low for patients with pouchitis, low for those receiving antibiotics, and moderate/high for preterm/low-birthweight infants.

For Clostridioides difficile infection, Crohn’s disease, ulcerative colitis, and irritable bowel syndrome, the panel recommended probiotics only in the context of a clinical trial, citing knowledge gaps in these areas.

They also noted that probiotics may not be suitable for those at high risk of infection.

“[F]or patients who place a high value on avoidance of potential harms, particularly those with severe illnesses or immunosuppression, it would be reasonable to select not to use probiotics,” the panelists wrote.

Concluding their discussion, Dr. Su and colleagues called for more high-quality research.

“We identified that significant knowledge gaps exist in this very promising and important area of research due to the significant heterogeneity between studies and variability in the probiotic strains studied,” they wrote. “The lack of consistent harms reporting makes it difficult to assess true harms. The lack of product manufacturing details prohibits true comparisons and decreases the feasibility of obtaining certain products by patients. Future high-quality studies are urgently needed which address these pitfalls.”

According to the panelists, the probiotic guideline will be updated in 3-5 years, or possibly earlier if practice-altering findings are published.

The investigators disclosed relationships with Nestex, AbbVie, Takeda, and others.

The role of probiotics in the management of gastrointestinal disorders remains largely unclear, according to a clinical practice guideline published by the American Gastroenterological Association (AGA).

Out of eight disorders reviewed by the guideline panel, four had enough relevant data to support conditional recommendations, while the other four were associated with knowledge gaps that precluded guidance, reported lead author Grace L. Su, MD, AGAF, of the University of Michigan, Ann Arbor, and colleagues.

“It is estimated that 3.9 million American adults used some form of probiotics or prebiotics ... in 2015, an amount which is four times that in 2007,” the guideline panelists wrote. Their report is in Gastroenterology. “Given widespread use and often biased sources of information, it is essential that clinicians have objective guidance for their patients about the appropriate use of and indications for probiotics.”

The creation of such guidance, however, proved a challenging task for the panel, who faced an “extremely varied” evidence base.

Dr. Su and colleagues, who were selected by the AGA Governing Board and Clinical Guidelines Committee, encountered “differences in the strain of microbe(s) used, dose, and route of administration.”

They noted that such differences can significantly affect clinical outcomes.

“Within species, different strains can have widely different activities and biologic effects,” they wrote. “Many immunologic, neurologic, and biochemical effects of gut microbiota are likely not only to be strain specific, but also dose specific. Furthermore, combinations of different microbial strains may also have widely different activity as some microbial activities are dependent on interactions between different strains.”

Beyond differences in treatments, the investigators also reported wide variability in endpoints and outcomes, as well as relatively small study populations compared with pharmacological trials.

Still, data were sufficient to provide some conditional recommendations.

The guideline supports probiotics for patients with pouchitis, those receiving antibiotic therapy, and preterm/low-birthweight infants. In contrast, the panel recommended against probiotics for children with acute infectious gastroenteritis, noting that this recommendation differs from those made by other medical organizations.

“While other society guidelines have previously recommended the use of probiotics in [children with acute infectious gastroenteritis], these guidelines were developed without utilizing GRADE methodology and also relied on data outside of North America which became available after the recommendations were made,” wrote Dr. Su and colleagues. They described a moderate quality of evidence relevant to this indication.

In comparison, the quality of evidence was very low for patients with pouchitis, low for those receiving antibiotics, and moderate/high for preterm/low-birthweight infants.

For Clostridioides difficile infection, Crohn’s disease, ulcerative colitis, and irritable bowel syndrome, the panel recommended probiotics only in the context of a clinical trial, citing knowledge gaps in these areas.

They also noted that probiotics may not be suitable for those at high risk of infection.

“[F]or patients who place a high value on avoidance of potential harms, particularly those with severe illnesses or immunosuppression, it would be reasonable to select not to use probiotics,” the panelists wrote.

Concluding their discussion, Dr. Su and colleagues called for more high-quality research.

“We identified that significant knowledge gaps exist in this very promising and important area of research due to the significant heterogeneity between studies and variability in the probiotic strains studied,” they wrote. “The lack of consistent harms reporting makes it difficult to assess true harms. The lack of product manufacturing details prohibits true comparisons and decreases the feasibility of obtaining certain products by patients. Future high-quality studies are urgently needed which address these pitfalls.”

According to the panelists, the probiotic guideline will be updated in 3-5 years, or possibly earlier if practice-altering findings are published.

The investigators disclosed relationships with Nestex, AbbVie, Takeda, and others.

The American Gastroenterological Association has released a new guideline for consultative management of patients with COVID-19.

The recommendations, which were written by Shahnaz Sultan, MD, AGAF, chair of the AGA Clinical Guidelines Committee, of the University of Minnesota, Minneapolis, and colleagues, were based on a meta-analysis of data from 47 studies involving 10,890 unique patients.

“We seek to summarize international data on the GI and liver manifestations of COVID-19 infection and treatment,” the panelists wrote in Gastroenterology. “Additionally, this document provides evidence-based clinical guidance on clinical questions that gastroenterologists may be consulted for.”

The guideline includes seven best practice statements.

The first three statements relate to COVID-19–related GI symptoms, which are estimated to occur in less than 10% of patients, and rarely in the absence of other COVID-19–related symptoms, according to Dr. Sultan and her copanelists.

“The overall prevalence of GI symptoms in the context of COVID-19, including nausea, vomiting, abdominal pain, and diarrhea, is lower than estimated previously,” the panelists wrote, referencing a previous meta-analysis by Ka Shing Cheung, MBBS, and colleagues that showed a prevalence of 17.6%.

“It is important to note that the majority of studies were focused on hospitalized patients with COVID-19, and the prevalence of diarrhea in patients with mild symptoms who were not hospitalized is not known.”

Since GI issues may precede other symptoms of COVID-19, the guideline recommends questioning outpatients with new-onset GI symptoms about other symptoms of COVID-19, with viral testing recommended in areas of high prevalence. Conversely, the panelists recommended that patients with suspected or known COVID-19 should undergo thorough history taking for GI symptoms, “including onset, characteristics, duration, and severity.”

The fourth practice statement advises against COVID-19 stool testing in routine clinical practice, either for diagnostic or monitoring purposes.

Although Dr. Cheung and colleagues reported that 48.1% of fecal specimens from patients with COVID-19 contained viral RNA, the panelists concluded that the practical relevance of this finding remains unknown.

“Stool infectivity and transmission have not been confirmed,” the panelists wrote, citing a lack of evidence and conflicting findings.

The final three practice statements address liver concerns.

First, any patient with suspected or confirmed COVID-19 who has elevated liver function tests should be evaluated for alternative etiologies. Second, hospitalized patients with suspected or confirmed COVID-19 should undergo baseline liver function testing, followed by liver monitoring throughout their stay, “particularly in the context of drug treatment for COVID-19.” And third, any patient receiving drugs to treat COVID-19 should be monitored for treatment-related hepatic and GI adverse effects.

Dr. Sultan and colleagues found that approximately 15% of patients with COVID-19 included in their meta-analysis had abnormal liver function tests, more often because of secondary effects rather than virally induced liver injury.

Although liver function test abnormalities were inconsistently reported across studies, and when available, often lacked relevant contextual data, such as information about underlying liver disease, published data suggest that abnormal liver values could predict more severe COVID-19, supporting baseline and serial liver testing, the panelists wrote.

Following these recommendations, the guideline includes a discussion of GI and hepatic adverse effects related to specific COVID-19 treatments.

According to the panelists, chloroquine and hydroxychloroquine may infrequently lead to GI disturbances, and rarely, liver injury, with the latter thought to be a sequela of a hypersensitivity reaction; among antiviral medications, lopinavir/ritonavir and favipiravir may cause GI adverse effects in approximately 5%-15% of patients, with potentially higher rates in children and those receiving higher doses.

“In particular, GI adverse events are poorly understood for both favipiravir and remdesivir,” the panelists wrote.

Hepatic adverse effects, ranging from mild elevations in aminotransferases to acute liver failure, have been documented, albeit rarely, among patients receiving lopinavir/ritonavir, according to the panelists. For remdesivir, liver injury has also been reported, although frequency is unknown, and for favipiravir, hepatic adverse events may be seen in 3% of patients, although, again, the panelists noted a scarcity of relevant findings.

In their concluding remarks, Dr. Sultan and colleagues called for more high-quality data, and encouraged clinicians to contribute to international registries, as these could help guide COVID-19 recommendations for patient subgroups.

The article was funded by the American Gastroenterological Association Institute.

SOURCE: Sultan S et al. Gastroenterology. 2020 May 11. doi: 10.1053/j.gastro.2020.05.001.

The American Gastroenterological Association has released a new guideline for consultative management of patients with COVID-19.

The recommendations, which were written by Shahnaz Sultan, MD, AGAF, chair of the AGA Clinical Guidelines Committee, of the University of Minnesota, Minneapolis, and colleagues, were based on a meta-analysis of data from 47 studies involving 10,890 unique patients.

“We seek to summarize international data on the GI and liver manifestations of COVID-19 infection and treatment,” the panelists wrote in Gastroenterology. “Additionally, this document provides evidence-based clinical guidance on clinical questions that gastroenterologists may be consulted for.”

The guideline includes seven best practice statements.

The first three statements relate to COVID-19–related GI symptoms, which are estimated to occur in less than 10% of patients, and rarely in the absence of other COVID-19–related symptoms, according to Dr. Sultan and her copanelists.

“The overall prevalence of GI symptoms in the context of COVID-19, including nausea, vomiting, abdominal pain, and diarrhea, is lower than estimated previously,” the panelists wrote, referencing a previous meta-analysis by Ka Shing Cheung, MBBS, and colleagues that showed a prevalence of 17.6%.

“It is important to note that the majority of studies were focused on hospitalized patients with COVID-19, and the prevalence of diarrhea in patients with mild symptoms who were not hospitalized is not known.”

Since GI issues may precede other symptoms of COVID-19, the guideline recommends questioning outpatients with new-onset GI symptoms about other symptoms of COVID-19, with viral testing recommended in areas of high prevalence. Conversely, the panelists recommended that patients with suspected or known COVID-19 should undergo thorough history taking for GI symptoms, “including onset, characteristics, duration, and severity.”

The fourth practice statement advises against COVID-19 stool testing in routine clinical practice, either for diagnostic or monitoring purposes.

Although Dr. Cheung and colleagues reported that 48.1% of fecal specimens from patients with COVID-19 contained viral RNA, the panelists concluded that the practical relevance of this finding remains unknown.

“Stool infectivity and transmission have not been confirmed,” the panelists wrote, citing a lack of evidence and conflicting findings.

The final three practice statements address liver concerns.

First, any patient with suspected or confirmed COVID-19 who has elevated liver function tests should be evaluated for alternative etiologies. Second, hospitalized patients with suspected or confirmed COVID-19 should undergo baseline liver function testing, followed by liver monitoring throughout their stay, “particularly in the context of drug treatment for COVID-19.” And third, any patient receiving drugs to treat COVID-19 should be monitored for treatment-related hepatic and GI adverse effects.

Dr. Sultan and colleagues found that approximately 15% of patients with COVID-19 included in their meta-analysis had abnormal liver function tests, more often because of secondary effects rather than virally induced liver injury.

Although liver function test abnormalities were inconsistently reported across studies, and when available, often lacked relevant contextual data, such as information about underlying liver disease, published data suggest that abnormal liver values could predict more severe COVID-19, supporting baseline and serial liver testing, the panelists wrote.

Following these recommendations, the guideline includes a discussion of GI and hepatic adverse effects related to specific COVID-19 treatments.

According to the panelists, chloroquine and hydroxychloroquine may infrequently lead to GI disturbances, and rarely, liver injury, with the latter thought to be a sequela of a hypersensitivity reaction; among antiviral medications, lopinavir/ritonavir and favipiravir may cause GI adverse effects in approximately 5%-15% of patients, with potentially higher rates in children and those receiving higher doses.

“In particular, GI adverse events are poorly understood for both favipiravir and remdesivir,” the panelists wrote.

Hepatic adverse effects, ranging from mild elevations in aminotransferases to acute liver failure, have been documented, albeit rarely, among patients receiving lopinavir/ritonavir, according to the panelists. For remdesivir, liver injury has also been reported, although frequency is unknown, and for favipiravir, hepatic adverse events may be seen in 3% of patients, although, again, the panelists noted a scarcity of relevant findings.

In their concluding remarks, Dr. Sultan and colleagues called for more high-quality data, and encouraged clinicians to contribute to international registries, as these could help guide COVID-19 recommendations for patient subgroups.

The article was funded by the American Gastroenterological Association Institute.

SOURCE: Sultan S et al. Gastroenterology. 2020 May 11. doi: 10.1053/j.gastro.2020.05.001.

The American Gastroenterological Association has released a new guideline for consultative management of patients with COVID-19.

The recommendations, which were written by Shahnaz Sultan, MD, AGAF, chair of the AGA Clinical Guidelines Committee, of the University of Minnesota, Minneapolis, and colleagues, were based on a meta-analysis of data from 47 studies involving 10,890 unique patients.

“We seek to summarize international data on the GI and liver manifestations of COVID-19 infection and treatment,” the panelists wrote in Gastroenterology. “Additionally, this document provides evidence-based clinical guidance on clinical questions that gastroenterologists may be consulted for.”

The guideline includes seven best practice statements.

The first three statements relate to COVID-19–related GI symptoms, which are estimated to occur in less than 10% of patients, and rarely in the absence of other COVID-19–related symptoms, according to Dr. Sultan and her copanelists.

“The overall prevalence of GI symptoms in the context of COVID-19, including nausea, vomiting, abdominal pain, and diarrhea, is lower than estimated previously,” the panelists wrote, referencing a previous meta-analysis by Ka Shing Cheung, MBBS, and colleagues that showed a prevalence of 17.6%.

“It is important to note that the majority of studies were focused on hospitalized patients with COVID-19, and the prevalence of diarrhea in patients with mild symptoms who were not hospitalized is not known.”

Since GI issues may precede other symptoms of COVID-19, the guideline recommends questioning outpatients with new-onset GI symptoms about other symptoms of COVID-19, with viral testing recommended in areas of high prevalence. Conversely, the panelists recommended that patients with suspected or known COVID-19 should undergo thorough history taking for GI symptoms, “including onset, characteristics, duration, and severity.”

The fourth practice statement advises against COVID-19 stool testing in routine clinical practice, either for diagnostic or monitoring purposes.

Although Dr. Cheung and colleagues reported that 48.1% of fecal specimens from patients with COVID-19 contained viral RNA, the panelists concluded that the practical relevance of this finding remains unknown.

“Stool infectivity and transmission have not been confirmed,” the panelists wrote, citing a lack of evidence and conflicting findings.

The final three practice statements address liver concerns.

First, any patient with suspected or confirmed COVID-19 who has elevated liver function tests should be evaluated for alternative etiologies. Second, hospitalized patients with suspected or confirmed COVID-19 should undergo baseline liver function testing, followed by liver monitoring throughout their stay, “particularly in the context of drug treatment for COVID-19.” And third, any patient receiving drugs to treat COVID-19 should be monitored for treatment-related hepatic and GI adverse effects.

Dr. Sultan and colleagues found that approximately 15% of patients with COVID-19 included in their meta-analysis had abnormal liver function tests, more often because of secondary effects rather than virally induced liver injury.

Although liver function test abnormalities were inconsistently reported across studies, and when available, often lacked relevant contextual data, such as information about underlying liver disease, published data suggest that abnormal liver values could predict more severe COVID-19, supporting baseline and serial liver testing, the panelists wrote.

Following these recommendations, the guideline includes a discussion of GI and hepatic adverse effects related to specific COVID-19 treatments.

According to the panelists, chloroquine and hydroxychloroquine may infrequently lead to GI disturbances, and rarely, liver injury, with the latter thought to be a sequela of a hypersensitivity reaction; among antiviral medications, lopinavir/ritonavir and favipiravir may cause GI adverse effects in approximately 5%-15% of patients, with potentially higher rates in children and those receiving higher doses.

“In particular, GI adverse events are poorly understood for both favipiravir and remdesivir,” the panelists wrote.

Hepatic adverse effects, ranging from mild elevations in aminotransferases to acute liver failure, have been documented, albeit rarely, among patients receiving lopinavir/ritonavir, according to the panelists. For remdesivir, liver injury has also been reported, although frequency is unknown, and for favipiravir, hepatic adverse events may be seen in 3% of patients, although, again, the panelists noted a scarcity of relevant findings.

In their concluding remarks, Dr. Sultan and colleagues called for more high-quality data, and encouraged clinicians to contribute to international registries, as these could help guide COVID-19 recommendations for patient subgroups.

The article was funded by the American Gastroenterological Association Institute.

SOURCE: Sultan S et al. Gastroenterology. 2020 May 11. doi: 10.1053/j.gastro.2020.05.001.

Endoscopic full-thickness resection (eFTR) of complex colorectal lesions appears safe and effective, based on prospective data from 20 Dutch hospitals.

Macroscopic complete en bloc resection was achieved in 83.9% of procedures with an adverse event rate of 9.3%, reported lead author Liselotte W. Zwager, a PhD candidate at the University of Amsterdam, and colleagues.

“With the advantage of enabling a transmural resection, eFTR offers an alternative to radical surgery in lesions considered incurable with current resection techniques such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD),” the investigators wrote in Endoscopy.

But more data are needed for widespread adoption, they noted. “Several studies have reported encouraging results on the short-term safety and efficacy of eFTR for numerous indications. However, firm conclusions on clinical results will require analysis of large prospective series of patients in everyday clinical practice.”

The present study provided data from 362 patients who underwent 367 procedures at 5 academic and 15 nonacademic centers in the Netherlands.

Patients were eligible for eFTR if polyps were nonlifting or in difficult-to-reach locations, or if T1 colorectal cancer (CRC) was suspected. In addition, eFTR was performed for subepithelial tumors, and as secondary completion treatment after incomplete endoscopic resection of T1 CRC with a positive or nonassessable resection margin. Lesions greater than 30 mm were excluded because of device diameter constraints.

The primary outcome was macroscopic complete en bloc resection. Secondary outcomes included adverse events, full-thickness resection rate, and clinical success, the latter of which was defined by tumor-free resection margins (R0).

Out of 367 procedures, eFTR was most frequently conducted because of incomplete resection of T1 CRC (41%), followed by nonlifting or difficult-to-reach polyps (36%), suspected T1 CRC (19%), and least often, subepithelial tumors (4%).

Complete en bloc resection was achieved in 83.9% of procedures. Excluding 21 procedures in which eFTR was not performed because of inaccessibility of the lesion (n = 7) or immobility of tissue prohibiting retraction of the lesion into the cap (n = 14), R0 was achieved in 82.4% of cases. Among the same group, full-thickness resection rate was comparable, at 83.2%.

Adverse events occurred in 34 patients (9.3%), among whom 10 (2.7%) underwent emergency surgery for perforations or appendicitis.

“In conclusion,” the investigators wrote, “eFTR is an exciting, innovative resection technique that is clinically feasible and safe for complex colorectal lesions, with the potential to obviate the need for surgical resection. Further efficacy studies on eFTR as a primary and secondary treatment option for T1 CRC are needed, focusing on both the short- and long-term oncologic results.”

Peter V. Draganov, MD, of the University of Florida, Gainesville, called the R0 resection rate “respectable,” and suggested that the study “reconfirms on a larger scale that eFTR with the full-thickness resection device is successful in the majority of cases.”

“The full-thickness resection device expands our armamentarium to remove difficult polyps and early CRC,” he said.

Still, Dr. Draganov, who has previously advised careful patient selection for eFTR, noted certain drawbacks of the technique. “The presented data highlight some of the limitations of the full-thickness resection device, including the relatively small size of the lesion [median diameter, 23 mm] that can be resected, and challenges related to accessing and capturing the lesion due to the limited visibility and maneuverability of the device.”

Ultimately, Dr. Draganov supported the investigators’ call for more data. “Before eFTR becomes a primary modality for management of T1 CRC, we do need follow-up data on long-term cancer-related outcomes,” he said.

The study was supported by Ovesco Endoscopy. The investigators disclosed additional relationships with Cook, Ethicon, Olympus, and others.

SOURCE: Zwager LW et al. Endoscopy. 2020 Jun 4. doi: 10.1055/a-1176-1107.

Endoscopic full-thickness resection (eFTR) of complex colorectal lesions appears safe and effective, based on prospective data from 20 Dutch hospitals.

Macroscopic complete en bloc resection was achieved in 83.9% of procedures with an adverse event rate of 9.3%, reported lead author Liselotte W. Zwager, a PhD candidate at the University of Amsterdam, and colleagues.

“With the advantage of enabling a transmural resection, eFTR offers an alternative to radical surgery in lesions considered incurable with current resection techniques such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD),” the investigators wrote in Endoscopy.

But more data are needed for widespread adoption, they noted. “Several studies have reported encouraging results on the short-term safety and efficacy of eFTR for numerous indications. However, firm conclusions on clinical results will require analysis of large prospective series of patients in everyday clinical practice.”

The present study provided data from 362 patients who underwent 367 procedures at 5 academic and 15 nonacademic centers in the Netherlands.

Patients were eligible for eFTR if polyps were nonlifting or in difficult-to-reach locations, or if T1 colorectal cancer (CRC) was suspected. In addition, eFTR was performed for subepithelial tumors, and as secondary completion treatment after incomplete endoscopic resection of T1 CRC with a positive or nonassessable resection margin. Lesions greater than 30 mm were excluded because of device diameter constraints.

The primary outcome was macroscopic complete en bloc resection. Secondary outcomes included adverse events, full-thickness resection rate, and clinical success, the latter of which was defined by tumor-free resection margins (R0).

Out of 367 procedures, eFTR was most frequently conducted because of incomplete resection of T1 CRC (41%), followed by nonlifting or difficult-to-reach polyps (36%), suspected T1 CRC (19%), and least often, subepithelial tumors (4%).

Complete en bloc resection was achieved in 83.9% of procedures. Excluding 21 procedures in which eFTR was not performed because of inaccessibility of the lesion (n = 7) or immobility of tissue prohibiting retraction of the lesion into the cap (n = 14), R0 was achieved in 82.4% of cases. Among the same group, full-thickness resection rate was comparable, at 83.2%.

Adverse events occurred in 34 patients (9.3%), among whom 10 (2.7%) underwent emergency surgery for perforations or appendicitis.

“In conclusion,” the investigators wrote, “eFTR is an exciting, innovative resection technique that is clinically feasible and safe for complex colorectal lesions, with the potential to obviate the need for surgical resection. Further efficacy studies on eFTR as a primary and secondary treatment option for T1 CRC are needed, focusing on both the short- and long-term oncologic results.”

Peter V. Draganov, MD, of the University of Florida, Gainesville, called the R0 resection rate “respectable,” and suggested that the study “reconfirms on a larger scale that eFTR with the full-thickness resection device is successful in the majority of cases.”

“The full-thickness resection device expands our armamentarium to remove difficult polyps and early CRC,” he said.

Still, Dr. Draganov, who has previously advised careful patient selection for eFTR, noted certain drawbacks of the technique. “The presented data highlight some of the limitations of the full-thickness resection device, including the relatively small size of the lesion [median diameter, 23 mm] that can be resected, and challenges related to accessing and capturing the lesion due to the limited visibility and maneuverability of the device.”

Ultimately, Dr. Draganov supported the investigators’ call for more data. “Before eFTR becomes a primary modality for management of T1 CRC, we do need follow-up data on long-term cancer-related outcomes,” he said.

The study was supported by Ovesco Endoscopy. The investigators disclosed additional relationships with Cook, Ethicon, Olympus, and others.

SOURCE: Zwager LW et al. Endoscopy. 2020 Jun 4. doi: 10.1055/a-1176-1107.

Endoscopic full-thickness resection (eFTR) of complex colorectal lesions appears safe and effective, based on prospective data from 20 Dutch hospitals.

Macroscopic complete en bloc resection was achieved in 83.9% of procedures with an adverse event rate of 9.3%, reported lead author Liselotte W. Zwager, a PhD candidate at the University of Amsterdam, and colleagues.

“With the advantage of enabling a transmural resection, eFTR offers an alternative to radical surgery in lesions considered incurable with current resection techniques such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD),” the investigators wrote in Endoscopy.

But more data are needed for widespread adoption, they noted. “Several studies have reported encouraging results on the short-term safety and efficacy of eFTR for numerous indications. However, firm conclusions on clinical results will require analysis of large prospective series of patients in everyday clinical practice.”

The present study provided data from 362 patients who underwent 367 procedures at 5 academic and 15 nonacademic centers in the Netherlands.

Patients were eligible for eFTR if polyps were nonlifting or in difficult-to-reach locations, or if T1 colorectal cancer (CRC) was suspected. In addition, eFTR was performed for subepithelial tumors, and as secondary completion treatment after incomplete endoscopic resection of T1 CRC with a positive or nonassessable resection margin. Lesions greater than 30 mm were excluded because of device diameter constraints.

The primary outcome was macroscopic complete en bloc resection. Secondary outcomes included adverse events, full-thickness resection rate, and clinical success, the latter of which was defined by tumor-free resection margins (R0).

Out of 367 procedures, eFTR was most frequently conducted because of incomplete resection of T1 CRC (41%), followed by nonlifting or difficult-to-reach polyps (36%), suspected T1 CRC (19%), and least often, subepithelial tumors (4%).

Complete en bloc resection was achieved in 83.9% of procedures. Excluding 21 procedures in which eFTR was not performed because of inaccessibility of the lesion (n = 7) or immobility of tissue prohibiting retraction of the lesion into the cap (n = 14), R0 was achieved in 82.4% of cases. Among the same group, full-thickness resection rate was comparable, at 83.2%.

Adverse events occurred in 34 patients (9.3%), among whom 10 (2.7%) underwent emergency surgery for perforations or appendicitis.

“In conclusion,” the investigators wrote, “eFTR is an exciting, innovative resection technique that is clinically feasible and safe for complex colorectal lesions, with the potential to obviate the need for surgical resection. Further efficacy studies on eFTR as a primary and secondary treatment option for T1 CRC are needed, focusing on both the short- and long-term oncologic results.”

Peter V. Draganov, MD, of the University of Florida, Gainesville, called the R0 resection rate “respectable,” and suggested that the study “reconfirms on a larger scale that eFTR with the full-thickness resection device is successful in the majority of cases.”

“The full-thickness resection device expands our armamentarium to remove difficult polyps and early CRC,” he said.

Still, Dr. Draganov, who has previously advised careful patient selection for eFTR, noted certain drawbacks of the technique. “The presented data highlight some of the limitations of the full-thickness resection device, including the relatively small size of the lesion [median diameter, 23 mm] that can be resected, and challenges related to accessing and capturing the lesion due to the limited visibility and maneuverability of the device.”

Ultimately, Dr. Draganov supported the investigators’ call for more data. “Before eFTR becomes a primary modality for management of T1 CRC, we do need follow-up data on long-term cancer-related outcomes,” he said.

The study was supported by Ovesco Endoscopy. The investigators disclosed additional relationships with Cook, Ethicon, Olympus, and others.

SOURCE: Zwager LW et al. Endoscopy. 2020 Jun 4. doi: 10.1055/a-1176-1107.

Patients with COVID-19 develop a distinct subset of pancreatitis hallmarked by duodenal and periduodenal inflammation, according to a recent case series.

Although all five patients presented with multiple predictive markers of severe pancreatitis, the subsequent clinical pathway “was much more benign than anticipated,” reported lead author Peter Szatmary, MB, BChir, PhD, of the University of Liverpool (England) and colleagues. Still, they noted prolonged hospital stays because of persistent inflammation and poor diabetic control.

“As the global pandemic of SARS-CoV-2 continues, nuances of the disease it precipitates in humans continue to emerge,” the investigators wrote in Gastroenterology. “[A] group from Wuhan reported a series of 9 patients with purported pancreatic injury in the context of SARS-CoV-2 infection, but did not provide robust evidence for pancreatitis relying on mild hyperamylasemia alone.”

For the present series, Dr. Szatmary and colleagues restricted diagnosis of pancreatitis to international consensus guidelines, which require “abdominal pain consistent with pancreatitis, serum amylase/lipase greater than three times the upper limit of normal, and characteristic findings on cross-sectional imaging.”

From middle of March to late April, the investigators identified 35 patients with acute pancreatitis at Royal Liverpool (England) University Hospital, 25 of whom tested negative for SARS-CoV-2, which resulted in study exclusion. An additional five patients were excluded from the series as another etiology for pancreatitis was clearly present, such as gallstones.

“The remaining 5 patients, all with SARS-CoV-2, presented atypically yet homogenously with a distinct metabolic-pancreatitis phenotype,” the investigators wrote.

All five patients were obese or overweight young men with a median body mass index of 30 kg/m² and age of 42 years. On presentation, all patients had elevated, but nondiagnostic, levels of amylase (median, 149 U/L). Contrast-enhanced abdominal CT revealed moderate to severe hepatic steatosis (less than 104 HU), which rapidly regressed within a week among patients who underwent repeat imaging.

“The pattern of pancreatic inflammation was similarly unusual in these patients,” the investigators wrote, going on to describe “mild pancreatic edema without significant pancreatic or peripancreatic necrosis, with distinct duodenal/periduodenal inflammation involving the second and third part of the duodenum.”

According to Dr. Szatmary and colleagues, these findings were “accompanied by a profound systemic inflammatory response,” including 1-2 criteria for systemic inflammatory response syndrome that increased to 2-4 criteria within 48 hours. During hospitalization, patients also exhibited a “dramatic elevation” of C-reactive protein, from a median of 31 mg/L upon admission to 485 mg/L within 48 hours.

Although these markers predicted severe disease, all cases followed a clinical course similar to “a typical attack of moderate pancreatitis,” the investigators wrote.

All patients were treated with IV fluids, four out of five received broad-spectrum IV antibiotics for pneumonitis, three out of five received fibrate and/or insulin therapy, and two out of five received pancreatic enzyme replacement therapy. No patients required corticosteroids, organ support, or respiratory support beyond low-flow oxygen. Median hospital stay was 14 days.

“We ... propose the combination of male sex, abdominal pain, metabolic stress, and CT-findings of predominantly pancreatico-duodenal inflammation with steatosis represent a distinct subset of pancreatitis in patients infected with SARS-CoV-2,” the investigators wrote.

They suggested that the endocrine pancreas may be “particularly vulnerable to this infection,” citing prolonged hospital stays because of poor diabetic control.

“[T]ransient dyslipidemias and impaired glucose tolerance may be common in SARS-CoV-2 patients and warrant further investigation,” they concluded.

Oscar J. Hines, MD, chief of the division of general surgery at UCLA Medical Center and leader in the field of pancreatitis management, said that the case series has a limited impact.

“The findings are unlikely to change practice and only call attention for physicians to the possibility of pancreatitis in COVID-positive patients,” Dr. Hines said.

The investigators reported grants from NIHR, Wellcome Trust, Mylan, and others.

SOURCE: Szatmary P et al. Gastroenterology. 2020 Jun 1. doi: 10.1053/j.gastro.2020.05.069.

Patients with COVID-19 develop a distinct subset of pancreatitis hallmarked by duodenal and periduodenal inflammation, according to a recent case series.

Although all five patients presented with multiple predictive markers of severe pancreatitis, the subsequent clinical pathway “was much more benign than anticipated,” reported lead author Peter Szatmary, MB, BChir, PhD, of the University of Liverpool (England) and colleagues. Still, they noted prolonged hospital stays because of persistent inflammation and poor diabetic control.

“As the global pandemic of SARS-CoV-2 continues, nuances of the disease it precipitates in humans continue to emerge,” the investigators wrote in Gastroenterology. “[A] group from Wuhan reported a series of 9 patients with purported pancreatic injury in the context of SARS-CoV-2 infection, but did not provide robust evidence for pancreatitis relying on mild hyperamylasemia alone.”

For the present series, Dr. Szatmary and colleagues restricted diagnosis of pancreatitis to international consensus guidelines, which require “abdominal pain consistent with pancreatitis, serum amylase/lipase greater than three times the upper limit of normal, and characteristic findings on cross-sectional imaging.”

From middle of March to late April, the investigators identified 35 patients with acute pancreatitis at Royal Liverpool (England) University Hospital, 25 of whom tested negative for SARS-CoV-2, which resulted in study exclusion. An additional five patients were excluded from the series as another etiology for pancreatitis was clearly present, such as gallstones.

“The remaining 5 patients, all with SARS-CoV-2, presented atypically yet homogenously with a distinct metabolic-pancreatitis phenotype,” the investigators wrote.

All five patients were obese or overweight young men with a median body mass index of 30 kg/m² and age of 42 years. On presentation, all patients had elevated, but nondiagnostic, levels of amylase (median, 149 U/L). Contrast-enhanced abdominal CT revealed moderate to severe hepatic steatosis (less than 104 HU), which rapidly regressed within a week among patients who underwent repeat imaging.

“The pattern of pancreatic inflammation was similarly unusual in these patients,” the investigators wrote, going on to describe “mild pancreatic edema without significant pancreatic or peripancreatic necrosis, with distinct duodenal/periduodenal inflammation involving the second and third part of the duodenum.”

According to Dr. Szatmary and colleagues, these findings were “accompanied by a profound systemic inflammatory response,” including 1-2 criteria for systemic inflammatory response syndrome that increased to 2-4 criteria within 48 hours. During hospitalization, patients also exhibited a “dramatic elevation” of C-reactive protein, from a median of 31 mg/L upon admission to 485 mg/L within 48 hours.

Although these markers predicted severe disease, all cases followed a clinical course similar to “a typical attack of moderate pancreatitis,” the investigators wrote.

All patients were treated with IV fluids, four out of five received broad-spectrum IV antibiotics for pneumonitis, three out of five received fibrate and/or insulin therapy, and two out of five received pancreatic enzyme replacement therapy. No patients required corticosteroids, organ support, or respiratory support beyond low-flow oxygen. Median hospital stay was 14 days.

“We ... propose the combination of male sex, abdominal pain, metabolic stress, and CT-findings of predominantly pancreatico-duodenal inflammation with steatosis represent a distinct subset of pancreatitis in patients infected with SARS-CoV-2,” the investigators wrote.

They suggested that the endocrine pancreas may be “particularly vulnerable to this infection,” citing prolonged hospital stays because of poor diabetic control.

“[T]ransient dyslipidemias and impaired glucose tolerance may be common in SARS-CoV-2 patients and warrant further investigation,” they concluded.

Oscar J. Hines, MD, chief of the division of general surgery at UCLA Medical Center and leader in the field of pancreatitis management, said that the case series has a limited impact.

“The findings are unlikely to change practice and only call attention for physicians to the possibility of pancreatitis in COVID-positive patients,” Dr. Hines said.

The investigators reported grants from NIHR, Wellcome Trust, Mylan, and others.

SOURCE: Szatmary P et al. Gastroenterology. 2020 Jun 1. doi: 10.1053/j.gastro.2020.05.069.

Patients with COVID-19 develop a distinct subset of pancreatitis hallmarked by duodenal and periduodenal inflammation, according to a recent case series.

Although all five patients presented with multiple predictive markers of severe pancreatitis, the subsequent clinical pathway “was much more benign than anticipated,” reported lead author Peter Szatmary, MB, BChir, PhD, of the University of Liverpool (England) and colleagues. Still, they noted prolonged hospital stays because of persistent inflammation and poor diabetic control.

“As the global pandemic of SARS-CoV-2 continues, nuances of the disease it precipitates in humans continue to emerge,” the investigators wrote in Gastroenterology. “[A] group from Wuhan reported a series of 9 patients with purported pancreatic injury in the context of SARS-CoV-2 infection, but did not provide robust evidence for pancreatitis relying on mild hyperamylasemia alone.”

For the present series, Dr. Szatmary and colleagues restricted diagnosis of pancreatitis to international consensus guidelines, which require “abdominal pain consistent with pancreatitis, serum amylase/lipase greater than three times the upper limit of normal, and characteristic findings on cross-sectional imaging.”

From middle of March to late April, the investigators identified 35 patients with acute pancreatitis at Royal Liverpool (England) University Hospital, 25 of whom tested negative for SARS-CoV-2, which resulted in study exclusion. An additional five patients were excluded from the series as another etiology for pancreatitis was clearly present, such as gallstones.

“The remaining 5 patients, all with SARS-CoV-2, presented atypically yet homogenously with a distinct metabolic-pancreatitis phenotype,” the investigators wrote.

All five patients were obese or overweight young men with a median body mass index of 30 kg/m² and age of 42 years. On presentation, all patients had elevated, but nondiagnostic, levels of amylase (median, 149 U/L). Contrast-enhanced abdominal CT revealed moderate to severe hepatic steatosis (less than 104 HU), which rapidly regressed within a week among patients who underwent repeat imaging.

“The pattern of pancreatic inflammation was similarly unusual in these patients,” the investigators wrote, going on to describe “mild pancreatic edema without significant pancreatic or peripancreatic necrosis, with distinct duodenal/periduodenal inflammation involving the second and third part of the duodenum.”

According to Dr. Szatmary and colleagues, these findings were “accompanied by a profound systemic inflammatory response,” including 1-2 criteria for systemic inflammatory response syndrome that increased to 2-4 criteria within 48 hours. During hospitalization, patients also exhibited a “dramatic elevation” of C-reactive protein, from a median of 31 mg/L upon admission to 485 mg/L within 48 hours.

Although these markers predicted severe disease, all cases followed a clinical course similar to “a typical attack of moderate pancreatitis,” the investigators wrote.

All patients were treated with IV fluids, four out of five received broad-spectrum IV antibiotics for pneumonitis, three out of five received fibrate and/or insulin therapy, and two out of five received pancreatic enzyme replacement therapy. No patients required corticosteroids, organ support, or respiratory support beyond low-flow oxygen. Median hospital stay was 14 days.

“We ... propose the combination of male sex, abdominal pain, metabolic stress, and CT-findings of predominantly pancreatico-duodenal inflammation with steatosis represent a distinct subset of pancreatitis in patients infected with SARS-CoV-2,” the investigators wrote.

They suggested that the endocrine pancreas may be “particularly vulnerable to this infection,” citing prolonged hospital stays because of poor diabetic control.

“[T]ransient dyslipidemias and impaired glucose tolerance may be common in SARS-CoV-2 patients and warrant further investigation,” they concluded.

Oscar J. Hines, MD, chief of the division of general surgery at UCLA Medical Center and leader in the field of pancreatitis management, said that the case series has a limited impact.

“The findings are unlikely to change practice and only call attention for physicians to the possibility of pancreatitis in COVID-positive patients,” Dr. Hines said.

The investigators reported grants from NIHR, Wellcome Trust, Mylan, and others.

SOURCE: Szatmary P et al. Gastroenterology. 2020 Jun 1. doi: 10.1053/j.gastro.2020.05.069.

Exposure to Shiga toxin induces a complex intestinal response involving transcriptional changes, necrosis, apoptotic cell death, cellular proliferation, and cross-talk between epithelial and mesenchymal cells, according to investigators.

The study explored new territory in Shiga toxin research, enabled by the use of human intestinal organoids (HIOs), reported lead author Suman Pradhan, PhD, of the University of Cincinnati, and colleagues.

Each year, Shiga toxin–producing Escherichia coli infections cause approximately 3 million cases of bloody diarrheal disease, with about 4,000 of those patients developing the life-threatening complication of hemolytic uremic syndrome (HUS), the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.

But little is known about the underlying biological processes driving Shiga-induced disease.

“Developing effective interventions for disease resulting from Shiga toxin is exacerbated by a lack of tractable model systems,” the investigators wrote. “Mice do not develop the symptoms characteristic of HUS, and the murine intestinal tract is resistant to Shiga toxin.”

To overcome this obstacle, Dr. Pradhan and colleagues turned to HIOs, which are grown in culture by directing differentiation of pluripotent stem cells. HIOs represent the small bowel, complete with a lumen surrounded by epithelial and mesenchymal layers that include typical cell types, such as goblet cells and myofibroblasts. The model is made more realistic by transplantation into mice, where it grows under the kidney capsule to form crypts, structured villi, and proliferating progenitor zones. And HIOs grown with neuronal precursors develop an enteric nervous system, complete with functional peristalsis.

For the present study, the investigators evaluated the effect of Shiga toxin on HIOs both in culture and after transplantation into mice.

First, they demonstrated that HIOs in culture expressed glycolipid Gb3, the Shiga toxin receptor. “Reports regarding expression of glycolipid Gb3 ... on human intestine have been inconsistent,” the investigators noted. “For negative reports, the inability to detect Gb3 could be owing to technical limitations.”

Next, Dr. Pradhan and colleagues showed that HIOs were susceptible to Shiga toxin whether it be delivered lumenally or basolaterally, which respectively represent intestinal exposure and exposure via circulating toxin or after breakdown of the epithelial barrier. Leakage from the lumen was observed with both Shiga toxin 1 (Stx1) and 2 (Stx2). Subsequent testing involved only Stx2, as this form is more relevant to human disease.

In addition to lumenal leakage, Stx2 exposure caused significant transcriptional up-regulation of multiple gene families, including those involved in cellular transport and metabolic processes. Increased expression also was observed for epithelial structural proteins, lineage-specific proteins, factors involved in mucus layer formation and stabilization, and cytokines interleukin-18 and CCL15.

In both epithelial and mesenchymal layers, transcriptional changes were accompanied by cellular necrosis and apoptosis, and, to a greater degree with interstitial exposure, cellular proliferation.

With lumenal exposure, mesenchymal necrosis was observed before loss of epithelial barrier function, indicating toxin access to mesenchymal cells. This phenomenon was explained by transcytosis, which the investigators observed in two-dimensional monolayers of enteroids grown in Transwells.

“[Shiga toxin] was transferred from the apical to the basolateral surface in the absence of loss of epithelial barrier function,” the investigators wrote, noting that this finding explains how Shiga toxin can quickly access the circulatory system, and from there damage the kidneys and brain, as seen in cases of HUS.

Mice with transplanted HIOs, and those receiving HIOs with an enteric nervous system (HIO + ENS), lost weight when organoids were injected with 10 ng of Stx2. Mice with HIO + ENS transplants developed more severe responses, prompting closer analysis.

Postmortem histologic examination of HIO + ENS transplants revealed epithelial damage and blood accumulation in the mesenchyme and villi. Additional staining showed signs of apoptosis and mesenchymal-epithelial transition.

Dr. Pradham and colleagues suggested that their findings could inform therapeutic research.

“If preventing cellular death is to be an effective intervention, it is likely that both necrosis and apoptosis need to be targeted,” the investigators wrote.

More generally, the study supports the use of HIOs as a disease model for future investigations.

“The advent of stem cell–derived human tissue models, both in vitro and in vivo, has a tremendous potential to increase our understanding of Shiga toxin disease and lead to development of therapeutic interventions,” the investigators concluded.

The study was funded by the National Institutes of Health, the Center for Clinical and Translational Science, the National Institute of Diabetes and Digestive and Kidney Diseases, and others. The investigators disclosed no conflicts of interest.

SOURCE: Pradhan S et al. Cell Mol Gastroenterol Hepatol. 2020 Mar 5. doi: 10.1016/j.jcmgh.2020.02.006.

Exposure to Shiga toxin induces a complex intestinal response involving transcriptional changes, necrosis, apoptotic cell death, cellular proliferation, and cross-talk between epithelial and mesenchymal cells, according to investigators.

The study explored new territory in Shiga toxin research, enabled by the use of human intestinal organoids (HIOs), reported lead author Suman Pradhan, PhD, of the University of Cincinnati, and colleagues.

Each year, Shiga toxin–producing Escherichia coli infections cause approximately 3 million cases of bloody diarrheal disease, with about 4,000 of those patients developing the life-threatening complication of hemolytic uremic syndrome (HUS), the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.

But little is known about the underlying biological processes driving Shiga-induced disease.

“Developing effective interventions for disease resulting from Shiga toxin is exacerbated by a lack of tractable model systems,” the investigators wrote. “Mice do not develop the symptoms characteristic of HUS, and the murine intestinal tract is resistant to Shiga toxin.”

To overcome this obstacle, Dr. Pradhan and colleagues turned to HIOs, which are grown in culture by directing differentiation of pluripotent stem cells. HIOs represent the small bowel, complete with a lumen surrounded by epithelial and mesenchymal layers that include typical cell types, such as goblet cells and myofibroblasts. The model is made more realistic by transplantation into mice, where it grows under the kidney capsule to form crypts, structured villi, and proliferating progenitor zones. And HIOs grown with neuronal precursors develop an enteric nervous system, complete with functional peristalsis.

For the present study, the investigators evaluated the effect of Shiga toxin on HIOs both in culture and after transplantation into mice.

First, they demonstrated that HIOs in culture expressed glycolipid Gb3, the Shiga toxin receptor. “Reports regarding expression of glycolipid Gb3 ... on human intestine have been inconsistent,” the investigators noted. “For negative reports, the inability to detect Gb3 could be owing to technical limitations.”

Next, Dr. Pradhan and colleagues showed that HIOs were susceptible to Shiga toxin whether it be delivered lumenally or basolaterally, which respectively represent intestinal exposure and exposure via circulating toxin or after breakdown of the epithelial barrier. Leakage from the lumen was observed with both Shiga toxin 1 (Stx1) and 2 (Stx2). Subsequent testing involved only Stx2, as this form is more relevant to human disease.

In addition to lumenal leakage, Stx2 exposure caused significant transcriptional up-regulation of multiple gene families, including those involved in cellular transport and metabolic processes. Increased expression also was observed for epithelial structural proteins, lineage-specific proteins, factors involved in mucus layer formation and stabilization, and cytokines interleukin-18 and CCL15.

In both epithelial and mesenchymal layers, transcriptional changes were accompanied by cellular necrosis and apoptosis, and, to a greater degree with interstitial exposure, cellular proliferation.

With lumenal exposure, mesenchymal necrosis was observed before loss of epithelial barrier function, indicating toxin access to mesenchymal cells. This phenomenon was explained by transcytosis, which the investigators observed in two-dimensional monolayers of enteroids grown in Transwells.

“[Shiga toxin] was transferred from the apical to the basolateral surface in the absence of loss of epithelial barrier function,” the investigators wrote, noting that this finding explains how Shiga toxin can quickly access the circulatory system, and from there damage the kidneys and brain, as seen in cases of HUS.

Mice with transplanted HIOs, and those receiving HIOs with an enteric nervous system (HIO + ENS), lost weight when organoids were injected with 10 ng of Stx2. Mice with HIO + ENS transplants developed more severe responses, prompting closer analysis.

Postmortem histologic examination of HIO + ENS transplants revealed epithelial damage and blood accumulation in the mesenchyme and villi. Additional staining showed signs of apoptosis and mesenchymal-epithelial transition.

Dr. Pradham and colleagues suggested that their findings could inform therapeutic research.

“If preventing cellular death is to be an effective intervention, it is likely that both necrosis and apoptosis need to be targeted,” the investigators wrote.

More generally, the study supports the use of HIOs as a disease model for future investigations.

“The advent of stem cell–derived human tissue models, both in vitro and in vivo, has a tremendous potential to increase our understanding of Shiga toxin disease and lead to development of therapeutic interventions,” the investigators concluded.

The study was funded by the National Institutes of Health, the Center for Clinical and Translational Science, the National Institute of Diabetes and Digestive and Kidney Diseases, and others. The investigators disclosed no conflicts of interest.

SOURCE: Pradhan S et al. Cell Mol Gastroenterol Hepatol. 2020 Mar 5. doi: 10.1016/j.jcmgh.2020.02.006.

Exposure to Shiga toxin induces a complex intestinal response involving transcriptional changes, necrosis, apoptotic cell death, cellular proliferation, and cross-talk between epithelial and mesenchymal cells, according to investigators.

The study explored new territory in Shiga toxin research, enabled by the use of human intestinal organoids (HIOs), reported lead author Suman Pradhan, PhD, of the University of Cincinnati, and colleagues.

Each year, Shiga toxin–producing Escherichia coli infections cause approximately 3 million cases of bloody diarrheal disease, with about 4,000 of those patients developing the life-threatening complication of hemolytic uremic syndrome (HUS), the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.

But little is known about the underlying biological processes driving Shiga-induced disease.

“Developing effective interventions for disease resulting from Shiga toxin is exacerbated by a lack of tractable model systems,” the investigators wrote. “Mice do not develop the symptoms characteristic of HUS, and the murine intestinal tract is resistant to Shiga toxin.”

To overcome this obstacle, Dr. Pradhan and colleagues turned to HIOs, which are grown in culture by directing differentiation of pluripotent stem cells. HIOs represent the small bowel, complete with a lumen surrounded by epithelial and mesenchymal layers that include typical cell types, such as goblet cells and myofibroblasts. The model is made more realistic by transplantation into mice, where it grows under the kidney capsule to form crypts, structured villi, and proliferating progenitor zones. And HIOs grown with neuronal precursors develop an enteric nervous system, complete with functional peristalsis.

For the present study, the investigators evaluated the effect of Shiga toxin on HIOs both in culture and after transplantation into mice.

First, they demonstrated that HIOs in culture expressed glycolipid Gb3, the Shiga toxin receptor. “Reports regarding expression of glycolipid Gb3 ... on human intestine have been inconsistent,” the investigators noted. “For negative reports, the inability to detect Gb3 could be owing to technical limitations.”

Next, Dr. Pradhan and colleagues showed that HIOs were susceptible to Shiga toxin whether it be delivered lumenally or basolaterally, which respectively represent intestinal exposure and exposure via circulating toxin or after breakdown of the epithelial barrier. Leakage from the lumen was observed with both Shiga toxin 1 (Stx1) and 2 (Stx2). Subsequent testing involved only Stx2, as this form is more relevant to human disease.

In addition to lumenal leakage, Stx2 exposure caused significant transcriptional up-regulation of multiple gene families, including those involved in cellular transport and metabolic processes. Increased expression also was observed for epithelial structural proteins, lineage-specific proteins, factors involved in mucus layer formation and stabilization, and cytokines interleukin-18 and CCL15.

In both epithelial and mesenchymal layers, transcriptional changes were accompanied by cellular necrosis and apoptosis, and, to a greater degree with interstitial exposure, cellular proliferation.

With lumenal exposure, mesenchymal necrosis was observed before loss of epithelial barrier function, indicating toxin access to mesenchymal cells. This phenomenon was explained by transcytosis, which the investigators observed in two-dimensional monolayers of enteroids grown in Transwells.

“[Shiga toxin] was transferred from the apical to the basolateral surface in the absence of loss of epithelial barrier function,” the investigators wrote, noting that this finding explains how Shiga toxin can quickly access the circulatory system, and from there damage the kidneys and brain, as seen in cases of HUS.

Mice with transplanted HIOs, and those receiving HIOs with an enteric nervous system (HIO + ENS), lost weight when organoids were injected with 10 ng of Stx2. Mice with HIO + ENS transplants developed more severe responses, prompting closer analysis.

Postmortem histologic examination of HIO + ENS transplants revealed epithelial damage and blood accumulation in the mesenchyme and villi. Additional staining showed signs of apoptosis and mesenchymal-epithelial transition.

Dr. Pradham and colleagues suggested that their findings could inform therapeutic research.

“If preventing cellular death is to be an effective intervention, it is likely that both necrosis and apoptosis need to be targeted,” the investigators wrote.

More generally, the study supports the use of HIOs as a disease model for future investigations.

“The advent of stem cell–derived human tissue models, both in vitro and in vivo, has a tremendous potential to increase our understanding of Shiga toxin disease and lead to development of therapeutic interventions,” the investigators concluded.

The study was funded by the National Institutes of Health, the Center for Clinical and Translational Science, the National Institute of Diabetes and Digestive and Kidney Diseases, and others. The investigators disclosed no conflicts of interest.

SOURCE: Pradhan S et al. Cell Mol Gastroenterol Hepatol. 2020 Mar 5. doi: 10.1016/j.jcmgh.2020.02.006.

Even without GI symptoms, many patients with COVID-19 shed viral RNA in feces, suggesting that stool testing and prevention of fecal-oral transmission may be needed to combat the ongoing pandemic, according to investigators.

A meta-analysis of 29 studies showed that 12% of patients with COVID-19 developed nausea, diarrhea, or vomiting, while 41% shed viral RNA in feces, reported lead author Sravanthi Parasa, MD, of Swedish Medical Center, Seattle.Writing in JAMA Network Open, Dr. Parasa and colleagues emphasized that respiratory symptoms remain the predominant form of disease; however, GI symptoms can occur.

“In fact, the first reported patient with COVID-19 in the U.S. reported GI symptoms of loose bowel movements and abdominal discomfort,” the investigators wrote, noting that the patient went on to test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in both respiratory and stool specimens.

“This raises the question of inadvertent human-to-human transmission via the fecal route despite public health emphasis on droplet transmission and precautions for contact with respiratory secretions,” the investigators wrote.

To address this question, the investigators conducted a systematic review and meta-analysis involving 23 published and 6 preprint studies involving a total of 4,805 patients, all of whom tested positive for SARS-CoV-2 based on PCR results from nasopharyngeal swabs. Dr. Parasa and colleagues noted that most of the studies “scored between 8 and 10 on the MINORS quality assessment,” suggesting moderate quality.

Pooled data from these studies showed that 4.6% of patients reported nausea or vomiting, while 7.4% reported diarrhea. Such symptoms may serve as an early warning flag for clinicians, the investigators noted.

“[T]he presence of GI symptoms may portend a worse outcome for patients infected with SARS-CoV-2,” they wrote, citing a study by Pan and colleagues, which found that GI symptoms were associated with lower rates of recovery and hospital discharge.

Regardless of GI symptoms, 40.5% of patients in the meta-analysis tested positive for viral RNA in feces (95% confidence interval, 27.4%-55.1%). Duration of viral shedding in feces lasted up to 11 days after symptom onset, or in a single-patient case study, 18 days after hospitalization.

The investigators called these duration figures “particularly concerning,” especially in light of a study published by Xiao and colleagues, which showed that 23.3% of patients with negative respiratory tests were still shedding live virus in feces.

“[T]he fecal-oral route of transmission could be an additional potential source of infection spread,” wrote Dr. Parasa and colleagues. “Our results also suggest that testing of the virus in feces ... could be helpful in disease monitoring and surveillance.”

David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, said that the findings confirm what has been suspected for some time: GI disease is relatively common with COVID-19.

“The evidence is clear now that a sizable percentage of patients have GI symptoms,” Dr. Johnson said in an interview.

GI issues may precede respiratory signs, he added, so clinicians should be aware that nausea, vomiting, or diarrhea could be early indicators of COVID-19, and possibly, a worse outcome.

“The other highlight of this study is that stool shedding may be extended beyond respiratory shedding,” Dr. Johnson said.

He suggested that this finding could influence current CDC criteria, which define absence of infectious risk by two consecutive, negative nasopharyngeal swabs. Instead, fecal testing may be needed, he said, along with measures to prevent fecal-oral transmission.

Dr. Johnson expressed particular concern for risk of infection via toilet plume, in which toilet flushing aerosolizes viral particles.

“As much as people try to social distance by 6 feet – you can do that when you walk into a store, or a building, but you can’t necessarily do that when you walk into a public toilet, where the plume may have been expansive for a period of time,” he said. “That toilet may never really get cleaned to a high level of disinfection, and those droplets set up potential for fecal-oral spread.”

Dr. Sharma disclosed relationships with Medtronic, Fujifilm, Boston Scientific, and others. Dr. Johnson disclosed no relevant conflicts of interest.

SOURCE: Parasa S et al. JAMA Network Open. 2020 Jun 11. doi: 10.1001/jamanetworkopen.2020.11335.

Even without GI symptoms, many patients with COVID-19 shed viral RNA in feces, suggesting that stool testing and prevention of fecal-oral transmission may be needed to combat the ongoing pandemic, according to investigators.

A meta-analysis of 29 studies showed that 12% of patients with COVID-19 developed nausea, diarrhea, or vomiting, while 41% shed viral RNA in feces, reported lead author Sravanthi Parasa, MD, of Swedish Medical Center, Seattle.Writing in JAMA Network Open, Dr. Parasa and colleagues emphasized that respiratory symptoms remain the predominant form of disease; however, GI symptoms can occur.

“In fact, the first reported patient with COVID-19 in the U.S. reported GI symptoms of loose bowel movements and abdominal discomfort,” the investigators wrote, noting that the patient went on to test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in both respiratory and stool specimens.

“This raises the question of inadvertent human-to-human transmission via the fecal route despite public health emphasis on droplet transmission and precautions for contact with respiratory secretions,” the investigators wrote.

To address this question, the investigators conducted a systematic review and meta-analysis involving 23 published and 6 preprint studies involving a total of 4,805 patients, all of whom tested positive for SARS-CoV-2 based on PCR results from nasopharyngeal swabs. Dr. Parasa and colleagues noted that most of the studies “scored between 8 and 10 on the MINORS quality assessment,” suggesting moderate quality.

Pooled data from these studies showed that 4.6% of patients reported nausea or vomiting, while 7.4% reported diarrhea. Such symptoms may serve as an early warning flag for clinicians, the investigators noted.

“[T]he presence of GI symptoms may portend a worse outcome for patients infected with SARS-CoV-2,” they wrote, citing a study by Pan and colleagues, which found that GI symptoms were associated with lower rates of recovery and hospital discharge.

Regardless of GI symptoms, 40.5% of patients in the meta-analysis tested positive for viral RNA in feces (95% confidence interval, 27.4%-55.1%). Duration of viral shedding in feces lasted up to 11 days after symptom onset, or in a single-patient case study, 18 days after hospitalization.

The investigators called these duration figures “particularly concerning,” especially in light of a study published by Xiao and colleagues, which showed that 23.3% of patients with negative respiratory tests were still shedding live virus in feces.

“[T]he fecal-oral route of transmission could be an additional potential source of infection spread,” wrote Dr. Parasa and colleagues. “Our results also suggest that testing of the virus in feces ... could be helpful in disease monitoring and surveillance.”

David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, said that the findings confirm what has been suspected for some time: GI disease is relatively common with COVID-19.

“The evidence is clear now that a sizable percentage of patients have GI symptoms,” Dr. Johnson said in an interview.

GI issues may precede respiratory signs, he added, so clinicians should be aware that nausea, vomiting, or diarrhea could be early indicators of COVID-19, and possibly, a worse outcome.

“The other highlight of this study is that stool shedding may be extended beyond respiratory shedding,” Dr. Johnson said.

He suggested that this finding could influence current CDC criteria, which define absence of infectious risk by two consecutive, negative nasopharyngeal swabs. Instead, fecal testing may be needed, he said, along with measures to prevent fecal-oral transmission.

Dr. Johnson expressed particular concern for risk of infection via toilet plume, in which toilet flushing aerosolizes viral particles.

“As much as people try to social distance by 6 feet – you can do that when you walk into a store, or a building, but you can’t necessarily do that when you walk into a public toilet, where the plume may have been expansive for a period of time,” he said. “That toilet may never really get cleaned to a high level of disinfection, and those droplets set up potential for fecal-oral spread.”

Dr. Sharma disclosed relationships with Medtronic, Fujifilm, Boston Scientific, and others. Dr. Johnson disclosed no relevant conflicts of interest.

SOURCE: Parasa S et al. JAMA Network Open. 2020 Jun 11. doi: 10.1001/jamanetworkopen.2020.11335.

Even without GI symptoms, many patients with COVID-19 shed viral RNA in feces, suggesting that stool testing and prevention of fecal-oral transmission may be needed to combat the ongoing pandemic, according to investigators.

A meta-analysis of 29 studies showed that 12% of patients with COVID-19 developed nausea, diarrhea, or vomiting, while 41% shed viral RNA in feces, reported lead author Sravanthi Parasa, MD, of Swedish Medical Center, Seattle.Writing in JAMA Network Open, Dr. Parasa and colleagues emphasized that respiratory symptoms remain the predominant form of disease; however, GI symptoms can occur.

“In fact, the first reported patient with COVID-19 in the U.S. reported GI symptoms of loose bowel movements and abdominal discomfort,” the investigators wrote, noting that the patient went on to test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in both respiratory and stool specimens.

“This raises the question of inadvertent human-to-human transmission via the fecal route despite public health emphasis on droplet transmission and precautions for contact with respiratory secretions,” the investigators wrote.

To address this question, the investigators conducted a systematic review and meta-analysis involving 23 published and 6 preprint studies involving a total of 4,805 patients, all of whom tested positive for SARS-CoV-2 based on PCR results from nasopharyngeal swabs. Dr. Parasa and colleagues noted that most of the studies “scored between 8 and 10 on the MINORS quality assessment,” suggesting moderate quality.

Pooled data from these studies showed that 4.6% of patients reported nausea or vomiting, while 7.4% reported diarrhea. Such symptoms may serve as an early warning flag for clinicians, the investigators noted.

“[T]he presence of GI symptoms may portend a worse outcome for patients infected with SARS-CoV-2,” they wrote, citing a study by Pan and colleagues, which found that GI symptoms were associated with lower rates of recovery and hospital discharge.

Regardless of GI symptoms, 40.5% of patients in the meta-analysis tested positive for viral RNA in feces (95% confidence interval, 27.4%-55.1%). Duration of viral shedding in feces lasted up to 11 days after symptom onset, or in a single-patient case study, 18 days after hospitalization.

The investigators called these duration figures “particularly concerning,” especially in light of a study published by Xiao and colleagues, which showed that 23.3% of patients with negative respiratory tests were still shedding live virus in feces.

“[T]he fecal-oral route of transmission could be an additional potential source of infection spread,” wrote Dr. Parasa and colleagues. “Our results also suggest that testing of the virus in feces ... could be helpful in disease monitoring and surveillance.”

David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, said that the findings confirm what has been suspected for some time: GI disease is relatively common with COVID-19.

“The evidence is clear now that a sizable percentage of patients have GI symptoms,” Dr. Johnson said in an interview.

GI issues may precede respiratory signs, he added, so clinicians should be aware that nausea, vomiting, or diarrhea could be early indicators of COVID-19, and possibly, a worse outcome.

“The other highlight of this study is that stool shedding may be extended beyond respiratory shedding,” Dr. Johnson said.

He suggested that this finding could influence current CDC criteria, which define absence of infectious risk by two consecutive, negative nasopharyngeal swabs. Instead, fecal testing may be needed, he said, along with measures to prevent fecal-oral transmission.

Dr. Johnson expressed particular concern for risk of infection via toilet plume, in which toilet flushing aerosolizes viral particles.

“As much as people try to social distance by 6 feet – you can do that when you walk into a store, or a building, but you can’t necessarily do that when you walk into a public toilet, where the plume may have been expansive for a period of time,” he said. “That toilet may never really get cleaned to a high level of disinfection, and those droplets set up potential for fecal-oral spread.”

Dr. Sharma disclosed relationships with Medtronic, Fujifilm, Boston Scientific, and others. Dr. Johnson disclosed no relevant conflicts of interest.

SOURCE: Parasa S et al. JAMA Network Open. 2020 Jun 11. doi: 10.1001/jamanetworkopen.2020.11335.