This transcript has been edited for clarity.

Hello. I’m Dr Maurie Markman, from City of Hope. I’d like to discuss what I consider to be an absolutely fascinating paper, and one that I will say has very interesting results but raises many more questions than it answers. I think that was the intent of the authors.

The paper is entitled, “Addition of metastasis-directed therapy to systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND): a multicenter, randomized phase 2 trial,” published in the Journal of Clinical Oncology.

You might ask what metastasis-directed therapy in pancreatic cancer means. Have we really made much of an impact on pancreatic cancer? In fact, in my earlier years of training, if somebody came up with the idea, or suggested as part of a trial or treatment of an individual patient, that they would focus on metastases in pancreas cancer, you might say they’re crazy, or you might say: “Yeah, but they probably don’t know anything about the disease and its natural history.” 

Now, fast forward several decades. Even with the recognized, modest advances in systemic therapy, what we see are tremendous, really remarkable advances in innovations in radiation therapy. Of course, this includes not only the use of radiation itself but also the imaging technology that is used to direct the radiation therapy. These advances have permitted asking the questions that are addressed in the current study. 

Again, this study is fascinating. They randomized a very small number. Again, it’s a randomized phase 2 study. It’s really more of a proof of principle here. They randomized 41 patients with five or fewer metastatic lesions — with oligometastatic disease, they could have numerous lesions — to undergo what they’ve described as comprehensive metastases-directed therapy.

Most of this was external beam radiation therapy and stereotactic radiation therapy, but there were some localized radiation implants as well, plus chemotherapy. This was comprehensive metastases-directed therapy to each of these sites plus chemotherapy vs chemotherapy alone.

What was shown in this trial? The progression-free survival (PFS) in the metastases-directed therapy group was 10.3 months vs 2.5 months in the group of patients who received chemotherapy only, with a hazard ratio of 0.43 and statistical significance.

Remember, this was a very small study, but we see more than a tripling in the PFS. There was no difference in overall survival, which is not at all surprising because it was a very small sample size. 

Very importantly — and essential to doing this trial ethically — a crossover was permitted at the time of progression, meaning that if a patient received chemotherapy only and progressed, they could potentially get stereotactic radiation to sites of metastatic disease. They might have also benefited from that kind of strategy to the metastasis-[therapy] so that overall survival in the small population may not be different. Again, there was a tripling of the time to disease progression.

Clearly, a larger study will be required to be more definitive. We would need more centers involved and maybe some modification in the study design in this trial because of any issues that the investigators may have identified. Of course, overall survival would be a fair endpoint to look at, but again, crossover would be essential, and that might influence an ultimate outcome. PFS is a very valid endpoint.

The only other point to mention is, with these results — and as I mentioned, advances in radiation and imaging — is it reasonable to potentially consider this type of approach for individual patients as a component of aggressive standard of care? Of course, this would be with very adequate informed consent from patients, because we don’t know what the impact will be. 

With the limited morbidity associated with the radiation, for an individual patient with pancreatic cancer who has an adequate performance status and limited metastases, if we give them chemotherapy and also directed radiation, is it reasonable to consider that as an appropriate treatment option outside the setting of a clinical trial?

I think this is a very valid question that needs to be addressed. In my opinion, the answer in some settings should be yes, but that needs to be discussed much more widely than simply in this randomized phase 2 trial.

Thank you for your attention.

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

This transcript has been edited for clarity.

Hello. I’m Dr Maurie Markman, from City of Hope. I’d like to discuss what I consider to be an absolutely fascinating paper, and one that I will say has very interesting results but raises many more questions than it answers. I think that was the intent of the authors.

The paper is entitled, “Addition of metastasis-directed therapy to systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND): a multicenter, randomized phase 2 trial,” published in the Journal of Clinical Oncology.

You might ask what metastasis-directed therapy in pancreatic cancer means. Have we really made much of an impact on pancreatic cancer? In fact, in my earlier years of training, if somebody came up with the idea, or suggested as part of a trial or treatment of an individual patient, that they would focus on metastases in pancreas cancer, you might say they’re crazy, or you might say: “Yeah, but they probably don’t know anything about the disease and its natural history.” 

Now, fast forward several decades. Even with the recognized, modest advances in systemic therapy, what we see are tremendous, really remarkable advances in innovations in radiation therapy. Of course, this includes not only the use of radiation itself but also the imaging technology that is used to direct the radiation therapy. These advances have permitted asking the questions that are addressed in the current study. 

Again, this study is fascinating. They randomized a very small number. Again, it’s a randomized phase 2 study. It’s really more of a proof of principle here. They randomized 41 patients with five or fewer metastatic lesions — with oligometastatic disease, they could have numerous lesions — to undergo what they’ve described as comprehensive metastases-directed therapy.

Most of this was external beam radiation therapy and stereotactic radiation therapy, but there were some localized radiation implants as well, plus chemotherapy. This was comprehensive metastases-directed therapy to each of these sites plus chemotherapy vs chemotherapy alone.

What was shown in this trial? The progression-free survival (PFS) in the metastases-directed therapy group was 10.3 months vs 2.5 months in the group of patients who received chemotherapy only, with a hazard ratio of 0.43 and statistical significance.

Remember, this was a very small study, but we see more than a tripling in the PFS. There was no difference in overall survival, which is not at all surprising because it was a very small sample size. 

Very importantly — and essential to doing this trial ethically — a crossover was permitted at the time of progression, meaning that if a patient received chemotherapy only and progressed, they could potentially get stereotactic radiation to sites of metastatic disease. They might have also benefited from that kind of strategy to the metastasis-[therapy] so that overall survival in the small population may not be different. Again, there was a tripling of the time to disease progression.

Clearly, a larger study will be required to be more definitive. We would need more centers involved and maybe some modification in the study design in this trial because of any issues that the investigators may have identified. Of course, overall survival would be a fair endpoint to look at, but again, crossover would be essential, and that might influence an ultimate outcome. PFS is a very valid endpoint.

The only other point to mention is, with these results — and as I mentioned, advances in radiation and imaging — is it reasonable to potentially consider this type of approach for individual patients as a component of aggressive standard of care? Of course, this would be with very adequate informed consent from patients, because we don’t know what the impact will be. 

With the limited morbidity associated with the radiation, for an individual patient with pancreatic cancer who has an adequate performance status and limited metastases, if we give them chemotherapy and also directed radiation, is it reasonable to consider that as an appropriate treatment option outside the setting of a clinical trial?

I think this is a very valid question that needs to be addressed. In my opinion, the answer in some settings should be yes, but that needs to be discussed much more widely than simply in this randomized phase 2 trial.

Thank you for your attention.

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

This transcript has been edited for clarity.

Hello. I’m Dr Maurie Markman, from City of Hope. I’d like to discuss what I consider to be an absolutely fascinating paper, and one that I will say has very interesting results but raises many more questions than it answers. I think that was the intent of the authors.

The paper is entitled, “Addition of metastasis-directed therapy to systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND): a multicenter, randomized phase 2 trial,” published in the Journal of Clinical Oncology.

You might ask what metastasis-directed therapy in pancreatic cancer means. Have we really made much of an impact on pancreatic cancer? In fact, in my earlier years of training, if somebody came up with the idea, or suggested as part of a trial or treatment of an individual patient, that they would focus on metastases in pancreas cancer, you might say they’re crazy, or you might say: “Yeah, but they probably don’t know anything about the disease and its natural history.” 

Now, fast forward several decades. Even with the recognized, modest advances in systemic therapy, what we see are tremendous, really remarkable advances in innovations in radiation therapy. Of course, this includes not only the use of radiation itself but also the imaging technology that is used to direct the radiation therapy. These advances have permitted asking the questions that are addressed in the current study. 

Again, this study is fascinating. They randomized a very small number. Again, it’s a randomized phase 2 study. It’s really more of a proof of principle here. They randomized 41 patients with five or fewer metastatic lesions — with oligometastatic disease, they could have numerous lesions — to undergo what they’ve described as comprehensive metastases-directed therapy.

Most of this was external beam radiation therapy and stereotactic radiation therapy, but there were some localized radiation implants as well, plus chemotherapy. This was comprehensive metastases-directed therapy to each of these sites plus chemotherapy vs chemotherapy alone.

What was shown in this trial? The progression-free survival (PFS) in the metastases-directed therapy group was 10.3 months vs 2.5 months in the group of patients who received chemotherapy only, with a hazard ratio of 0.43 and statistical significance.

Remember, this was a very small study, but we see more than a tripling in the PFS. There was no difference in overall survival, which is not at all surprising because it was a very small sample size. 

Very importantly — and essential to doing this trial ethically — a crossover was permitted at the time of progression, meaning that if a patient received chemotherapy only and progressed, they could potentially get stereotactic radiation to sites of metastatic disease. They might have also benefited from that kind of strategy to the metastasis-[therapy] so that overall survival in the small population may not be different. Again, there was a tripling of the time to disease progression.

Clearly, a larger study will be required to be more definitive. We would need more centers involved and maybe some modification in the study design in this trial because of any issues that the investigators may have identified. Of course, overall survival would be a fair endpoint to look at, but again, crossover would be essential, and that might influence an ultimate outcome. PFS is a very valid endpoint.

The only other point to mention is, with these results — and as I mentioned, advances in radiation and imaging — is it reasonable to potentially consider this type of approach for individual patients as a component of aggressive standard of care? Of course, this would be with very adequate informed consent from patients, because we don’t know what the impact will be. 

With the limited morbidity associated with the radiation, for an individual patient with pancreatic cancer who has an adequate performance status and limited metastases, if we give them chemotherapy and also directed radiation, is it reasonable to consider that as an appropriate treatment option outside the setting of a clinical trial?

I think this is a very valid question that needs to be addressed. In my opinion, the answer in some settings should be yes, but that needs to be discussed much more widely than simply in this randomized phase 2 trial.

Thank you for your attention.

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

Neighborhood-level social determinants of health (SDOH) are associated with the burden, comorbidities, and mortality of metabolic dysfunction-associated steatotic disease (MASLD). These health mediators should be considered along with individual SDOH in clinical care and healthcare quality and equity improvement, a large retrospective study of adults with MASLD at a multi-state healthcare institution concluded.

Across quartiles, patients in the most disadvantaged neighborhoods (according to home addresses) vs the least disadvantaged had worse outcomes and were also disproportionately Hispanic, Black, and Native American/Alaska Native, more often Spanish-speaking in primary language, and more often uninsured or on Medicaid, according to Karn Wijarnpreecha, MD, MPH, of the Division of Gastroenterology and Hepatology at University of Arizona College of Medicine–Phoenix, and colleagues writing in Clinical Gastroenterology and Hepatology.

Even after adjustment for measures in the Social Deprivation Index (SDI), the incidence of death, cirrhosis, diabetes mellitus (DM), and major adverse cardiovascular events (MACE) was higher in Native American/Alaska Native patients compared with their non-Hispanic White counterparts. The SDI is a composite measure of seven demographic characteristics from the American Community Survey, with scores ranging from 1 to 100 and weighted based on characteristics from national percentile rankings.

Aligning with the growing prevalence of obesity and DM, MASLD has increased substantially over the past three decades, and is now the leading cause of chronic liver disease in this country and the world. 

This rise in prevalence has underscored health disparities in MASLD and prompted research into linkd between liver disease and SDOH, defined as the conditions under which people are born, grow, live, work, and age. These are fundamental drivers of health disparities, including those in MASLD.
 

Study Details

Primary outcomes were MASLD burden, mortality, and comorbidities by neighborhood SDOH, assessed using the SDI in cross-sectional and longitudinal analyses.

A total of 69,191 adult patients (more than 50% female) diagnosed with MASLD were included, 45,003 of whom had at least 365 days of follow-up. They were treated from July 2012 to June 2023 in Banner Health Systems, a network that includes primary-, secondary-, and tertiary-care centers in Arizona, Colorado, Wyoming, Nevada, Nebraska, and California.

The median follow-up time was 48 months. Among patients across SDI quartiles (age range 49 to 62 years), 1390 patients (3.1%) died, 902 (2.0%) developed cirrhosis, 1087 (2.4%) developed LRE, 6537 (14.5%) developed DM, 2057 (4.6%) developed cancer, and 5409 (12.0%) developed MACE.

Those living in the most disadvantaged quartile of neighborhoods compared with the least had the following higher odds:

• cirrhosis, adjusted odds ratio [aOR], 1.42 (P < .001)
• any cardiovascular (CVD) disease, aOR, 1.20 (P < .001),
• coronary artery disease, aOR, 1.17 (P < .001)
• congestive heart failure, aOR, 1.43 (P < .001)
• cerebrovascular accident, aOR, 1.19 (P = .001)
• DM, aOR, 1.57 (P < .001)
• hypertension, aOR, 1.38 (P < .001).

They also had increased incidence of death (adjusted hazard ratio [aHR], 1.47; P < .001), LRE (aHR, 1.31; P = .012), DM (aHR, 1.47; P < .001), and MACE (aHR, 1.24; P < .001). 

The study expands upon previous SDOH-related research in liver disease and is the largest analysis of neighborhood-level SDOH in patients with MASLD to date. “Our findings are consistent with a recent study by Chen et al of over 15,900 patients with MASLD in Michigan that found neighborhood-level social disadvantage was associated with increased mortality and incident LREs and CVD,” Wijarnpreecha and colleagues wrote. 

“Beyond screening patients for individual-level SDOH, neighborhood-level determinants of health should also be considered, as they are important mediators between the environment and the individual,” they added, calling for studies to better understand the specific neighborhood SDOH that drive the disparate outcomes. In practice, integration of these measures into medical records might inform clinicians which patients would benefit from social services or help guide quality improvement projects and community partnerships.

Wijarnpreecha had no conflicts of interest to disclose. Several coauthors reported research support, consulting/advisory work, or stock ownership for various private-sector companies.
 

Neighborhood-level social determinants of health (SDOH) are associated with the burden, comorbidities, and mortality of metabolic dysfunction-associated steatotic disease (MASLD). These health mediators should be considered along with individual SDOH in clinical care and healthcare quality and equity improvement, a large retrospective study of adults with MASLD at a multi-state healthcare institution concluded.

Across quartiles, patients in the most disadvantaged neighborhoods (according to home addresses) vs the least disadvantaged had worse outcomes and were also disproportionately Hispanic, Black, and Native American/Alaska Native, more often Spanish-speaking in primary language, and more often uninsured or on Medicaid, according to Karn Wijarnpreecha, MD, MPH, of the Division of Gastroenterology and Hepatology at University of Arizona College of Medicine–Phoenix, and colleagues writing in Clinical Gastroenterology and Hepatology.

Even after adjustment for measures in the Social Deprivation Index (SDI), the incidence of death, cirrhosis, diabetes mellitus (DM), and major adverse cardiovascular events (MACE) was higher in Native American/Alaska Native patients compared with their non-Hispanic White counterparts. The SDI is a composite measure of seven demographic characteristics from the American Community Survey, with scores ranging from 1 to 100 and weighted based on characteristics from national percentile rankings.

Aligning with the growing prevalence of obesity and DM, MASLD has increased substantially over the past three decades, and is now the leading cause of chronic liver disease in this country and the world. 

This rise in prevalence has underscored health disparities in MASLD and prompted research into linkd between liver disease and SDOH, defined as the conditions under which people are born, grow, live, work, and age. These are fundamental drivers of health disparities, including those in MASLD.
 

Study Details

Primary outcomes were MASLD burden, mortality, and comorbidities by neighborhood SDOH, assessed using the SDI in cross-sectional and longitudinal analyses.

A total of 69,191 adult patients (more than 50% female) diagnosed with MASLD were included, 45,003 of whom had at least 365 days of follow-up. They were treated from July 2012 to June 2023 in Banner Health Systems, a network that includes primary-, secondary-, and tertiary-care centers in Arizona, Colorado, Wyoming, Nevada, Nebraska, and California.

The median follow-up time was 48 months. Among patients across SDI quartiles (age range 49 to 62 years), 1390 patients (3.1%) died, 902 (2.0%) developed cirrhosis, 1087 (2.4%) developed LRE, 6537 (14.5%) developed DM, 2057 (4.6%) developed cancer, and 5409 (12.0%) developed MACE.

Those living in the most disadvantaged quartile of neighborhoods compared with the least had the following higher odds:

• cirrhosis, adjusted odds ratio [aOR], 1.42 (P < .001)
• any cardiovascular (CVD) disease, aOR, 1.20 (P < .001),
• coronary artery disease, aOR, 1.17 (P < .001)
• congestive heart failure, aOR, 1.43 (P < .001)
• cerebrovascular accident, aOR, 1.19 (P = .001)
• DM, aOR, 1.57 (P < .001)
• hypertension, aOR, 1.38 (P < .001).

They also had increased incidence of death (adjusted hazard ratio [aHR], 1.47; P < .001), LRE (aHR, 1.31; P = .012), DM (aHR, 1.47; P < .001), and MACE (aHR, 1.24; P < .001). 

The study expands upon previous SDOH-related research in liver disease and is the largest analysis of neighborhood-level SDOH in patients with MASLD to date. “Our findings are consistent with a recent study by Chen et al of over 15,900 patients with MASLD in Michigan that found neighborhood-level social disadvantage was associated with increased mortality and incident LREs and CVD,” Wijarnpreecha and colleagues wrote. 

“Beyond screening patients for individual-level SDOH, neighborhood-level determinants of health should also be considered, as they are important mediators between the environment and the individual,” they added, calling for studies to better understand the specific neighborhood SDOH that drive the disparate outcomes. In practice, integration of these measures into medical records might inform clinicians which patients would benefit from social services or help guide quality improvement projects and community partnerships.

Wijarnpreecha had no conflicts of interest to disclose. Several coauthors reported research support, consulting/advisory work, or stock ownership for various private-sector companies.
 

Neighborhood-level social determinants of health (SDOH) are associated with the burden, comorbidities, and mortality of metabolic dysfunction-associated steatotic disease (MASLD). These health mediators should be considered along with individual SDOH in clinical care and healthcare quality and equity improvement, a large retrospective study of adults with MASLD at a multi-state healthcare institution concluded.

Across quartiles, patients in the most disadvantaged neighborhoods (according to home addresses) vs the least disadvantaged had worse outcomes and were also disproportionately Hispanic, Black, and Native American/Alaska Native, more often Spanish-speaking in primary language, and more often uninsured or on Medicaid, according to Karn Wijarnpreecha, MD, MPH, of the Division of Gastroenterology and Hepatology at University of Arizona College of Medicine–Phoenix, and colleagues writing in Clinical Gastroenterology and Hepatology.

Even after adjustment for measures in the Social Deprivation Index (SDI), the incidence of death, cirrhosis, diabetes mellitus (DM), and major adverse cardiovascular events (MACE) was higher in Native American/Alaska Native patients compared with their non-Hispanic White counterparts. The SDI is a composite measure of seven demographic characteristics from the American Community Survey, with scores ranging from 1 to 100 and weighted based on characteristics from national percentile rankings.

Aligning with the growing prevalence of obesity and DM, MASLD has increased substantially over the past three decades, and is now the leading cause of chronic liver disease in this country and the world. 

This rise in prevalence has underscored health disparities in MASLD and prompted research into linkd between liver disease and SDOH, defined as the conditions under which people are born, grow, live, work, and age. These are fundamental drivers of health disparities, including those in MASLD.
 

Study Details

Primary outcomes were MASLD burden, mortality, and comorbidities by neighborhood SDOH, assessed using the SDI in cross-sectional and longitudinal analyses.

A total of 69,191 adult patients (more than 50% female) diagnosed with MASLD were included, 45,003 of whom had at least 365 days of follow-up. They were treated from July 2012 to June 2023 in Banner Health Systems, a network that includes primary-, secondary-, and tertiary-care centers in Arizona, Colorado, Wyoming, Nevada, Nebraska, and California.

The median follow-up time was 48 months. Among patients across SDI quartiles (age range 49 to 62 years), 1390 patients (3.1%) died, 902 (2.0%) developed cirrhosis, 1087 (2.4%) developed LRE, 6537 (14.5%) developed DM, 2057 (4.6%) developed cancer, and 5409 (12.0%) developed MACE.

Those living in the most disadvantaged quartile of neighborhoods compared with the least had the following higher odds:

• cirrhosis, adjusted odds ratio [aOR], 1.42 (P < .001)
• any cardiovascular (CVD) disease, aOR, 1.20 (P < .001),
• coronary artery disease, aOR, 1.17 (P < .001)
• congestive heart failure, aOR, 1.43 (P < .001)
• cerebrovascular accident, aOR, 1.19 (P = .001)
• DM, aOR, 1.57 (P < .001)
• hypertension, aOR, 1.38 (P < .001).

They also had increased incidence of death (adjusted hazard ratio [aHR], 1.47; P < .001), LRE (aHR, 1.31; P = .012), DM (aHR, 1.47; P < .001), and MACE (aHR, 1.24; P < .001). 

The study expands upon previous SDOH-related research in liver disease and is the largest analysis of neighborhood-level SDOH in patients with MASLD to date. “Our findings are consistent with a recent study by Chen et al of over 15,900 patients with MASLD in Michigan that found neighborhood-level social disadvantage was associated with increased mortality and incident LREs and CVD,” Wijarnpreecha and colleagues wrote. 

“Beyond screening patients for individual-level SDOH, neighborhood-level determinants of health should also be considered, as they are important mediators between the environment and the individual,” they added, calling for studies to better understand the specific neighborhood SDOH that drive the disparate outcomes. In practice, integration of these measures into medical records might inform clinicians which patients would benefit from social services or help guide quality improvement projects and community partnerships.

Wijarnpreecha had no conflicts of interest to disclose. Several coauthors reported research support, consulting/advisory work, or stock ownership for various private-sector companies.
 

A head-to-head comparison of the JAK inhibitor drug tofacitinib and chimeric monoclonal antibody infliximab in the treatment of acute severe ulcerative colitis (ASUC) shows that, contrary to concerns, tofacitinib is not associated with worse postoperative complications and in fact may reduce the risk of the need for colectomy.

“Tofacitinib has shown efficacy in managing ASUC, but concerns about postoperative complications have limited its adoption,” reported the authors in research published in Clinical Gastroenterology and Hepatology.“This study shows that tofacitinib is safe and doesn’t impair wound healing or lead to more infections if the patient needs an urgent colectomy, which is unfortunately common in this population,” senior author Jeffrey A. Berinstein, MD, of the Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, told GI & Hepatology News. 

Recent treatment advances for UC have provided significant benefits in reducing the severity of symptoms; however, about a quarter of patients go on to experience flares, with fecal urgency, rectal bleeding, and severe abdominal pain of ASUC potentially requiring hospitalization.

The standard of care for those patients is rapid induction with intravenous (IV) corticosteroids; however, up to 30% of patients don’t respond to those interventions, and even with subsequent treatment of cyclosporine and infliximab helping to reduce the risk for an urgent colectomy, patients often don’t respond, and ultimately, up to a third of patients with ASUC end up having to receive a colectomy.

While JAK inhibitor therapies, including tofacitinib and upadacitinib, have recently emerged as potentially important treatment options in such cases, showing reductions in the risk for colectomy, concerns about the drugs’ downstream biologic effects have given many clinicians reservations about their use.

“Anecdotally, gastroenterologists and surgeons have expressed concern about JAK inhibitors leading to poor wound healing, as well as increasing both intraoperative and postoperative complications, despite limited data to support these claims,” the authors wrote.

To better understand those possible risks, first author Charlotte Larson, MD, of the Department of Internal Medicine, Michigan Medicine, and colleagues conducted a multicenter, retrospective, case-control study of 109 patients hospitalized with ASUC at two centers in the US and 14 in France.

Of the patients, 41 were treated with tofacitinib and 68 with infliximab prior to colectomy. 

Among patients treated with tofacitinib, five (12.2%) received infliximab and four (9.8%) received cyclosporine rescue immediately prior to receiving tofacitinib during the index admission. In the infliximab group, one (1.5%) received rescue cyclosporine.

In a univariate analysis, the tofacitinib-treated patients showed significantly lower overall rates of postoperative complications than infliximab-treated patients (31.7% vs 64.7%; odds ratio [OR], 0.33; P = .006).

The tofacitinib-treated group also had lower rates of serious postoperative complications (12% vs 28.9; OR, 0.20; P = .016).

After adjusting for multivariate factors including age, inflammatory burden, nutrition status, 90-day cumulative corticosteroid exposure and open surgery, there was a trend favoring tofacitinib but no statistically significant difference between the two treatments in terms of serious postoperative complications (P = .061). 

However, a significantly lower rate of overall postoperative complications with tofacitinib was observed after the adjustment (odds ratio, 0.38; P = .023).

Importantly, a subanalysis showed that the 63.4% of tofacitinib-treated patients receiving the standard FDA-approved induction dose of 10 mg twice daily did indeed have significantly lower rates than infliximab-treated patients in terms of serious postoperative complications (OR, .10; P = .031), as well as overall postoperative complications (OR, 0.23; P = .003), whereas neither of the outcomes were significantly improved among the 36.6% of patients who received the higher-intensity thrice-daily tofacitinib dose (P = .3 and P = .4, respectively).

Further complicating the matter, in a previous case-control study that the research team conducted, it was the off-label, 10 mg thrice-daily dose of tofacitinib that performed favorably and was associated with a significantly lower risk for colectomy than the twice-daily dose (hazard ratio 0.28; P = .018); the twice-daily dose was not protective.

Berinstein added that a hypothesis for the benefits overall, with either dose, is that tofacitinib’s anti-inflammatory properties are key.

“We believe that lowering inflammation as much as possible, with the colon less inflamed, could be providing the benefit in lowering complications rate in surgery,” he explained.

Regarding the dosing, “it’s a careful trade-off,” Berinstein added. “Obviously, we want to avoid the need for a colectomy in the first place, as it is a life-changing surgery, but we don’t want to increase the risk of infections.” 

In other findings, the tofacitinib group had no increased risk for postoperative venous thrombotic embolisms (VTEs), which is important as tofacitinib exposure has previously been associated with an increased risk for VTEs independent of other prothrombotic factors common to patients with ASUC, including decreased ambulation, active inflammation, corticosteroid use, and major colorectal surgery.

“This observed absence of an increased VTE risk may alleviate some of the hypothetical postoperative safety concern attributed to JAK inhibitor therapy in this high-risk population,” the authors wrote.

Overall, the results underscore that “providers should feel comfortable using this medication if they need it and if they think it’s most likely to help their patients avoid colectomy,” Berinstein said.

“They should not give pause over concerns of postoperative complications because we didn’t show that,” he said.

Commenting on the study, Joseph D. Feuerstein, MD, AGAF, of the Department of Medicine and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, noted that, in general, in patients with ASUC who fail on IV steroids, “the main treatments are infliximab, cyclosporine, or a JAK inhibitor like tofacitinib or upadacitinib, [and] knowing that if someone needs surgery, the complication rates are similar and that pre-operative use is okay is reassuring.”

Regarding the protective effect observed with some circumstances, “I don’t put too much weight into that,” he noted. “[One] could speculate that it is somehow related to faster half-life of the drug, and it might not sit around as long,” he said.

Feuerstein added that “the study design being retrospective is a limitation, but this is the best data we have to date.”

Berinstein and Feuerstein had no disclosures to report.

A version of this article appeared on Medscape.com . 

A head-to-head comparison of the JAK inhibitor drug tofacitinib and chimeric monoclonal antibody infliximab in the treatment of acute severe ulcerative colitis (ASUC) shows that, contrary to concerns, tofacitinib is not associated with worse postoperative complications and in fact may reduce the risk of the need for colectomy.

“Tofacitinib has shown efficacy in managing ASUC, but concerns about postoperative complications have limited its adoption,” reported the authors in research published in Clinical Gastroenterology and Hepatology.“This study shows that tofacitinib is safe and doesn’t impair wound healing or lead to more infections if the patient needs an urgent colectomy, which is unfortunately common in this population,” senior author Jeffrey A. Berinstein, MD, of the Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, told GI & Hepatology News. 

Recent treatment advances for UC have provided significant benefits in reducing the severity of symptoms; however, about a quarter of patients go on to experience flares, with fecal urgency, rectal bleeding, and severe abdominal pain of ASUC potentially requiring hospitalization.

The standard of care for those patients is rapid induction with intravenous (IV) corticosteroids; however, up to 30% of patients don’t respond to those interventions, and even with subsequent treatment of cyclosporine and infliximab helping to reduce the risk for an urgent colectomy, patients often don’t respond, and ultimately, up to a third of patients with ASUC end up having to receive a colectomy.

While JAK inhibitor therapies, including tofacitinib and upadacitinib, have recently emerged as potentially important treatment options in such cases, showing reductions in the risk for colectomy, concerns about the drugs’ downstream biologic effects have given many clinicians reservations about their use.

“Anecdotally, gastroenterologists and surgeons have expressed concern about JAK inhibitors leading to poor wound healing, as well as increasing both intraoperative and postoperative complications, despite limited data to support these claims,” the authors wrote.

To better understand those possible risks, first author Charlotte Larson, MD, of the Department of Internal Medicine, Michigan Medicine, and colleagues conducted a multicenter, retrospective, case-control study of 109 patients hospitalized with ASUC at two centers in the US and 14 in France.

Of the patients, 41 were treated with tofacitinib and 68 with infliximab prior to colectomy. 

Among patients treated with tofacitinib, five (12.2%) received infliximab and four (9.8%) received cyclosporine rescue immediately prior to receiving tofacitinib during the index admission. In the infliximab group, one (1.5%) received rescue cyclosporine.

In a univariate analysis, the tofacitinib-treated patients showed significantly lower overall rates of postoperative complications than infliximab-treated patients (31.7% vs 64.7%; odds ratio [OR], 0.33; P = .006).

The tofacitinib-treated group also had lower rates of serious postoperative complications (12% vs 28.9; OR, 0.20; P = .016).

After adjusting for multivariate factors including age, inflammatory burden, nutrition status, 90-day cumulative corticosteroid exposure and open surgery, there was a trend favoring tofacitinib but no statistically significant difference between the two treatments in terms of serious postoperative complications (P = .061). 

However, a significantly lower rate of overall postoperative complications with tofacitinib was observed after the adjustment (odds ratio, 0.38; P = .023).

Importantly, a subanalysis showed that the 63.4% of tofacitinib-treated patients receiving the standard FDA-approved induction dose of 10 mg twice daily did indeed have significantly lower rates than infliximab-treated patients in terms of serious postoperative complications (OR, .10; P = .031), as well as overall postoperative complications (OR, 0.23; P = .003), whereas neither of the outcomes were significantly improved among the 36.6% of patients who received the higher-intensity thrice-daily tofacitinib dose (P = .3 and P = .4, respectively).

Further complicating the matter, in a previous case-control study that the research team conducted, it was the off-label, 10 mg thrice-daily dose of tofacitinib that performed favorably and was associated with a significantly lower risk for colectomy than the twice-daily dose (hazard ratio 0.28; P = .018); the twice-daily dose was not protective.

Berinstein added that a hypothesis for the benefits overall, with either dose, is that tofacitinib’s anti-inflammatory properties are key.

“We believe that lowering inflammation as much as possible, with the colon less inflamed, could be providing the benefit in lowering complications rate in surgery,” he explained.

Regarding the dosing, “it’s a careful trade-off,” Berinstein added. “Obviously, we want to avoid the need for a colectomy in the first place, as it is a life-changing surgery, but we don’t want to increase the risk of infections.” 

In other findings, the tofacitinib group had no increased risk for postoperative venous thrombotic embolisms (VTEs), which is important as tofacitinib exposure has previously been associated with an increased risk for VTEs independent of other prothrombotic factors common to patients with ASUC, including decreased ambulation, active inflammation, corticosteroid use, and major colorectal surgery.

“This observed absence of an increased VTE risk may alleviate some of the hypothetical postoperative safety concern attributed to JAK inhibitor therapy in this high-risk population,” the authors wrote.

Overall, the results underscore that “providers should feel comfortable using this medication if they need it and if they think it’s most likely to help their patients avoid colectomy,” Berinstein said.

“They should not give pause over concerns of postoperative complications because we didn’t show that,” he said.

Commenting on the study, Joseph D. Feuerstein, MD, AGAF, of the Department of Medicine and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, noted that, in general, in patients with ASUC who fail on IV steroids, “the main treatments are infliximab, cyclosporine, or a JAK inhibitor like tofacitinib or upadacitinib, [and] knowing that if someone needs surgery, the complication rates are similar and that pre-operative use is okay is reassuring.”

Regarding the protective effect observed with some circumstances, “I don’t put too much weight into that,” he noted. “[One] could speculate that it is somehow related to faster half-life of the drug, and it might not sit around as long,” he said.

Feuerstein added that “the study design being retrospective is a limitation, but this is the best data we have to date.”

Berinstein and Feuerstein had no disclosures to report.

A version of this article appeared on Medscape.com . 

A head-to-head comparison of the JAK inhibitor drug tofacitinib and chimeric monoclonal antibody infliximab in the treatment of acute severe ulcerative colitis (ASUC) shows that, contrary to concerns, tofacitinib is not associated with worse postoperative complications and in fact may reduce the risk of the need for colectomy.

“Tofacitinib has shown efficacy in managing ASUC, but concerns about postoperative complications have limited its adoption,” reported the authors in research published in Clinical Gastroenterology and Hepatology.“This study shows that tofacitinib is safe and doesn’t impair wound healing or lead to more infections if the patient needs an urgent colectomy, which is unfortunately common in this population,” senior author Jeffrey A. Berinstein, MD, of the Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, told GI & Hepatology News. 

Recent treatment advances for UC have provided significant benefits in reducing the severity of symptoms; however, about a quarter of patients go on to experience flares, with fecal urgency, rectal bleeding, and severe abdominal pain of ASUC potentially requiring hospitalization.

The standard of care for those patients is rapid induction with intravenous (IV) corticosteroids; however, up to 30% of patients don’t respond to those interventions, and even with subsequent treatment of cyclosporine and infliximab helping to reduce the risk for an urgent colectomy, patients often don’t respond, and ultimately, up to a third of patients with ASUC end up having to receive a colectomy.

While JAK inhibitor therapies, including tofacitinib and upadacitinib, have recently emerged as potentially important treatment options in such cases, showing reductions in the risk for colectomy, concerns about the drugs’ downstream biologic effects have given many clinicians reservations about their use.

“Anecdotally, gastroenterologists and surgeons have expressed concern about JAK inhibitors leading to poor wound healing, as well as increasing both intraoperative and postoperative complications, despite limited data to support these claims,” the authors wrote.

To better understand those possible risks, first author Charlotte Larson, MD, of the Department of Internal Medicine, Michigan Medicine, and colleagues conducted a multicenter, retrospective, case-control study of 109 patients hospitalized with ASUC at two centers in the US and 14 in France.

Of the patients, 41 were treated with tofacitinib and 68 with infliximab prior to colectomy. 

Among patients treated with tofacitinib, five (12.2%) received infliximab and four (9.8%) received cyclosporine rescue immediately prior to receiving tofacitinib during the index admission. In the infliximab group, one (1.5%) received rescue cyclosporine.

In a univariate analysis, the tofacitinib-treated patients showed significantly lower overall rates of postoperative complications than infliximab-treated patients (31.7% vs 64.7%; odds ratio [OR], 0.33; P = .006).

The tofacitinib-treated group also had lower rates of serious postoperative complications (12% vs 28.9; OR, 0.20; P = .016).

After adjusting for multivariate factors including age, inflammatory burden, nutrition status, 90-day cumulative corticosteroid exposure and open surgery, there was a trend favoring tofacitinib but no statistically significant difference between the two treatments in terms of serious postoperative complications (P = .061). 

However, a significantly lower rate of overall postoperative complications with tofacitinib was observed after the adjustment (odds ratio, 0.38; P = .023).

Importantly, a subanalysis showed that the 63.4% of tofacitinib-treated patients receiving the standard FDA-approved induction dose of 10 mg twice daily did indeed have significantly lower rates than infliximab-treated patients in terms of serious postoperative complications (OR, .10; P = .031), as well as overall postoperative complications (OR, 0.23; P = .003), whereas neither of the outcomes were significantly improved among the 36.6% of patients who received the higher-intensity thrice-daily tofacitinib dose (P = .3 and P = .4, respectively).

Further complicating the matter, in a previous case-control study that the research team conducted, it was the off-label, 10 mg thrice-daily dose of tofacitinib that performed favorably and was associated with a significantly lower risk for colectomy than the twice-daily dose (hazard ratio 0.28; P = .018); the twice-daily dose was not protective.

Berinstein added that a hypothesis for the benefits overall, with either dose, is that tofacitinib’s anti-inflammatory properties are key.

“We believe that lowering inflammation as much as possible, with the colon less inflamed, could be providing the benefit in lowering complications rate in surgery,” he explained.

Regarding the dosing, “it’s a careful trade-off,” Berinstein added. “Obviously, we want to avoid the need for a colectomy in the first place, as it is a life-changing surgery, but we don’t want to increase the risk of infections.” 

In other findings, the tofacitinib group had no increased risk for postoperative venous thrombotic embolisms (VTEs), which is important as tofacitinib exposure has previously been associated with an increased risk for VTEs independent of other prothrombotic factors common to patients with ASUC, including decreased ambulation, active inflammation, corticosteroid use, and major colorectal surgery.

“This observed absence of an increased VTE risk may alleviate some of the hypothetical postoperative safety concern attributed to JAK inhibitor therapy in this high-risk population,” the authors wrote.

Overall, the results underscore that “providers should feel comfortable using this medication if they need it and if they think it’s most likely to help their patients avoid colectomy,” Berinstein said.

“They should not give pause over concerns of postoperative complications because we didn’t show that,” he said.

Commenting on the study, Joseph D. Feuerstein, MD, AGAF, of the Department of Medicine and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, noted that, in general, in patients with ASUC who fail on IV steroids, “the main treatments are infliximab, cyclosporine, or a JAK inhibitor like tofacitinib or upadacitinib, [and] knowing that if someone needs surgery, the complication rates are similar and that pre-operative use is okay is reassuring.”

Regarding the protective effect observed with some circumstances, “I don’t put too much weight into that,” he noted. “[One] could speculate that it is somehow related to faster half-life of the drug, and it might not sit around as long,” he said.

Feuerstein added that “the study design being retrospective is a limitation, but this is the best data we have to date.”

Berinstein and Feuerstein had no disclosures to report.

A version of this article appeared on Medscape.com . 

The American Gastroenterological Association (AGA) has released a comprehensive clinical practice update on lifting agents for endoscopic surgery.

Published in Clinical Gastroenterology and Hepatology, the commentary reviews available agents and provides clinically relevant commentary on their indications and use — with the caveat that it is not a formal systematic review but rather empirical advice for endoscopists. No formal rating of the quality of evidence or strength of recommendations was performed.

Led by Tobias Zuchelli, MD, a clinical associate professor at Michigan State University and a gastroenterologist at the Henry Ford Health System in Detroit, the expert panel noted that endoscopists are increasingly resecting precancerous lesions and early cancers of the gastrointestinal tract.

“Although new endoscopic procedures have been developed, there had not been much in terms of high-quality guidance on lifting agents,” panelist Amit V. Patel, MD, a professor of medicine at Duke University and director of Endoscopy at Durham Veterans Affairs Medical Center in Durham, North Carolina, told GI & Hepatology News. “With our better understanding and use of techniques, this commentary was timely. It summarizes the available data on the topic and includes our clinical experiences.”

Filling that knowledge gap, the document reviews in detail the timing and methods of agent injection according to procedure type, including the dynamic needle approach, the empirical merits of different agents such as saline (with or without blue contrast) and viscous agents, as well as lift-enhancing assistive devices — for example, the ERBEJET 2 high-pressure water jet, an adjustable hydrosurgical device to facilitate lifting. A chart provides an at-a-glance summary of agents and their pros and cons.

“The feedback from gastroenterologists so far has been quite positive on social media and on GI channels,” Patel said.

Endoscopic resection has evolved from snare polypectomy to endoscopic mucosal resection (EMR) and now, endoscopic submucosal dissection (ESD). The primary benefit of submucosal lifting is the creation of a separating submucosal cushion between the lesion and muscularis propria (MP), which reduces the risk for immediate or delayed perforation of the muscle. Adding a contrast agent also demarcates lesion margins and stains the submucosa, which is fundamental to ESD and allows for assessment of MP injury during EMR.

For decades, homemade solutions were used to lift lesions before removal, with the sentinel agent being normal saline, later mixed with a blue contrast agent, usually indigo carmine or methylene blue. The authors noted that some endoscopists performing ESD start the submucosal injection and incision using a prepackaged viscous solution. “The endoscopist may continue with the viscous fluid or transition to saline or another less expensive solution,” they wrote.

Saline tends to dissipate more quickly than viscous solutions, however. In 2015, the polymer compound SIC-8000 became the first FDA-approved submucosal injection agent. Since then, several other fluids have come on the market, although homemade agents remain available.

Among the update’s recommendations, the fluid selected for EMR should be determined by lesion size, predicted histology, and endoscopist preference. Based on the US Multi-Society Task Force (USMSTF) on Colorectal Cancer, submucosal injection is optional for nonpedunculated colorectal lesions (NPCRLs) of intermediate size (10-19 mm).

Cold snare polypectomy without submucosal injection was later found to be non-inferior to other resection methods utilizing submucosal injection for NPCRLs ≤ 15 mm. 

The update noted that the USMSTF considers EMR first-line therapy for most NPCRLs ≥ 20 mm and advocates viscous solutions as preferred, while the use of lifting agents for pedunculated polyps is generally at the discretion of the endoscopist.

For Patel, the main “clinical pearls” in the update are adding a contrast agent to normal saline, using a viscous agent for cold EMR, and manipulating the injection needle first tangentially and then dynamically toward the lumen to maximize separation of the lesion.

In terms of the ideal, an optimal lifting solution would be readily available, inexpensive, and premixed, providing a sustained submucosal cushion. “However, this ideal solution currently does not exist. Injection fluids should, therefore, be selected based on planned resection method, predicted histology, local expertise and preferences, and cost,” the panelists wrote.

Added Patel, “A lot of the agents out there check most of these boxes, but we’re hoping for further development toward the ideal.”

Offering a nonparticipant’s perspective on the overview, Wasseem Skef, MD, a gastroenterologist at UTHealth Houston, found the update very useful. “It always helps to have the literature summarized,” he told GI & Hepatology News. “It’s a pretty balanced review that pulls together the various options but allows people to stick to their preferred practice.”

In his practice, the lifting agent selected depends on the type of resection. “Viscous agents are generally more popular for EMR-type resections,” Skef said. One unanswered question, he noted, is whether adding a hemostatic agent would be superior to a viscous agent alone. “But overall, this is a nice summary of available agents. Gastroenterologists should consider these different options if doing procedures like EMR.”

This review was sponsored by the AGA Institute. 

Zuchelli is a consultant for Boston Scientific. Patel consults for Medpace, Renexxion, and Sanofi. Skef reported having no relevant disclosures.

A version of this article appeared on Medscape.com . 

The American Gastroenterological Association (AGA) has released a comprehensive clinical practice update on lifting agents for endoscopic surgery.

Published in Clinical Gastroenterology and Hepatology, the commentary reviews available agents and provides clinically relevant commentary on their indications and use — with the caveat that it is not a formal systematic review but rather empirical advice for endoscopists. No formal rating of the quality of evidence or strength of recommendations was performed.

Led by Tobias Zuchelli, MD, a clinical associate professor at Michigan State University and a gastroenterologist at the Henry Ford Health System in Detroit, the expert panel noted that endoscopists are increasingly resecting precancerous lesions and early cancers of the gastrointestinal tract.

“Although new endoscopic procedures have been developed, there had not been much in terms of high-quality guidance on lifting agents,” panelist Amit V. Patel, MD, a professor of medicine at Duke University and director of Endoscopy at Durham Veterans Affairs Medical Center in Durham, North Carolina, told GI & Hepatology News. “With our better understanding and use of techniques, this commentary was timely. It summarizes the available data on the topic and includes our clinical experiences.”

Filling that knowledge gap, the document reviews in detail the timing and methods of agent injection according to procedure type, including the dynamic needle approach, the empirical merits of different agents such as saline (with or without blue contrast) and viscous agents, as well as lift-enhancing assistive devices — for example, the ERBEJET 2 high-pressure water jet, an adjustable hydrosurgical device to facilitate lifting. A chart provides an at-a-glance summary of agents and their pros and cons.

“The feedback from gastroenterologists so far has been quite positive on social media and on GI channels,” Patel said.

Endoscopic resection has evolved from snare polypectomy to endoscopic mucosal resection (EMR) and now, endoscopic submucosal dissection (ESD). The primary benefit of submucosal lifting is the creation of a separating submucosal cushion between the lesion and muscularis propria (MP), which reduces the risk for immediate or delayed perforation of the muscle. Adding a contrast agent also demarcates lesion margins and stains the submucosa, which is fundamental to ESD and allows for assessment of MP injury during EMR.

For decades, homemade solutions were used to lift lesions before removal, with the sentinel agent being normal saline, later mixed with a blue contrast agent, usually indigo carmine or methylene blue. The authors noted that some endoscopists performing ESD start the submucosal injection and incision using a prepackaged viscous solution. “The endoscopist may continue with the viscous fluid or transition to saline or another less expensive solution,” they wrote.

Saline tends to dissipate more quickly than viscous solutions, however. In 2015, the polymer compound SIC-8000 became the first FDA-approved submucosal injection agent. Since then, several other fluids have come on the market, although homemade agents remain available.

Among the update’s recommendations, the fluid selected for EMR should be determined by lesion size, predicted histology, and endoscopist preference. Based on the US Multi-Society Task Force (USMSTF) on Colorectal Cancer, submucosal injection is optional for nonpedunculated colorectal lesions (NPCRLs) of intermediate size (10-19 mm).

Cold snare polypectomy without submucosal injection was later found to be non-inferior to other resection methods utilizing submucosal injection for NPCRLs ≤ 15 mm. 

The update noted that the USMSTF considers EMR first-line therapy for most NPCRLs ≥ 20 mm and advocates viscous solutions as preferred, while the use of lifting agents for pedunculated polyps is generally at the discretion of the endoscopist.

For Patel, the main “clinical pearls” in the update are adding a contrast agent to normal saline, using a viscous agent for cold EMR, and manipulating the injection needle first tangentially and then dynamically toward the lumen to maximize separation of the lesion.

In terms of the ideal, an optimal lifting solution would be readily available, inexpensive, and premixed, providing a sustained submucosal cushion. “However, this ideal solution currently does not exist. Injection fluids should, therefore, be selected based on planned resection method, predicted histology, local expertise and preferences, and cost,” the panelists wrote.

Added Patel, “A lot of the agents out there check most of these boxes, but we’re hoping for further development toward the ideal.”

Offering a nonparticipant’s perspective on the overview, Wasseem Skef, MD, a gastroenterologist at UTHealth Houston, found the update very useful. “It always helps to have the literature summarized,” he told GI & Hepatology News. “It’s a pretty balanced review that pulls together the various options but allows people to stick to their preferred practice.”

In his practice, the lifting agent selected depends on the type of resection. “Viscous agents are generally more popular for EMR-type resections,” Skef said. One unanswered question, he noted, is whether adding a hemostatic agent would be superior to a viscous agent alone. “But overall, this is a nice summary of available agents. Gastroenterologists should consider these different options if doing procedures like EMR.”

This review was sponsored by the AGA Institute. 

Zuchelli is a consultant for Boston Scientific. Patel consults for Medpace, Renexxion, and Sanofi. Skef reported having no relevant disclosures.

A version of this article appeared on Medscape.com . 

The American Gastroenterological Association (AGA) has released a comprehensive clinical practice update on lifting agents for endoscopic surgery.

Published in Clinical Gastroenterology and Hepatology, the commentary reviews available agents and provides clinically relevant commentary on their indications and use — with the caveat that it is not a formal systematic review but rather empirical advice for endoscopists. No formal rating of the quality of evidence or strength of recommendations was performed.

Led by Tobias Zuchelli, MD, a clinical associate professor at Michigan State University and a gastroenterologist at the Henry Ford Health System in Detroit, the expert panel noted that endoscopists are increasingly resecting precancerous lesions and early cancers of the gastrointestinal tract.

“Although new endoscopic procedures have been developed, there had not been much in terms of high-quality guidance on lifting agents,” panelist Amit V. Patel, MD, a professor of medicine at Duke University and director of Endoscopy at Durham Veterans Affairs Medical Center in Durham, North Carolina, told GI & Hepatology News. “With our better understanding and use of techniques, this commentary was timely. It summarizes the available data on the topic and includes our clinical experiences.”

Filling that knowledge gap, the document reviews in detail the timing and methods of agent injection according to procedure type, including the dynamic needle approach, the empirical merits of different agents such as saline (with or without blue contrast) and viscous agents, as well as lift-enhancing assistive devices — for example, the ERBEJET 2 high-pressure water jet, an adjustable hydrosurgical device to facilitate lifting. A chart provides an at-a-glance summary of agents and their pros and cons.

“The feedback from gastroenterologists so far has been quite positive on social media and on GI channels,” Patel said.

Endoscopic resection has evolved from snare polypectomy to endoscopic mucosal resection (EMR) and now, endoscopic submucosal dissection (ESD). The primary benefit of submucosal lifting is the creation of a separating submucosal cushion between the lesion and muscularis propria (MP), which reduces the risk for immediate or delayed perforation of the muscle. Adding a contrast agent also demarcates lesion margins and stains the submucosa, which is fundamental to ESD and allows for assessment of MP injury during EMR.

For decades, homemade solutions were used to lift lesions before removal, with the sentinel agent being normal saline, later mixed with a blue contrast agent, usually indigo carmine or methylene blue. The authors noted that some endoscopists performing ESD start the submucosal injection and incision using a prepackaged viscous solution. “The endoscopist may continue with the viscous fluid or transition to saline or another less expensive solution,” they wrote.

Saline tends to dissipate more quickly than viscous solutions, however. In 2015, the polymer compound SIC-8000 became the first FDA-approved submucosal injection agent. Since then, several other fluids have come on the market, although homemade agents remain available.

Among the update’s recommendations, the fluid selected for EMR should be determined by lesion size, predicted histology, and endoscopist preference. Based on the US Multi-Society Task Force (USMSTF) on Colorectal Cancer, submucosal injection is optional for nonpedunculated colorectal lesions (NPCRLs) of intermediate size (10-19 mm).

Cold snare polypectomy without submucosal injection was later found to be non-inferior to other resection methods utilizing submucosal injection for NPCRLs ≤ 15 mm. 

The update noted that the USMSTF considers EMR first-line therapy for most NPCRLs ≥ 20 mm and advocates viscous solutions as preferred, while the use of lifting agents for pedunculated polyps is generally at the discretion of the endoscopist.

For Patel, the main “clinical pearls” in the update are adding a contrast agent to normal saline, using a viscous agent for cold EMR, and manipulating the injection needle first tangentially and then dynamically toward the lumen to maximize separation of the lesion.

In terms of the ideal, an optimal lifting solution would be readily available, inexpensive, and premixed, providing a sustained submucosal cushion. “However, this ideal solution currently does not exist. Injection fluids should, therefore, be selected based on planned resection method, predicted histology, local expertise and preferences, and cost,” the panelists wrote.

Added Patel, “A lot of the agents out there check most of these boxes, but we’re hoping for further development toward the ideal.”

Offering a nonparticipant’s perspective on the overview, Wasseem Skef, MD, a gastroenterologist at UTHealth Houston, found the update very useful. “It always helps to have the literature summarized,” he told GI & Hepatology News. “It’s a pretty balanced review that pulls together the various options but allows people to stick to their preferred practice.”

In his practice, the lifting agent selected depends on the type of resection. “Viscous agents are generally more popular for EMR-type resections,” Skef said. One unanswered question, he noted, is whether adding a hemostatic agent would be superior to a viscous agent alone. “But overall, this is a nice summary of available agents. Gastroenterologists should consider these different options if doing procedures like EMR.”

This review was sponsored by the AGA Institute. 

Zuchelli is a consultant for Boston Scientific. Patel consults for Medpace, Renexxion, and Sanofi. Skef reported having no relevant disclosures.

A version of this article appeared on Medscape.com . 

The prevalence of irritable bowel syndrome (IBS) and chronic idiopathic constipation among US adults rose significantly during the COVID-19 pandemic, with a near doubling of the national rate of IBS over 2 years, a study has found.

The uptick is probably due to not only the direct impact of SARS-CoV-2 infection on the gastrointestinal tract but also to the psychological stress associated with pandemic life, the study team said. 

“COVID infection itself can definitely cause gastrointestinal symptoms like diarrhea, nausea, and abdominal pain — and for some people, those symptoms can linger and lead to chronic conditions like IBS,” Christopher V. Almario, MD, MSHPM, lead author and gastroenterologist at Cedars-Sinai Medical Center, Los Angeles, California, told GI & Hepatology News. 

“But the stress of living through the pandemic — lockdowns, fear, isolation — also likely played a major role as well in the increased prevalence of digestive disorders. Both the infection itself and the psychological toll of the pandemic can disrupt the gut-brain axis and trigger chronic digestive disorders like IBS,” Almario said. 

The study was published in Neurogastroenterology & Motility.

 

Growing Burden of Gut Disorders 

Disorders of gut-brain interaction (DGBIs) are a heterogeneous group of conditions in which gastrointestinal symptoms occur without any detectable structural or biochemical abnormalities in the digestive tract. They include IBS, functional dyspepsia, and chronic idiopathic constipation, among others. 

DGBIs are highly prevalent. Research has shown that nearly 40% of people in the US meet Rome IV criteria for at least one DGBI. 

Almario and colleagues assessed trends in prevalence of these conditions during the COVID-19 pandemic. Starting in May 2020 through May 2022, they conducted a series of online surveys with more than 160,000 adults aged 18 or older using validated Rome IV diagnostic questionnaires. 

Results showed that during the pandemic, IBS prevalence rose from 6.1% in May 2020 to 11.0% by May 2022, an increase of 0.188% per month (adjusted P < .001). 

Chronic idiopathic constipation showed a smaller but statistically significant increase, from 6.0% to 6.4% (0.056% per month; adjusted P < .001). 

Within the IBS subtypes, mixed-type IBS showed the largest relative increase (0.085% per month), followed by IBS with constipation (0.041% per month) and IBS with diarrhea (0.037% per month). 

There were no significant changes in the prevalence of other DGBIs, such as functional bloating, functional diarrhea, or functional dyspepsia, during the study period. 

Almario told GI & Hepatology News only about 9% of those surveyed reported a positive COVID test at the time of the surveys, but that figure probably underrepresents actual infections, especially in the early months of the pandemic. “Most of the survey responses came in during the earlier phases of the pandemic, and the percentage reporting a positive test increased over time,” he explained. 

Almario also noted that this study did not directly compare digestive disorder rates between infected and uninfected individuals. However, a separate study by the Cedars-Sinai team currently undergoing peer review addresses that question more directly. “That study, along with several other studies, show that having COVID increases the risk of developing conditions like IBS and functional dyspepsia,” Almario said. 

Taken together, the findings “underscore the increasing healthcare and economic burden of DGBI in the post-pandemic era, emphasizing the need for targeted efforts to effectively diagnose and manage these complex conditions,” they wrote. 

“This will be especially challenging for healthcare systems to address, given the existing shortage of primary care physicians and gastroenterologists — clinicians who primarily manage individuals with DGBI,” they noted. 

Support for this study was received from Ironwood Pharmaceuticals and Salix Pharmaceuticals in the form of institutional research grants to Cedars-Sinai. Almario has consulted for Exact Sciences, Greenspace Labs, Owlstone Medical, Salix Pharmaceuticals, and Universal DX.

A version of this article appeared on Medscape.com.

The prevalence of irritable bowel syndrome (IBS) and chronic idiopathic constipation among US adults rose significantly during the COVID-19 pandemic, with a near doubling of the national rate of IBS over 2 years, a study has found.

The uptick is probably due to not only the direct impact of SARS-CoV-2 infection on the gastrointestinal tract but also to the psychological stress associated with pandemic life, the study team said. 

“COVID infection itself can definitely cause gastrointestinal symptoms like diarrhea, nausea, and abdominal pain — and for some people, those symptoms can linger and lead to chronic conditions like IBS,” Christopher V. Almario, MD, MSHPM, lead author and gastroenterologist at Cedars-Sinai Medical Center, Los Angeles, California, told GI & Hepatology News. 

“But the stress of living through the pandemic — lockdowns, fear, isolation — also likely played a major role as well in the increased prevalence of digestive disorders. Both the infection itself and the psychological toll of the pandemic can disrupt the gut-brain axis and trigger chronic digestive disorders like IBS,” Almario said. 

The study was published in Neurogastroenterology & Motility.

 

Growing Burden of Gut Disorders 

Disorders of gut-brain interaction (DGBIs) are a heterogeneous group of conditions in which gastrointestinal symptoms occur without any detectable structural or biochemical abnormalities in the digestive tract. They include IBS, functional dyspepsia, and chronic idiopathic constipation, among others. 

DGBIs are highly prevalent. Research has shown that nearly 40% of people in the US meet Rome IV criteria for at least one DGBI. 

Almario and colleagues assessed trends in prevalence of these conditions during the COVID-19 pandemic. Starting in May 2020 through May 2022, they conducted a series of online surveys with more than 160,000 adults aged 18 or older using validated Rome IV diagnostic questionnaires. 

Results showed that during the pandemic, IBS prevalence rose from 6.1% in May 2020 to 11.0% by May 2022, an increase of 0.188% per month (adjusted P < .001). 

Chronic idiopathic constipation showed a smaller but statistically significant increase, from 6.0% to 6.4% (0.056% per month; adjusted P < .001). 

Within the IBS subtypes, mixed-type IBS showed the largest relative increase (0.085% per month), followed by IBS with constipation (0.041% per month) and IBS with diarrhea (0.037% per month). 

There were no significant changes in the prevalence of other DGBIs, such as functional bloating, functional diarrhea, or functional dyspepsia, during the study period. 

Almario told GI & Hepatology News only about 9% of those surveyed reported a positive COVID test at the time of the surveys, but that figure probably underrepresents actual infections, especially in the early months of the pandemic. “Most of the survey responses came in during the earlier phases of the pandemic, and the percentage reporting a positive test increased over time,” he explained. 

Almario also noted that this study did not directly compare digestive disorder rates between infected and uninfected individuals. However, a separate study by the Cedars-Sinai team currently undergoing peer review addresses that question more directly. “That study, along with several other studies, show that having COVID increases the risk of developing conditions like IBS and functional dyspepsia,” Almario said. 

Taken together, the findings “underscore the increasing healthcare and economic burden of DGBI in the post-pandemic era, emphasizing the need for targeted efforts to effectively diagnose and manage these complex conditions,” they wrote. 

“This will be especially challenging for healthcare systems to address, given the existing shortage of primary care physicians and gastroenterologists — clinicians who primarily manage individuals with DGBI,” they noted. 

Support for this study was received from Ironwood Pharmaceuticals and Salix Pharmaceuticals in the form of institutional research grants to Cedars-Sinai. Almario has consulted for Exact Sciences, Greenspace Labs, Owlstone Medical, Salix Pharmaceuticals, and Universal DX.

A version of this article appeared on Medscape.com.

The prevalence of irritable bowel syndrome (IBS) and chronic idiopathic constipation among US adults rose significantly during the COVID-19 pandemic, with a near doubling of the national rate of IBS over 2 years, a study has found.

The uptick is probably due to not only the direct impact of SARS-CoV-2 infection on the gastrointestinal tract but also to the psychological stress associated with pandemic life, the study team said. 

“COVID infection itself can definitely cause gastrointestinal symptoms like diarrhea, nausea, and abdominal pain — and for some people, those symptoms can linger and lead to chronic conditions like IBS,” Christopher V. Almario, MD, MSHPM, lead author and gastroenterologist at Cedars-Sinai Medical Center, Los Angeles, California, told GI & Hepatology News. 

“But the stress of living through the pandemic — lockdowns, fear, isolation — also likely played a major role as well in the increased prevalence of digestive disorders. Both the infection itself and the psychological toll of the pandemic can disrupt the gut-brain axis and trigger chronic digestive disorders like IBS,” Almario said. 

The study was published in Neurogastroenterology & Motility.

 

Growing Burden of Gut Disorders 

Disorders of gut-brain interaction (DGBIs) are a heterogeneous group of conditions in which gastrointestinal symptoms occur without any detectable structural or biochemical abnormalities in the digestive tract. They include IBS, functional dyspepsia, and chronic idiopathic constipation, among others. 

DGBIs are highly prevalent. Research has shown that nearly 40% of people in the US meet Rome IV criteria for at least one DGBI. 

Almario and colleagues assessed trends in prevalence of these conditions during the COVID-19 pandemic. Starting in May 2020 through May 2022, they conducted a series of online surveys with more than 160,000 adults aged 18 or older using validated Rome IV diagnostic questionnaires. 

Results showed that during the pandemic, IBS prevalence rose from 6.1% in May 2020 to 11.0% by May 2022, an increase of 0.188% per month (adjusted P < .001). 

Chronic idiopathic constipation showed a smaller but statistically significant increase, from 6.0% to 6.4% (0.056% per month; adjusted P < .001). 

Within the IBS subtypes, mixed-type IBS showed the largest relative increase (0.085% per month), followed by IBS with constipation (0.041% per month) and IBS with diarrhea (0.037% per month). 

There were no significant changes in the prevalence of other DGBIs, such as functional bloating, functional diarrhea, or functional dyspepsia, during the study period. 

Almario told GI & Hepatology News only about 9% of those surveyed reported a positive COVID test at the time of the surveys, but that figure probably underrepresents actual infections, especially in the early months of the pandemic. “Most of the survey responses came in during the earlier phases of the pandemic, and the percentage reporting a positive test increased over time,” he explained. 

Almario also noted that this study did not directly compare digestive disorder rates between infected and uninfected individuals. However, a separate study by the Cedars-Sinai team currently undergoing peer review addresses that question more directly. “That study, along with several other studies, show that having COVID increases the risk of developing conditions like IBS and functional dyspepsia,” Almario said. 

Taken together, the findings “underscore the increasing healthcare and economic burden of DGBI in the post-pandemic era, emphasizing the need for targeted efforts to effectively diagnose and manage these complex conditions,” they wrote. 

“This will be especially challenging for healthcare systems to address, given the existing shortage of primary care physicians and gastroenterologists — clinicians who primarily manage individuals with DGBI,” they noted. 

Support for this study was received from Ironwood Pharmaceuticals and Salix Pharmaceuticals in the form of institutional research grants to Cedars-Sinai. Almario has consulted for Exact Sciences, Greenspace Labs, Owlstone Medical, Salix Pharmaceuticals, and Universal DX.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has issued an early alert for three Medtronic pH-monitoring capsule devices. The notice follows two letters sent in June to customers by the devices’ manufacturer Medtronic and its subsidiary Given Imaging Inc., recommending that customers using certain Bravo CF Capsule Delivery Devices (lot numbers below) for esophageal pH monitoring be removed from all sites of use and sale.

All three of the capsule models listed below are thought to pose a potential risk because the capsules fail to attach to the esophagus’s mucosal wall or to detach from the delivery device as intended owing to a misapplication of adhesive during manufacture. The devices transmit pH data to a recorder attached to the waist of the patient, who interacts with the recorder to indicate symptoms, thereby allowing the physician to compare the symptoms with the occurrence of reflux episodes.

Risks associated with the devices include aspiration/inhalation, perforation of the esophagus, obstruction of the airway, hemorrhage/blood loss/bleeding, laceration of the esophagus, a delay in diagnosis, and foreign bodies remaining in the patient.

Medtronic has reported 33 serious injuries but no deaths associated with the devices.

The lot numbers of the three affected units, which should be identified and quarantined immediately are:

• Bravo CF Capsule Delivery Device, 5-pk, Product Number FGS-0635, Unique Device Identifier-Device Identifier (UDI-DI) 07290101369707
• Bravo CF Capsule Delivery Device 5-pk, FGS-0635, UDI-DI 10613994000009
• Bravo CF Capsule Delivery Device 1-pk, FGS-0636, UDI-DI 07290101369714

These lot identifiers can be found on both the 5-pks’ FGS-0635 outer labels and on the 1-pk FGS-036 individual unit. Customers are advised to return all unused affected products to Medtronic for replacement or credit. In addition, they should pass on this notice to all those who need to be aware within their organizations or to any organizations to which the affected products have been distributed.

They are also advised to check the FDA recall website above for updates as it continues to review information about this potentially high-risk device issue. 

Healthcare professionals with concerns or reports of adverse events can contact Medtronic at 800-448-3644 or MedWatch: The FDA Safety Information and Adverse Event Reporting Program.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has issued an early alert for three Medtronic pH-monitoring capsule devices. The notice follows two letters sent in June to customers by the devices’ manufacturer Medtronic and its subsidiary Given Imaging Inc., recommending that customers using certain Bravo CF Capsule Delivery Devices (lot numbers below) for esophageal pH monitoring be removed from all sites of use and sale.

All three of the capsule models listed below are thought to pose a potential risk because the capsules fail to attach to the esophagus’s mucosal wall or to detach from the delivery device as intended owing to a misapplication of adhesive during manufacture. The devices transmit pH data to a recorder attached to the waist of the patient, who interacts with the recorder to indicate symptoms, thereby allowing the physician to compare the symptoms with the occurrence of reflux episodes.

Risks associated with the devices include aspiration/inhalation, perforation of the esophagus, obstruction of the airway, hemorrhage/blood loss/bleeding, laceration of the esophagus, a delay in diagnosis, and foreign bodies remaining in the patient.

Medtronic has reported 33 serious injuries but no deaths associated with the devices.

The lot numbers of the three affected units, which should be identified and quarantined immediately are:

• Bravo CF Capsule Delivery Device, 5-pk, Product Number FGS-0635, Unique Device Identifier-Device Identifier (UDI-DI) 07290101369707
• Bravo CF Capsule Delivery Device 5-pk, FGS-0635, UDI-DI 10613994000009
• Bravo CF Capsule Delivery Device 1-pk, FGS-0636, UDI-DI 07290101369714

These lot identifiers can be found on both the 5-pks’ FGS-0635 outer labels and on the 1-pk FGS-036 individual unit. Customers are advised to return all unused affected products to Medtronic for replacement or credit. In addition, they should pass on this notice to all those who need to be aware within their organizations or to any organizations to which the affected products have been distributed.

They are also advised to check the FDA recall website above for updates as it continues to review information about this potentially high-risk device issue. 

Healthcare professionals with concerns or reports of adverse events can contact Medtronic at 800-448-3644 or MedWatch: The FDA Safety Information and Adverse Event Reporting Program.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has issued an early alert for three Medtronic pH-monitoring capsule devices. The notice follows two letters sent in June to customers by the devices’ manufacturer Medtronic and its subsidiary Given Imaging Inc., recommending that customers using certain Bravo CF Capsule Delivery Devices (lot numbers below) for esophageal pH monitoring be removed from all sites of use and sale.

All three of the capsule models listed below are thought to pose a potential risk because the capsules fail to attach to the esophagus’s mucosal wall or to detach from the delivery device as intended owing to a misapplication of adhesive during manufacture. The devices transmit pH data to a recorder attached to the waist of the patient, who interacts with the recorder to indicate symptoms, thereby allowing the physician to compare the symptoms with the occurrence of reflux episodes.

Risks associated with the devices include aspiration/inhalation, perforation of the esophagus, obstruction of the airway, hemorrhage/blood loss/bleeding, laceration of the esophagus, a delay in diagnosis, and foreign bodies remaining in the patient.

Medtronic has reported 33 serious injuries but no deaths associated with the devices.

The lot numbers of the three affected units, which should be identified and quarantined immediately are:

• Bravo CF Capsule Delivery Device, 5-pk, Product Number FGS-0635, Unique Device Identifier-Device Identifier (UDI-DI) 07290101369707
• Bravo CF Capsule Delivery Device 5-pk, FGS-0635, UDI-DI 10613994000009
• Bravo CF Capsule Delivery Device 1-pk, FGS-0636, UDI-DI 07290101369714

These lot identifiers can be found on both the 5-pks’ FGS-0635 outer labels and on the 1-pk FGS-036 individual unit. Customers are advised to return all unused affected products to Medtronic for replacement or credit. In addition, they should pass on this notice to all those who need to be aware within their organizations or to any organizations to which the affected products have been distributed.

They are also advised to check the FDA recall website above for updates as it continues to review information about this potentially high-risk device issue. 

Healthcare professionals with concerns or reports of adverse events can contact Medtronic at 800-448-3644 or MedWatch: The FDA Safety Information and Adverse Event Reporting Program.
 

A version of this article appeared on Medscape.com.

Scientists are working hard to develop new treatments and therapies, and to discover cures to advance the field and better patient care. But they can’t do this without research funding.

A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs.  

Donations to the AGA Research Foundation help support and fund investigators with a research grant in the field of gastroenterology and hepatology.

Treatment options for digestive diseases begin with rigorous research, but the limited funding available for physician-scientists to conduct research puts the field at risk of losing talented investigators.

As an AGA member, you have the power to make a difference. By increasing the number of talented women and men doing state-of-the-art research, you can help improve care for all patients suffering from digestive diseases.

Your gift to the AGA Research Foundation will catalyze discovery and career growth for a promising researcher in gastroenterology and hepatology. Please help us fund the next generation of GI researchers by donating today at https://foundation.gastro.org.







 

Scientists are working hard to develop new treatments and therapies, and to discover cures to advance the field and better patient care. But they can’t do this without research funding.

A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs.  

Donations to the AGA Research Foundation help support and fund investigators with a research grant in the field of gastroenterology and hepatology.

Treatment options for digestive diseases begin with rigorous research, but the limited funding available for physician-scientists to conduct research puts the field at risk of losing talented investigators.

As an AGA member, you have the power to make a difference. By increasing the number of talented women and men doing state-of-the-art research, you can help improve care for all patients suffering from digestive diseases.

Your gift to the AGA Research Foundation will catalyze discovery and career growth for a promising researcher in gastroenterology and hepatology. Please help us fund the next generation of GI researchers by donating today at https://foundation.gastro.org.







 

Scientists are working hard to develop new treatments and therapies, and to discover cures to advance the field and better patient care. But they can’t do this without research funding.

A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs.  

Donations to the AGA Research Foundation help support and fund investigators with a research grant in the field of gastroenterology and hepatology.

Treatment options for digestive diseases begin with rigorous research, but the limited funding available for physician-scientists to conduct research puts the field at risk of losing talented investigators.

As an AGA member, you have the power to make a difference. By increasing the number of talented women and men doing state-of-the-art research, you can help improve care for all patients suffering from digestive diseases.

Your gift to the AGA Research Foundation will catalyze discovery and career growth for a promising researcher in gastroenterology and hepatology. Please help us fund the next generation of GI researchers by donating today at https://foundation.gastro.org.







 

About 530,000 to 628,000 episodes of bloodstream infections (BSI) occur annually in the US.¹ Early identification and treatment of bacteremia are essential to improve patient outcomes because it allows for more timely targeted antibiotic therapy.² Organism identification and susceptibility testing can take 2 to 5 days, prolonging the use of broad-spectrum empiric antibiotics and increasing the risk of adverse events.^3,4 The Infectious Disease Society of America recommends the use of rapid diagnostic testing and antimicrobial stewardship programs (ASPs) to improve rates of antibiotic susceptibilities to targeted antibiotics and optimize resource utilization.³ Rapid blood culture identification (BCID) technologies reduce the duration of empiric antibiotics in patients with contaminated blood cultures, resulting in shorter hospital stays and saving money per each patient tested.⁴

In March 2023, Veteran Health Indiana (VHI) implemented the BioFire FilmArray Blood Culture Identification (BCID2), a BSI panel test that identifies select gram-negative bacteria, gram-positive bacteria, yeast, and antimicrobial resistance genes with an aggregate sensitivity of 99% and a specificity of 99.8%. The BCID2 presents clinically relevant information faster than traditional culture methods, allowing clinicians to make more efficient and educated antibiotic regimen decisions than with previous methods.⁵

It takes 24 to 48 hours from blood collection for culture incubation, positivity, and gram staining to occur at VHI. If the gram stain is positive, the blood culture is placed on the BioFire BCID2 in addition to traditional culture medium. BioFire BCID2 results are ready in 45 to 60 minutes. Results are uploaded into the electronic health record (EHR) ≤ 2 hours after they are obtained and the primary team is notified if the test is positive for certain critical results. Susceptibility testing of an identified organism typically requires an additional 24 to 48 hours for finalization. VHI Infectious Disease created an evidence-based antibiotic recommendation chart for certain medication(s) and alternate therapies based on the reported organism and its interpreted presence of resistance markers (eg, ceftriaxone for Escherichia coli when extended-spectrum beta lactamases are not detected vs meropenem if extended-spectrum beta lactamases marker are present). These charts optimize the antibiotic regimen while awaiting susceptibility finalizations.

Two previous studies describe the impact of rapid diagnostic testing technology at US Department of Veterans Affairs (VA) medical centers.^6,7 In Texas, the ASP reviewed BCID panel results via clinical decision support software for about 1 hour per day.⁶ A Los Angeles study analyzed the impact of Biofire BCID with an interpretation guide centered on unnecessary vancomycin use and determined that shorter duration of the medication may have been the result of more frequent infectious disease consultation.⁷

This study assessed the time to optimal antibiotic de-escalation before and after the implementation of BioFire BCID2 with results reviewed by the ASP without active notification or assistance of any clinical decision support technology. The primary objective was to evaluate difference in time to optimal antibiotics from blood culture draw pre- vs postintervention. Secondary objectives included differences in time to organism identification, difference in time on broad-spectrum antibiotics, and difference in time to appropriate antibiotics.

Methods

This quasi-experimental retrospective chart review assessed the impact of BioFire BCID2 use on timely antibiotic de-escalation for patients who experienced a BSI at VHI between March 1, 2022, and October 1, 2023. Microbiology laboratory records identified eligible patients with positive blood cultures within the study time frame. Data were collected from the VHI EHR.

Patients were included if they had a positive bacterial blood culture and received ≥ 1 antibiotic indicated for bacteremia while receiving inpatient care. Patients were excluded if they died prior to blood culture results, transferred out of VHI, left against medical advice, or had untreated contaminants in blood culture results (ie, never received antibiotics aimed at the contaminated culture).

Patient lists were generated for before and after implementation of BioFire BCID2 (pre- and postintervention) using the VHI EHR and microbiology laboratory record system. The pre- and postinterventions groups were different sizes. As a result, a random sampling of the preintervention group was selected and included patients from March 1, 2022, through March 26, 2023. The postintervention group was smaller due to time constraints between initiation of BioFire BCID2 for data collection and included all patients from March 27, 2023, through October 1, 2023.

Optimal antibiotics were defined as escalation from inappropriate therapy to broader agent(s), de-escalation from broad-spectrum therapy to targeted agent(s), discontinuation of therapy due to an organism being identified as a contaminant, or optimization of a regimen to the preferred antimicrobial agent based on evidence-based consensus guidelines. Broad-spectrum antibiotics included: piperacillin/tazobactam, cefepime, ceftazidime, ceftazidime-avibactam, cefiderocol, carbapenems, fluroquinolones, vancomycin, daptomycin, ceftaroline, linezolid, or aztreonam. Appropriate antibiotics were defined as those with activity toward the final identified organism(s).

Deidentified participant data were entered into Microsoft Excel and kept on a secure VA server to complete statistical analyses. Parametric continuous data, such as age, were analyzed using the t-test, while nonparametric continuous data, such as time to optimal antibiotics, were analyzed using the Mann-Whitney U test. Categorical data, like sex and race, were analyzed using either Fisher exact test for small sample sizes or X² test for a larger sample size. Statistical significance levels was defined as P < .05.

Results

Using patient lists drawn from the EHR and the microbiology laboratory records, 110 electronic charts were randomly selected for review. Fifteen patients were excluded: 8 had untreated contaminants, 4 died, and 3 were transferred out of VHI. Of the 95 patients included, 48 were in the preintervention group and 47 were in the postintervention group (Figure 1).

Baseline characteristics were similar between the 2 groups (Table 1). Most patients were White males aged > 70 years in the EHR. The urinary tract was the most common source of infection, impacting 12 patients in each group (Figure 2). Escherichia coli, Klebsiella, Staphylococcus, and Streptococcus were the most common bloodstream isolates identified.

The median time to optimal antibiotics in the preintervention group was 58.5 hours vs 43.4 hours in the postintervention group (P = .11). The median time to organism identification was 37.8 hours in the preintervention group vs 16.9 hours in the postintervention group (P < .001). The median time on broad-spectrum antibiotics was 45.2 hours in the preintervention group vs 46.6 hours in the postintervention group (P = .99). The median time on appropriate antibiotics in the preintervention group was 2.3 hours vs 1.9 hours in the postintervention group (P = .79). Differences in other measured outcomes between the groups were not statistically significant (Table 2).

Although implementation of rapid diagnostic technology reduced the median time to optimal antibiotics, the results were not statistically significant. Shorter time to organism identification in the postintervention group compared to the preintervention group was the lone statistically significant metric (P < .001).

Discussion

A lack of statistical significance in the primary outcome may have been due to nonadherence to facility de-escalation protocols or a suboptimal BioFire BCID2 result notification system. Additionally, use of rapid BCID at VHI may improve over time as clinicians become more familiar with the technology. Gaps in clinical pharmacy coverage during the night shift may have also contributed to delays in antibiotic optimization, particularly if other clinicians are not equipped with the knowledge or training to appropriately deescalate antibiotics based on microorganisms identified. A 2017 study by Donner et al concluded that physician interpretation of BCID results is suboptimal and should be augmented with clinical decision support tools as new technology becomes available.⁸ Despite the statistically insignificant results of this study, it did highlight potential areas of improvement which can lead to improved patient care.

Previous research has evaluated the impact of rapid BCID technology on antibiotic treatment and clinical outcomes. Chiasson et al found that median time to optimal therapy was 73.8 hours in the pre-BCID arm compared to 34.7 hours in the post- BCID arm (P ≤ .001), emphasizing the importance of combining rapid BCID with clinical decision support tools and pharmacy input.⁶ Senok et al found that BCID2 implementation led to a significant decrease in median time to culture result, which informed optimal antibiotic therapy and decreased 30-day mortality in the intensive care setting.⁹ In contrast, the current study did not stratify patients according to medical ward or illness severity even though clinicians may be less likely to de-escalate antibiotic therapy in critically ill patients.

Bae et al reported findings consistent with the current study and concluded that BCID did not affect the clinical outcomes of overall BSIs; however, it contributed to early administration of effective antibiotics in cases of BSIs caused by multidrug-resistant organisms.¹⁰ Results of this study were not stratified according to multidrug-resistant organisms because the sample size was too small. The current study also included patients with polymicrobial infections, which may have impacted the results due to a less streamlined approach to antibiotic optimization.

Limitations

This single-center, retrospective study had a small sample size, short time frame, and lacked patient diversity, and therefore may not be generalizable to other health care systems. The sample size was limited by shorter date range and smaller patient list between BioFire BCID2 implementation and data collection, which was used to determine the number of charts selected in each group. Some patients received antibiotics prior to blood cultures being drawn, which may falsely decrease time to optimal/ appropriate antibiotics and falsely increase time on broad spectrum/any antibiotics due to early antibiotic administration. The total number of patients on broad-spectrum antibiotics differed from the total number of patients for other outcomes because several patients never received the defined broad spectrum antibiotics.

Conclusions

When combined with a pre-existing ASP without active notification, the implementation of BioFire BCID2 did not return statistically significant data showing a decrease in time to optimal antibiotics, time to appropriate antibiotics, or time on broad-spectrum antibiotics at VHI. To make this program more successful, pharmacist intervention and clinical decision support tools may be needed.

Additional research is required to determine the optimal integration of antimicrobial stewardship, rapid diagnostic technology, and pharmacy services for maximum benefit. Even though the primary outcome was not statistically significant, the results may be clinically significant from a stewardship perspective. Realigning microbiology workflows to mimic other research, which emphasizes the importance of funneling rapid BCID results through the ASP, may improve outcomes. Future studies may be warranted following the implementation of clinical decision support tools to assess their impact on stewardship practices and patient outcomes.

About 530,000 to 628,000 episodes of bloodstream infections (BSI) occur annually in the US.¹ Early identification and treatment of bacteremia are essential to improve patient outcomes because it allows for more timely targeted antibiotic therapy.² Organism identification and susceptibility testing can take 2 to 5 days, prolonging the use of broad-spectrum empiric antibiotics and increasing the risk of adverse events.^3,4 The Infectious Disease Society of America recommends the use of rapid diagnostic testing and antimicrobial stewardship programs (ASPs) to improve rates of antibiotic susceptibilities to targeted antibiotics and optimize resource utilization.³ Rapid blood culture identification (BCID) technologies reduce the duration of empiric antibiotics in patients with contaminated blood cultures, resulting in shorter hospital stays and saving money per each patient tested.⁴

In March 2023, Veteran Health Indiana (VHI) implemented the BioFire FilmArray Blood Culture Identification (BCID2), a BSI panel test that identifies select gram-negative bacteria, gram-positive bacteria, yeast, and antimicrobial resistance genes with an aggregate sensitivity of 99% and a specificity of 99.8%. The BCID2 presents clinically relevant information faster than traditional culture methods, allowing clinicians to make more efficient and educated antibiotic regimen decisions than with previous methods.⁵

It takes 24 to 48 hours from blood collection for culture incubation, positivity, and gram staining to occur at VHI. If the gram stain is positive, the blood culture is placed on the BioFire BCID2 in addition to traditional culture medium. BioFire BCID2 results are ready in 45 to 60 minutes. Results are uploaded into the electronic health record (EHR) ≤ 2 hours after they are obtained and the primary team is notified if the test is positive for certain critical results. Susceptibility testing of an identified organism typically requires an additional 24 to 48 hours for finalization. VHI Infectious Disease created an evidence-based antibiotic recommendation chart for certain medication(s) and alternate therapies based on the reported organism and its interpreted presence of resistance markers (eg, ceftriaxone for Escherichia coli when extended-spectrum beta lactamases are not detected vs meropenem if extended-spectrum beta lactamases marker are present). These charts optimize the antibiotic regimen while awaiting susceptibility finalizations.

Two previous studies describe the impact of rapid diagnostic testing technology at US Department of Veterans Affairs (VA) medical centers.^6,7 In Texas, the ASP reviewed BCID panel results via clinical decision support software for about 1 hour per day.⁶ A Los Angeles study analyzed the impact of Biofire BCID with an interpretation guide centered on unnecessary vancomycin use and determined that shorter duration of the medication may have been the result of more frequent infectious disease consultation.⁷

This study assessed the time to optimal antibiotic de-escalation before and after the implementation of BioFire BCID2 with results reviewed by the ASP without active notification or assistance of any clinical decision support technology. The primary objective was to evaluate difference in time to optimal antibiotics from blood culture draw pre- vs postintervention. Secondary objectives included differences in time to organism identification, difference in time on broad-spectrum antibiotics, and difference in time to appropriate antibiotics.

Methods

This quasi-experimental retrospective chart review assessed the impact of BioFire BCID2 use on timely antibiotic de-escalation for patients who experienced a BSI at VHI between March 1, 2022, and October 1, 2023. Microbiology laboratory records identified eligible patients with positive blood cultures within the study time frame. Data were collected from the VHI EHR.

Patients were included if they had a positive bacterial blood culture and received ≥ 1 antibiotic indicated for bacteremia while receiving inpatient care. Patients were excluded if they died prior to blood culture results, transferred out of VHI, left against medical advice, or had untreated contaminants in blood culture results (ie, never received antibiotics aimed at the contaminated culture).

Patient lists were generated for before and after implementation of BioFire BCID2 (pre- and postintervention) using the VHI EHR and microbiology laboratory record system. The pre- and postinterventions groups were different sizes. As a result, a random sampling of the preintervention group was selected and included patients from March 1, 2022, through March 26, 2023. The postintervention group was smaller due to time constraints between initiation of BioFire BCID2 for data collection and included all patients from March 27, 2023, through October 1, 2023.

Optimal antibiotics were defined as escalation from inappropriate therapy to broader agent(s), de-escalation from broad-spectrum therapy to targeted agent(s), discontinuation of therapy due to an organism being identified as a contaminant, or optimization of a regimen to the preferred antimicrobial agent based on evidence-based consensus guidelines. Broad-spectrum antibiotics included: piperacillin/tazobactam, cefepime, ceftazidime, ceftazidime-avibactam, cefiderocol, carbapenems, fluroquinolones, vancomycin, daptomycin, ceftaroline, linezolid, or aztreonam. Appropriate antibiotics were defined as those with activity toward the final identified organism(s).

Deidentified participant data were entered into Microsoft Excel and kept on a secure VA server to complete statistical analyses. Parametric continuous data, such as age, were analyzed using the t-test, while nonparametric continuous data, such as time to optimal antibiotics, were analyzed using the Mann-Whitney U test. Categorical data, like sex and race, were analyzed using either Fisher exact test for small sample sizes or X² test for a larger sample size. Statistical significance levels was defined as P < .05.

Results

Using patient lists drawn from the EHR and the microbiology laboratory records, 110 electronic charts were randomly selected for review. Fifteen patients were excluded: 8 had untreated contaminants, 4 died, and 3 were transferred out of VHI. Of the 95 patients included, 48 were in the preintervention group and 47 were in the postintervention group (Figure 1).

Baseline characteristics were similar between the 2 groups (Table 1). Most patients were White males aged > 70 years in the EHR. The urinary tract was the most common source of infection, impacting 12 patients in each group (Figure 2). Escherichia coli, Klebsiella, Staphylococcus, and Streptococcus were the most common bloodstream isolates identified.

The median time to optimal antibiotics in the preintervention group was 58.5 hours vs 43.4 hours in the postintervention group (P = .11). The median time to organism identification was 37.8 hours in the preintervention group vs 16.9 hours in the postintervention group (P < .001). The median time on broad-spectrum antibiotics was 45.2 hours in the preintervention group vs 46.6 hours in the postintervention group (P = .99). The median time on appropriate antibiotics in the preintervention group was 2.3 hours vs 1.9 hours in the postintervention group (P = .79). Differences in other measured outcomes between the groups were not statistically significant (Table 2).

Although implementation of rapid diagnostic technology reduced the median time to optimal antibiotics, the results were not statistically significant. Shorter time to organism identification in the postintervention group compared to the preintervention group was the lone statistically significant metric (P < .001).

Discussion

A lack of statistical significance in the primary outcome may have been due to nonadherence to facility de-escalation protocols or a suboptimal BioFire BCID2 result notification system. Additionally, use of rapid BCID at VHI may improve over time as clinicians become more familiar with the technology. Gaps in clinical pharmacy coverage during the night shift may have also contributed to delays in antibiotic optimization, particularly if other clinicians are not equipped with the knowledge or training to appropriately deescalate antibiotics based on microorganisms identified. A 2017 study by Donner et al concluded that physician interpretation of BCID results is suboptimal and should be augmented with clinical decision support tools as new technology becomes available.⁸ Despite the statistically insignificant results of this study, it did highlight potential areas of improvement which can lead to improved patient care.

Previous research has evaluated the impact of rapid BCID technology on antibiotic treatment and clinical outcomes. Chiasson et al found that median time to optimal therapy was 73.8 hours in the pre-BCID arm compared to 34.7 hours in the post- BCID arm (P ≤ .001), emphasizing the importance of combining rapid BCID with clinical decision support tools and pharmacy input.⁶ Senok et al found that BCID2 implementation led to a significant decrease in median time to culture result, which informed optimal antibiotic therapy and decreased 30-day mortality in the intensive care setting.⁹ In contrast, the current study did not stratify patients according to medical ward or illness severity even though clinicians may be less likely to de-escalate antibiotic therapy in critically ill patients.

Bae et al reported findings consistent with the current study and concluded that BCID did not affect the clinical outcomes of overall BSIs; however, it contributed to early administration of effective antibiotics in cases of BSIs caused by multidrug-resistant organisms.¹⁰ Results of this study were not stratified according to multidrug-resistant organisms because the sample size was too small. The current study also included patients with polymicrobial infections, which may have impacted the results due to a less streamlined approach to antibiotic optimization.

Limitations

This single-center, retrospective study had a small sample size, short time frame, and lacked patient diversity, and therefore may not be generalizable to other health care systems. The sample size was limited by shorter date range and smaller patient list between BioFire BCID2 implementation and data collection, which was used to determine the number of charts selected in each group. Some patients received antibiotics prior to blood cultures being drawn, which may falsely decrease time to optimal/ appropriate antibiotics and falsely increase time on broad spectrum/any antibiotics due to early antibiotic administration. The total number of patients on broad-spectrum antibiotics differed from the total number of patients for other outcomes because several patients never received the defined broad spectrum antibiotics.

Conclusions

When combined with a pre-existing ASP without active notification, the implementation of BioFire BCID2 did not return statistically significant data showing a decrease in time to optimal antibiotics, time to appropriate antibiotics, or time on broad-spectrum antibiotics at VHI. To make this program more successful, pharmacist intervention and clinical decision support tools may be needed.

Additional research is required to determine the optimal integration of antimicrobial stewardship, rapid diagnostic technology, and pharmacy services for maximum benefit. Even though the primary outcome was not statistically significant, the results may be clinically significant from a stewardship perspective. Realigning microbiology workflows to mimic other research, which emphasizes the importance of funneling rapid BCID results through the ASP, may improve outcomes. Future studies may be warranted following the implementation of clinical decision support tools to assess their impact on stewardship practices and patient outcomes.

About 530,000 to 628,000 episodes of bloodstream infections (BSI) occur annually in the US.¹ Early identification and treatment of bacteremia are essential to improve patient outcomes because it allows for more timely targeted antibiotic therapy.² Organism identification and susceptibility testing can take 2 to 5 days, prolonging the use of broad-spectrum empiric antibiotics and increasing the risk of adverse events.^3,4 The Infectious Disease Society of America recommends the use of rapid diagnostic testing and antimicrobial stewardship programs (ASPs) to improve rates of antibiotic susceptibilities to targeted antibiotics and optimize resource utilization.³ Rapid blood culture identification (BCID) technologies reduce the duration of empiric antibiotics in patients with contaminated blood cultures, resulting in shorter hospital stays and saving money per each patient tested.⁴

In March 2023, Veteran Health Indiana (VHI) implemented the BioFire FilmArray Blood Culture Identification (BCID2), a BSI panel test that identifies select gram-negative bacteria, gram-positive bacteria, yeast, and antimicrobial resistance genes with an aggregate sensitivity of 99% and a specificity of 99.8%. The BCID2 presents clinically relevant information faster than traditional culture methods, allowing clinicians to make more efficient and educated antibiotic regimen decisions than with previous methods.⁵

It takes 24 to 48 hours from blood collection for culture incubation, positivity, and gram staining to occur at VHI. If the gram stain is positive, the blood culture is placed on the BioFire BCID2 in addition to traditional culture medium. BioFire BCID2 results are ready in 45 to 60 minutes. Results are uploaded into the electronic health record (EHR) ≤ 2 hours after they are obtained and the primary team is notified if the test is positive for certain critical results. Susceptibility testing of an identified organism typically requires an additional 24 to 48 hours for finalization. VHI Infectious Disease created an evidence-based antibiotic recommendation chart for certain medication(s) and alternate therapies based on the reported organism and its interpreted presence of resistance markers (eg, ceftriaxone for Escherichia coli when extended-spectrum beta lactamases are not detected vs meropenem if extended-spectrum beta lactamases marker are present). These charts optimize the antibiotic regimen while awaiting susceptibility finalizations.

Two previous studies describe the impact of rapid diagnostic testing technology at US Department of Veterans Affairs (VA) medical centers.^6,7 In Texas, the ASP reviewed BCID panel results via clinical decision support software for about 1 hour per day.⁶ A Los Angeles study analyzed the impact of Biofire BCID with an interpretation guide centered on unnecessary vancomycin use and determined that shorter duration of the medication may have been the result of more frequent infectious disease consultation.⁷

This study assessed the time to optimal antibiotic de-escalation before and after the implementation of BioFire BCID2 with results reviewed by the ASP without active notification or assistance of any clinical decision support technology. The primary objective was to evaluate difference in time to optimal antibiotics from blood culture draw pre- vs postintervention. Secondary objectives included differences in time to organism identification, difference in time on broad-spectrum antibiotics, and difference in time to appropriate antibiotics.

Methods

This quasi-experimental retrospective chart review assessed the impact of BioFire BCID2 use on timely antibiotic de-escalation for patients who experienced a BSI at VHI between March 1, 2022, and October 1, 2023. Microbiology laboratory records identified eligible patients with positive blood cultures within the study time frame. Data were collected from the VHI EHR.

Patients were included if they had a positive bacterial blood culture and received ≥ 1 antibiotic indicated for bacteremia while receiving inpatient care. Patients were excluded if they died prior to blood culture results, transferred out of VHI, left against medical advice, or had untreated contaminants in blood culture results (ie, never received antibiotics aimed at the contaminated culture).

Patient lists were generated for before and after implementation of BioFire BCID2 (pre- and postintervention) using the VHI EHR and microbiology laboratory record system. The pre- and postinterventions groups were different sizes. As a result, a random sampling of the preintervention group was selected and included patients from March 1, 2022, through March 26, 2023. The postintervention group was smaller due to time constraints between initiation of BioFire BCID2 for data collection and included all patients from March 27, 2023, through October 1, 2023.

Optimal antibiotics were defined as escalation from inappropriate therapy to broader agent(s), de-escalation from broad-spectrum therapy to targeted agent(s), discontinuation of therapy due to an organism being identified as a contaminant, or optimization of a regimen to the preferred antimicrobial agent based on evidence-based consensus guidelines. Broad-spectrum antibiotics included: piperacillin/tazobactam, cefepime, ceftazidime, ceftazidime-avibactam, cefiderocol, carbapenems, fluroquinolones, vancomycin, daptomycin, ceftaroline, linezolid, or aztreonam. Appropriate antibiotics were defined as those with activity toward the final identified organism(s).

Deidentified participant data were entered into Microsoft Excel and kept on a secure VA server to complete statistical analyses. Parametric continuous data, such as age, were analyzed using the t-test, while nonparametric continuous data, such as time to optimal antibiotics, were analyzed using the Mann-Whitney U test. Categorical data, like sex and race, were analyzed using either Fisher exact test for small sample sizes or X² test for a larger sample size. Statistical significance levels was defined as P < .05.

Results

Using patient lists drawn from the EHR and the microbiology laboratory records, 110 electronic charts were randomly selected for review. Fifteen patients were excluded: 8 had untreated contaminants, 4 died, and 3 were transferred out of VHI. Of the 95 patients included, 48 were in the preintervention group and 47 were in the postintervention group (Figure 1).

Baseline characteristics were similar between the 2 groups (Table 1). Most patients were White males aged > 70 years in the EHR. The urinary tract was the most common source of infection, impacting 12 patients in each group (Figure 2). Escherichia coli, Klebsiella, Staphylococcus, and Streptococcus were the most common bloodstream isolates identified.

The median time to optimal antibiotics in the preintervention group was 58.5 hours vs 43.4 hours in the postintervention group (P = .11). The median time to organism identification was 37.8 hours in the preintervention group vs 16.9 hours in the postintervention group (P < .001). The median time on broad-spectrum antibiotics was 45.2 hours in the preintervention group vs 46.6 hours in the postintervention group (P = .99). The median time on appropriate antibiotics in the preintervention group was 2.3 hours vs 1.9 hours in the postintervention group (P = .79). Differences in other measured outcomes between the groups were not statistically significant (Table 2).

Although implementation of rapid diagnostic technology reduced the median time to optimal antibiotics, the results were not statistically significant. Shorter time to organism identification in the postintervention group compared to the preintervention group was the lone statistically significant metric (P < .001).

Discussion

A lack of statistical significance in the primary outcome may have been due to nonadherence to facility de-escalation protocols or a suboptimal BioFire BCID2 result notification system. Additionally, use of rapid BCID at VHI may improve over time as clinicians become more familiar with the technology. Gaps in clinical pharmacy coverage during the night shift may have also contributed to delays in antibiotic optimization, particularly if other clinicians are not equipped with the knowledge or training to appropriately deescalate antibiotics based on microorganisms identified. A 2017 study by Donner et al concluded that physician interpretation of BCID results is suboptimal and should be augmented with clinical decision support tools as new technology becomes available.⁸ Despite the statistically insignificant results of this study, it did highlight potential areas of improvement which can lead to improved patient care.

Previous research has evaluated the impact of rapid BCID technology on antibiotic treatment and clinical outcomes. Chiasson et al found that median time to optimal therapy was 73.8 hours in the pre-BCID arm compared to 34.7 hours in the post- BCID arm (P ≤ .001), emphasizing the importance of combining rapid BCID with clinical decision support tools and pharmacy input.⁶ Senok et al found that BCID2 implementation led to a significant decrease in median time to culture result, which informed optimal antibiotic therapy and decreased 30-day mortality in the intensive care setting.⁹ In contrast, the current study did not stratify patients according to medical ward or illness severity even though clinicians may be less likely to de-escalate antibiotic therapy in critically ill patients.

Bae et al reported findings consistent with the current study and concluded that BCID did not affect the clinical outcomes of overall BSIs; however, it contributed to early administration of effective antibiotics in cases of BSIs caused by multidrug-resistant organisms.¹⁰ Results of this study were not stratified according to multidrug-resistant organisms because the sample size was too small. The current study also included patients with polymicrobial infections, which may have impacted the results due to a less streamlined approach to antibiotic optimization.

Limitations

This single-center, retrospective study had a small sample size, short time frame, and lacked patient diversity, and therefore may not be generalizable to other health care systems. The sample size was limited by shorter date range and smaller patient list between BioFire BCID2 implementation and data collection, which was used to determine the number of charts selected in each group. Some patients received antibiotics prior to blood cultures being drawn, which may falsely decrease time to optimal/ appropriate antibiotics and falsely increase time on broad spectrum/any antibiotics due to early antibiotic administration. The total number of patients on broad-spectrum antibiotics differed from the total number of patients for other outcomes because several patients never received the defined broad spectrum antibiotics.

Conclusions

When combined with a pre-existing ASP without active notification, the implementation of BioFire BCID2 did not return statistically significant data showing a decrease in time to optimal antibiotics, time to appropriate antibiotics, or time on broad-spectrum antibiotics at VHI. To make this program more successful, pharmacist intervention and clinical decision support tools may be needed.

Additional research is required to determine the optimal integration of antimicrobial stewardship, rapid diagnostic technology, and pharmacy services for maximum benefit. Even though the primary outcome was not statistically significant, the results may be clinically significant from a stewardship perspective. Realigning microbiology workflows to mimic other research, which emphasizes the importance of funneling rapid BCID results through the ASP, may improve outcomes. Future studies may be warranted following the implementation of clinical decision support tools to assess their impact on stewardship practices and patient outcomes.

Tinea versicolor (TV) is a common, chronic, and recurrent superficial fungal infection caused by Malassezia species, most commonly Malassezia furfur (M. furfur)—a dimorphic fungus that is a part of the normal skin flora and resides in the stratum corneum.¹ TV manifests as hypopigmented, hyperpigmented, or erythematous macules and patches with scaling, typically found on the trunk and proximal upper extremities. The condition is most common among young to middle-aged individuals exposed to high temperatures and humidity.¹

While many cases respond to topical antifungal treatment, application can be cumbersome, particularly in large areas that are difficult to reach. An efficient and cost effective in-office treatment option could alleviate patient burden and improve satisfaction. This article presents a case of TV successfully treated with an in-office salicylic acid (SA) 30% peel, an uncommon application of this medication.

Case Presentation

An 18-year-old female active-duty US Army service member with a history of acne vulgaris presented to a dermatology clinic with a mildly pruritic rash that had been present for several weeks. An examination revealed hyperpigmented macules and patches with overlying fine scales across the patient’s back and bilateral arms (Figures 1 and 2). She reported no history of similar lesions. The patient had recently completed a military basic training course during which she wore a uniform jacket and trousers daily in hot and humid conditions. A skin scraping was obtained. Microscopic examination with potassium hydroxide preparation revealed hyphae and spores, consistent with TV.

The diagnosis of TV and treatment options (topical ketoconazole 2% shampoo, topical terbinafine, or oral fluconazole) were discussed with the patient. Due to military training-related constraints, residence in the barracks, and personal preference, the patient felt unable to regularly apply topical medications to the entirety of the affected area and preferred to avoid oral medication. The decision was made to pursue in-clinic treatment with a SA 30% peel. The affected areas (back and bilateral arms) were thoroughly cleansed and prepped with alcohol. SA 30% in hydroethanolic solution was applied evenly to the affected area. The patient was observed for pseudofrosting, a precipitation of SA crystals that indicates peel completion (Figure 3). The peel was left in place, as it is self-neutralizing, and the patient was instructed to shower that same day with a gentle cleanser. This procedure was repeated 10 days later. Both treatments were well tolerated, with only a transient burning sensation reported during the application. At 3-week follow-up, the patient presented with complete resolution of her arm lesions and significant improvement of the back lesions (Figures 4 and 5). She also reported improvement in the acne vulgaris on her back.

Discussion

SA 30% is a lipid-soluble hydroxybenzoic acid with comedolytic and desmolytic qualities. This results in the disruption of epidermal cell cohesion and promotes exfoliation.² Lipophilic properties allow SA to penetrate sebaceous glands and disrupt sebum production, making it particularly effective in seborrheic conditions such as acne. This mechanism may have increased therapeutic effect in this case.³ Additionally, as a salicylate, SA possesses anti-inflammatory properties, though this effect is most pronounced at lower concentrations. SA 30% is considered a superficial peel, as the depth of chemexfoliation is limited to the epidermis.³ A modified SA preparation is a safe and effective treatment for moderate-to-severe acne vulgaris. The apparent pseudofrost during application is due to precipitated SA, rather than the precipitation of dermal proteins seen in deeper peels, such as trichloroacetic acid.² Unlike glycolic or pyruvic acid peels, SA does not require neutralization.

SA is cost-effective and has been used safely in all skin types to treat various epidermal conditions, including acne vulgaris, melasma, photodamage, freckles, lentigines and postinflammatory hyperpigmentation (PIH).² Mild adverse effects occur in about 15% to 30% of patients and include prolonged erythema, intense exfoliation, dryness, crusting, and pigmentary dyschromias. Rare adverse effects include systemic toxicity (salicylism) and hypoglycemia. Contraindications to SA 30% peels include history of allergy to salicylates, active bacterial or viral infection, dermatitis in the treatment area, pregnancy, and skin malignancy.²

Chemical peels are typically used with caution in patients with skin of color due to a higher risk of PIH. However, SA 30% has been shown to be safe and effective in these populations.⁴ A study by Grimes found that 88% of patients with Fitzpatrick skin types V and VI experienced significant improvement in PIH, melasma, or enlarged pores with minimal to no adverse effects.⁴ Subsequent larger studies have reinforced these findings. In a study involving 250 patients with Fitzpatrick skin types IV and V, no patients experienced PIH, confirming the safety of SA in darker skin tones. This is likely due to the superficial nature of the peel, which does not affect the basal layer of the epidermis where melanocytes reside, reducing the risk of pigmentary complications. Additionally, SA peels are self-neutralizing, unlike glycolic or trichloroacetic acid peels, which require manual neutralization and carry a higher risk of PIH if not neutralized properly.⁵

SA has been as shown to be a moderately successful treatment for PIH. The Grimes study found that 4 of 5 patients with Fitzpatrick skin types IV and V saw a 75% improvement in PIH after SA peels.⁴ Davis et al found a nonsignificant trend toward skin lightening in Korean adults treated for acne and PIH, with significant decreases in erythema and improvements in greasiness, dryness, and scaliness.⁶ Importantly, the risk of PIH following TV is higher in patients with skin of color.⁷ SA may be effective in treating TV and PIH, offering a multifactorial approach by addressing both conditions while posing a low risk for causing PIH.⁸

TV and other Malassezia spp infections are common concerns in dermatology and primary care, with Malassezia-associated superficial mycoses (eg, dandruff, pityriasis versicolor, and folliculitis) affecting up to 50% of the population worldwide.⁹ Despite this, there has been little recent advancement in antifungal treatments. Ketoconazole, terbinafine, and fluconazole have been in use since the 1980s and 1990s.⁸ Most antifungal drugs target ergosterol, a component of the fungal cell wall.¹⁰ Additionally, Malassezia spp have been increasingly reported to cause invasive infections in immunocompromised patients.¹¹ Given the rise in antifungal resistance, the judicious use of antifungals and implementation of novel treatment strategies is essential.

While SA lacks intrinsic antifungal properties, different combinations (Whitfield ointment consisting of 3% SA and 6% benzoic acid; 2% sulfur and 2% SA) have been effective in the treatment of TV.¹ It is theorized that the effectiveness of SA against TV is due to its ability to exfoliate and acidify the stratum corneum, the natural habitat of M. furfur.

SA also reduces sebum production by downregulating sebocyte lipogenesis via the sterol regulatory element-binding protein-1 pathway and suppressing the nuclear factor κB (NF-κB) pathway, a key pathway in inflammation.¹² These mechanisms make SA an effective acne treatment. Additionally, M. furfur is a lipid-dependent yeast, thus the decreased lipogenesis by sebocytes may be beneficial in treating TV as well.¹² A study of 25 patients with TV in India found that 88% achieved clinical and microbiological cure after 4 once-weekly treatments of a SA 30% peel.⁸

In a study of deployed military personnel, fungal infections affected about 11% of participants.¹³ Contributing factors to the development of fungal infections included excessive sweating, humid conditions, and limited access to hygiene facilities. In such settings, traditional antifungal therapies may be less effective or challenging to adhere to, making alternative treatments more desirable. SA peels could offer a practical solution in these circumstances, as they are easily applied in the clinic, require no neutralization or downtime, and do not require the patient to apply medications between visits.

In this case, the patient demonstrated significant improvement with 2 SA peels, with noted improvement in her acne. SA 30% peel was highlighted as a useful treatment option for patients with TV who struggle with topical medication adherence; furthermore, it may be particularly beneficial for patients with concomitant acne.

Conclusions

This case demonstrates the successful use of in-office SA 30% peel as a treatment for TV. The rapid improvement and resolution of lesions with minimal adverse effects suggest that SA peel may serve as a valuable alternative for patients with extensive disease in difficult-to-reach affected areas, or those who are dissatisfied with traditional therapies. Additionally, the concurrent improvement of the patient’s back acne underscores the dual therapeutic potential of this treatment. Given the ease of application, cost effectiveness, and favorable safety profile, SA 30% peel is a viable option in the management of TV, especially in cases where topical or oral antifungals are impractical. Further studies could help establish standardized protocols and assess long-term outcomes of this treatment modality.

Tinea versicolor (TV) is a common, chronic, and recurrent superficial fungal infection caused by Malassezia species, most commonly Malassezia furfur (M. furfur)—a dimorphic fungus that is a part of the normal skin flora and resides in the stratum corneum.¹ TV manifests as hypopigmented, hyperpigmented, or erythematous macules and patches with scaling, typically found on the trunk and proximal upper extremities. The condition is most common among young to middle-aged individuals exposed to high temperatures and humidity.¹

While many cases respond to topical antifungal treatment, application can be cumbersome, particularly in large areas that are difficult to reach. An efficient and cost effective in-office treatment option could alleviate patient burden and improve satisfaction. This article presents a case of TV successfully treated with an in-office salicylic acid (SA) 30% peel, an uncommon application of this medication.

Case Presentation

An 18-year-old female active-duty US Army service member with a history of acne vulgaris presented to a dermatology clinic with a mildly pruritic rash that had been present for several weeks. An examination revealed hyperpigmented macules and patches with overlying fine scales across the patient’s back and bilateral arms (Figures 1 and 2). She reported no history of similar lesions. The patient had recently completed a military basic training course during which she wore a uniform jacket and trousers daily in hot and humid conditions. A skin scraping was obtained. Microscopic examination with potassium hydroxide preparation revealed hyphae and spores, consistent with TV.

The diagnosis of TV and treatment options (topical ketoconazole 2% shampoo, topical terbinafine, or oral fluconazole) were discussed with the patient. Due to military training-related constraints, residence in the barracks, and personal preference, the patient felt unable to regularly apply topical medications to the entirety of the affected area and preferred to avoid oral medication. The decision was made to pursue in-clinic treatment with a SA 30% peel. The affected areas (back and bilateral arms) were thoroughly cleansed and prepped with alcohol. SA 30% in hydroethanolic solution was applied evenly to the affected area. The patient was observed for pseudofrosting, a precipitation of SA crystals that indicates peel completion (Figure 3). The peel was left in place, as it is self-neutralizing, and the patient was instructed to shower that same day with a gentle cleanser. This procedure was repeated 10 days later. Both treatments were well tolerated, with only a transient burning sensation reported during the application. At 3-week follow-up, the patient presented with complete resolution of her arm lesions and significant improvement of the back lesions (Figures 4 and 5). She also reported improvement in the acne vulgaris on her back.

Discussion

SA 30% is a lipid-soluble hydroxybenzoic acid with comedolytic and desmolytic qualities. This results in the disruption of epidermal cell cohesion and promotes exfoliation.² Lipophilic properties allow SA to penetrate sebaceous glands and disrupt sebum production, making it particularly effective in seborrheic conditions such as acne. This mechanism may have increased therapeutic effect in this case.³ Additionally, as a salicylate, SA possesses anti-inflammatory properties, though this effect is most pronounced at lower concentrations. SA 30% is considered a superficial peel, as the depth of chemexfoliation is limited to the epidermis.³ A modified SA preparation is a safe and effective treatment for moderate-to-severe acne vulgaris. The apparent pseudofrost during application is due to precipitated SA, rather than the precipitation of dermal proteins seen in deeper peels, such as trichloroacetic acid.² Unlike glycolic or pyruvic acid peels, SA does not require neutralization.

SA is cost-effective and has been used safely in all skin types to treat various epidermal conditions, including acne vulgaris, melasma, photodamage, freckles, lentigines and postinflammatory hyperpigmentation (PIH).² Mild adverse effects occur in about 15% to 30% of patients and include prolonged erythema, intense exfoliation, dryness, crusting, and pigmentary dyschromias. Rare adverse effects include systemic toxicity (salicylism) and hypoglycemia. Contraindications to SA 30% peels include history of allergy to salicylates, active bacterial or viral infection, dermatitis in the treatment area, pregnancy, and skin malignancy.²

Chemical peels are typically used with caution in patients with skin of color due to a higher risk of PIH. However, SA 30% has been shown to be safe and effective in these populations.⁴ A study by Grimes found that 88% of patients with Fitzpatrick skin types V and VI experienced significant improvement in PIH, melasma, or enlarged pores with minimal to no adverse effects.⁴ Subsequent larger studies have reinforced these findings. In a study involving 250 patients with Fitzpatrick skin types IV and V, no patients experienced PIH, confirming the safety of SA in darker skin tones. This is likely due to the superficial nature of the peel, which does not affect the basal layer of the epidermis where melanocytes reside, reducing the risk of pigmentary complications. Additionally, SA peels are self-neutralizing, unlike glycolic or trichloroacetic acid peels, which require manual neutralization and carry a higher risk of PIH if not neutralized properly.⁵

SA has been as shown to be a moderately successful treatment for PIH. The Grimes study found that 4 of 5 patients with Fitzpatrick skin types IV and V saw a 75% improvement in PIH after SA peels.⁴ Davis et al found a nonsignificant trend toward skin lightening in Korean adults treated for acne and PIH, with significant decreases in erythema and improvements in greasiness, dryness, and scaliness.⁶ Importantly, the risk of PIH following TV is higher in patients with skin of color.⁷ SA may be effective in treating TV and PIH, offering a multifactorial approach by addressing both conditions while posing a low risk for causing PIH.⁸

TV and other Malassezia spp infections are common concerns in dermatology and primary care, with Malassezia-associated superficial mycoses (eg, dandruff, pityriasis versicolor, and folliculitis) affecting up to 50% of the population worldwide.⁹ Despite this, there has been little recent advancement in antifungal treatments. Ketoconazole, terbinafine, and fluconazole have been in use since the 1980s and 1990s.⁸ Most antifungal drugs target ergosterol, a component of the fungal cell wall.¹⁰ Additionally, Malassezia spp have been increasingly reported to cause invasive infections in immunocompromised patients.¹¹ Given the rise in antifungal resistance, the judicious use of antifungals and implementation of novel treatment strategies is essential.

While SA lacks intrinsic antifungal properties, different combinations (Whitfield ointment consisting of 3% SA and 6% benzoic acid; 2% sulfur and 2% SA) have been effective in the treatment of TV.¹ It is theorized that the effectiveness of SA against TV is due to its ability to exfoliate and acidify the stratum corneum, the natural habitat of M. furfur.

SA also reduces sebum production by downregulating sebocyte lipogenesis via the sterol regulatory element-binding protein-1 pathway and suppressing the nuclear factor κB (NF-κB) pathway, a key pathway in inflammation.¹² These mechanisms make SA an effective acne treatment. Additionally, M. furfur is a lipid-dependent yeast, thus the decreased lipogenesis by sebocytes may be beneficial in treating TV as well.¹² A study of 25 patients with TV in India found that 88% achieved clinical and microbiological cure after 4 once-weekly treatments of a SA 30% peel.⁸

In a study of deployed military personnel, fungal infections affected about 11% of participants.¹³ Contributing factors to the development of fungal infections included excessive sweating, humid conditions, and limited access to hygiene facilities. In such settings, traditional antifungal therapies may be less effective or challenging to adhere to, making alternative treatments more desirable. SA peels could offer a practical solution in these circumstances, as they are easily applied in the clinic, require no neutralization or downtime, and do not require the patient to apply medications between visits.

In this case, the patient demonstrated significant improvement with 2 SA peels, with noted improvement in her acne. SA 30% peel was highlighted as a useful treatment option for patients with TV who struggle with topical medication adherence; furthermore, it may be particularly beneficial for patients with concomitant acne.

Conclusions

This case demonstrates the successful use of in-office SA 30% peel as a treatment for TV. The rapid improvement and resolution of lesions with minimal adverse effects suggest that SA peel may serve as a valuable alternative for patients with extensive disease in difficult-to-reach affected areas, or those who are dissatisfied with traditional therapies. Additionally, the concurrent improvement of the patient’s back acne underscores the dual therapeutic potential of this treatment. Given the ease of application, cost effectiveness, and favorable safety profile, SA 30% peel is a viable option in the management of TV, especially in cases where topical or oral antifungals are impractical. Further studies could help establish standardized protocols and assess long-term outcomes of this treatment modality.

Tinea versicolor (TV) is a common, chronic, and recurrent superficial fungal infection caused by Malassezia species, most commonly Malassezia furfur (M. furfur)—a dimorphic fungus that is a part of the normal skin flora and resides in the stratum corneum.¹ TV manifests as hypopigmented, hyperpigmented, or erythematous macules and patches with scaling, typically found on the trunk and proximal upper extremities. The condition is most common among young to middle-aged individuals exposed to high temperatures and humidity.¹

While many cases respond to topical antifungal treatment, application can be cumbersome, particularly in large areas that are difficult to reach. An efficient and cost effective in-office treatment option could alleviate patient burden and improve satisfaction. This article presents a case of TV successfully treated with an in-office salicylic acid (SA) 30% peel, an uncommon application of this medication.

Case Presentation

An 18-year-old female active-duty US Army service member with a history of acne vulgaris presented to a dermatology clinic with a mildly pruritic rash that had been present for several weeks. An examination revealed hyperpigmented macules and patches with overlying fine scales across the patient’s back and bilateral arms (Figures 1 and 2). She reported no history of similar lesions. The patient had recently completed a military basic training course during which she wore a uniform jacket and trousers daily in hot and humid conditions. A skin scraping was obtained. Microscopic examination with potassium hydroxide preparation revealed hyphae and spores, consistent with TV.

The diagnosis of TV and treatment options (topical ketoconazole 2% shampoo, topical terbinafine, or oral fluconazole) were discussed with the patient. Due to military training-related constraints, residence in the barracks, and personal preference, the patient felt unable to regularly apply topical medications to the entirety of the affected area and preferred to avoid oral medication. The decision was made to pursue in-clinic treatment with a SA 30% peel. The affected areas (back and bilateral arms) were thoroughly cleansed and prepped with alcohol. SA 30% in hydroethanolic solution was applied evenly to the affected area. The patient was observed for pseudofrosting, a precipitation of SA crystals that indicates peel completion (Figure 3). The peel was left in place, as it is self-neutralizing, and the patient was instructed to shower that same day with a gentle cleanser. This procedure was repeated 10 days later. Both treatments were well tolerated, with only a transient burning sensation reported during the application. At 3-week follow-up, the patient presented with complete resolution of her arm lesions and significant improvement of the back lesions (Figures 4 and 5). She also reported improvement in the acne vulgaris on her back.

Discussion

SA 30% is a lipid-soluble hydroxybenzoic acid with comedolytic and desmolytic qualities. This results in the disruption of epidermal cell cohesion and promotes exfoliation.² Lipophilic properties allow SA to penetrate sebaceous glands and disrupt sebum production, making it particularly effective in seborrheic conditions such as acne. This mechanism may have increased therapeutic effect in this case.³ Additionally, as a salicylate, SA possesses anti-inflammatory properties, though this effect is most pronounced at lower concentrations. SA 30% is considered a superficial peel, as the depth of chemexfoliation is limited to the epidermis.³ A modified SA preparation is a safe and effective treatment for moderate-to-severe acne vulgaris. The apparent pseudofrost during application is due to precipitated SA, rather than the precipitation of dermal proteins seen in deeper peels, such as trichloroacetic acid.² Unlike glycolic or pyruvic acid peels, SA does not require neutralization.

SA is cost-effective and has been used safely in all skin types to treat various epidermal conditions, including acne vulgaris, melasma, photodamage, freckles, lentigines and postinflammatory hyperpigmentation (PIH).² Mild adverse effects occur in about 15% to 30% of patients and include prolonged erythema, intense exfoliation, dryness, crusting, and pigmentary dyschromias. Rare adverse effects include systemic toxicity (salicylism) and hypoglycemia. Contraindications to SA 30% peels include history of allergy to salicylates, active bacterial or viral infection, dermatitis in the treatment area, pregnancy, and skin malignancy.²

Chemical peels are typically used with caution in patients with skin of color due to a higher risk of PIH. However, SA 30% has been shown to be safe and effective in these populations.⁴ A study by Grimes found that 88% of patients with Fitzpatrick skin types V and VI experienced significant improvement in PIH, melasma, or enlarged pores with minimal to no adverse effects.⁴ Subsequent larger studies have reinforced these findings. In a study involving 250 patients with Fitzpatrick skin types IV and V, no patients experienced PIH, confirming the safety of SA in darker skin tones. This is likely due to the superficial nature of the peel, which does not affect the basal layer of the epidermis where melanocytes reside, reducing the risk of pigmentary complications. Additionally, SA peels are self-neutralizing, unlike glycolic or trichloroacetic acid peels, which require manual neutralization and carry a higher risk of PIH if not neutralized properly.⁵

SA has been as shown to be a moderately successful treatment for PIH. The Grimes study found that 4 of 5 patients with Fitzpatrick skin types IV and V saw a 75% improvement in PIH after SA peels.⁴ Davis et al found a nonsignificant trend toward skin lightening in Korean adults treated for acne and PIH, with significant decreases in erythema and improvements in greasiness, dryness, and scaliness.⁶ Importantly, the risk of PIH following TV is higher in patients with skin of color.⁷ SA may be effective in treating TV and PIH, offering a multifactorial approach by addressing both conditions while posing a low risk for causing PIH.⁸

TV and other Malassezia spp infections are common concerns in dermatology and primary care, with Malassezia-associated superficial mycoses (eg, dandruff, pityriasis versicolor, and folliculitis) affecting up to 50% of the population worldwide.⁹ Despite this, there has been little recent advancement in antifungal treatments. Ketoconazole, terbinafine, and fluconazole have been in use since the 1980s and 1990s.⁸ Most antifungal drugs target ergosterol, a component of the fungal cell wall.¹⁰ Additionally, Malassezia spp have been increasingly reported to cause invasive infections in immunocompromised patients.¹¹ Given the rise in antifungal resistance, the judicious use of antifungals and implementation of novel treatment strategies is essential.

While SA lacks intrinsic antifungal properties, different combinations (Whitfield ointment consisting of 3% SA and 6% benzoic acid; 2% sulfur and 2% SA) have been effective in the treatment of TV.¹ It is theorized that the effectiveness of SA against TV is due to its ability to exfoliate and acidify the stratum corneum, the natural habitat of M. furfur.

SA also reduces sebum production by downregulating sebocyte lipogenesis via the sterol regulatory element-binding protein-1 pathway and suppressing the nuclear factor κB (NF-κB) pathway, a key pathway in inflammation.¹² These mechanisms make SA an effective acne treatment. Additionally, M. furfur is a lipid-dependent yeast, thus the decreased lipogenesis by sebocytes may be beneficial in treating TV as well.¹² A study of 25 patients with TV in India found that 88% achieved clinical and microbiological cure after 4 once-weekly treatments of a SA 30% peel.⁸

In a study of deployed military personnel, fungal infections affected about 11% of participants.¹³ Contributing factors to the development of fungal infections included excessive sweating, humid conditions, and limited access to hygiene facilities. In such settings, traditional antifungal therapies may be less effective or challenging to adhere to, making alternative treatments more desirable. SA peels could offer a practical solution in these circumstances, as they are easily applied in the clinic, require no neutralization or downtime, and do not require the patient to apply medications between visits.

In this case, the patient demonstrated significant improvement with 2 SA peels, with noted improvement in her acne. SA 30% peel was highlighted as a useful treatment option for patients with TV who struggle with topical medication adherence; furthermore, it may be particularly beneficial for patients with concomitant acne.

Conclusions

This case demonstrates the successful use of in-office SA 30% peel as a treatment for TV. The rapid improvement and resolution of lesions with minimal adverse effects suggest that SA peel may serve as a valuable alternative for patients with extensive disease in difficult-to-reach affected areas, or those who are dissatisfied with traditional therapies. Additionally, the concurrent improvement of the patient’s back acne underscores the dual therapeutic potential of this treatment. Given the ease of application, cost effectiveness, and favorable safety profile, SA 30% peel is a viable option in the management of TV, especially in cases where topical or oral antifungals are impractical. Further studies could help establish standardized protocols and assess long-term outcomes of this treatment modality.

The extensive surface of the gastrointestinal tract presents an interface between the human body and its environment. Residing within the intestinal lumen, ingested food and various microorganisms are an essential aspect of this relationship. The trillions of microorganisms, primarily commensal bacteria hosted by the human gut, constitute the human gut microbiome.

There is growing evidence that the human gut microbiome plays a role in maintaining normal body function and homeostasis.¹ Research, such as the National Institute of Health Microbiome Project, is helping to show the impact of gut microorganisms and their negative influence on metabolic diseases and chronic inflammatory disorders.^2-5 An imbalance in the microbiota, known as dysbiosis, has been associated with metabolic and cardiovascular diseases (CVD), including hypertension, diabetes mellitus, obesity, and coronary artery disease (CAD). Gut dysbiosis has also been associated with cardiac arrhythmias, including atrial fibrillation (AF) and ventricular arrhythmias (Figure).^6-12

Whether gut dysbiosis is a cause or effect of the human disease process is unclear. While further research is warranted, some evidence of causation has been found. In 2018, Yoshida et al demonstrated an association between patients with CAD who had a significantly lower burden of the gut bacteria species Bacteroides vulgatus and Bacteroides dorei compared to that of patients without CAD. The study found that administration of these Bacteroides species reduced atherosclerotic lesion formation in atherosclerosis-prone mice.¹³ If altering gut microbial composition can affect the disease process, it may indicate a causative role for gut dysbiosis in disease pathogenesis. Furthermore, this finding also suggests agents may be used to alter the gut microbiome and potentially prevent and treat diseases. An altered gut microbiome may serve as an early marker for human disease, aiding in timely diagnosis and institution of disease-modifying treatments.

This review outlines the broad relationship of the pathways and intermediaries that may be involved in mediating the interaction between the gut microbiome and cardiac arrhythmias based on rapidly increasing evidence. A comprehensive search among PubMed and Google Scholar databases was conducted to find articles relevant to the topic.

Potential Intermediaries

Potential pathways for how the gut microbiome and cardiovascular system interact are subjects of active research. However, recent research may point to potential mechanisms of the association between the systems. The gut microbiome may influence human physiology through 3 principal routes: the autonomic nervous system, inflammatory pathways, and metabolic processes.

Autonomic Nervous System

The concept of bidirectional communication between the gut and central nervous system, known as the microbiota-gut-brain axis, is widely accepted.¹⁴ Proposed mediators of this interaction include the vagus nerve, the sympathetic nervous system, and the hypothalamic-pituitary-adrenal axis; cytokines produced by the immune system, tryptophan metabolism, and the production of short-chain fatty acids (SCFAs).^15,16

The gut microbiome appears to have a direct impact on the autonomic nervous system, through which it can influence cardiovascular function. Muller et al described how the gut microbiome modulated gut-extrinsic sympathetic neurons and that the depletion of gut microbiota led to activation of both brainstem sensory nuclei and efferent sympathetic premotor glutamatergic neurons.¹⁶ Meng et al found that systemic injection of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) led to significantly increased activity in the paraventricular nucleus, a hypothalamic structure essential to the central autonomic network. Their study demonstrated that systemic TMAO also led to increased left stellate ganglion (LSG) activity, a known contributor to cardiac sympathetic tone.¹²

Inflammatory Pathways

Inflammatory responses are another pathway for the gut microbiome to influence the cardiovascular system. SCFAs are a set of gut microbial metabolites produced in the colon by bacterial fermentation and decomposition of resistant starches and dietary fibers.¹⁷ These metabolites are increasingly recognized for their role in modulating disease processes, including cardiac disease. Aguilar et al found that the progression of atherosclerosis was slowed in apolipoprotein E (Apo-E) knockout mice by a chow diet supplemented with butyrate, a SCFA, suggesting it is an atheroprotective therapeutic agent. Less adhesion and migration of macrophages, reduced inflammation, improved plaque stability, and lowered atherosclerosis progression.¹⁸ Wei et al demonstrated in animal models that direct microinjection of the proinflammatory factors interleukin (IL)-1Β and tumor necrosis factor (TNF)-αdirectly into the subfornical organ increased heart rate, mean blood pressure, and renal sympathetic nerve activity.¹⁹

Metabolic Processes

Serotonin (5-HT), a metabolite of tryptophan, is a neurotransmitter that regulates many bodily functions and plays a significant role in the microbiota-brain gut axis.²⁰ Oral ingestion of the bacterial species Bifidobacterium infantis increased plasma tryptophan in rat models.²¹ Additionally, many other microorganisms, including species of Candida, Streptococcus, Escherichia, and Enterococcus are known to produce 5-HT.²² While a relationship between the gut microbiome and plasma 5-HT has been established, interactions between 5-HT and the cardiovascular system are complex. Research has shown that stimulation of 5-HT_1A receptors produces bradycardic and vasopressor effects, while stimulation of the 5-HT₂ receptor induces vasoconstriction and tachycardia.²³

A high-fiber diet can lower the incidence of hypertension, although the mechanisms are not clear. One potential reason could be alteration in gut bacteria, as a diet high in fiber has been shown to increase the prevalence of acetate-producing bacteria.²⁴

Atherosclerosis

Research investigating the relationship of the gut microbiome with arrhythmias is in its early stages; however, the connection of the gut microbiome and atherosclerosis is more established.²⁵ Contemporary studies have shown various gut microorganisms associated with atherosclerosis.²⁶ Jie et al reported that patients with atherosclerotic cardiovascular disease had increased Enterobacteriaceae loads and oral cavity-associated bacteria with lower levels of butyrate producing bacteria when compared with healthy controls.²⁷ In addition, microbial metabolites such as TMAO appear to promote atherosclerosis by increasing vascular inflammation and platelet reactivity.²⁶ Researchers are investigating the modulation of these associations to help reduce atherosclerotic burden. Kasahara et al found that Roseburia intestinalis could reduce atherosclerotic disease in mice through the production of butyrate.²⁸ Roberts et al established that administration of TMAO inhibitors reduced TMAO levels while reducing thrombus formation without observable toxicity or increased bleeding risk.²⁹

Atrial Arrhythmias

The gut microbiome can also specifically affect cardiac arrhythmogenesis, and multiple studies suggest possible mediators of this interaction. Certain gut microbiome derived metabolites like TMAO may have a role in promoting AF.³⁰ Other gut microbial metabolites like lipopolysaccharides and indoxyl sulfate are implicated in atrial electrical instability.^31,32 Microbe-derived free fatty acids such as palmitic acid and adrenic acid can precipitate arrhythmogenesis. ^33,34 Preponderances of certain gut bacteria like Ruminococcus, Streptococcus, and Enterococcus, as well as reductions of Faecalibacterium, Alistipes, Oscillibacter, and Bilophila have been detected in patients with AF.⁸ Tabata et al found that certain clusters of bacterial groups led by Ruminococcus species seem to show higher prevalence in patients with AF, whereas the genus Enterobacter was significantly lower compared with control subjects. That study also noted that gut microbial composition is affected by diet and antacid use.³⁵ Gut microbiome-derived serotonin may be another mediator for AF, which may be related to the fact that 5-HT₄ receptors are present in atrial tissue.³⁶

Ventricular Arrhythmias

A critical component to the development of malignant ventricular arrhythmias is an imbalance in autonomic tone; in particular, the overactivation of the sympathetic nervous system.³⁷ Animal models have shown that augmentation of the sympathetic nervous system plays an essential role in the subsequent development of ventricular arrhythmias. ³⁸ Several studies have established the LSG as an important component of the cardiac sympathetic nervous system pathway. ^38,39 Ablation of the LSG has been shown to effectively reduce the burden of malignant arrhythmias, further pointing toward the role of excess sympathetic activity.^37,39 Stellate ganglion denervation has become an established method for managing life-threatening ventricular arrhythmias.⁴⁰

Gut metabolites may have significant effects on cardiac sympathetic activity. Meng et al investigated the effect of TMAO on the LSG in animals and its overall effect on the incidence of ventricular arrhythmias under ischemic conditions. To fully explore this interaction, they examined the effect of TMAO on LSG function though 2 mechanisms: local administration of TMAO within the LSG and systemic administration of TMAO leading to activation of the central sympathetic nervous system. In both protocols, left anterior descending coronary artery occlusion was performed after TMAO administration. Injection of TMAO directly into the LSG was found to significantly increase the cardiac sympathetic tone and incidence of ventricular arrhythmias. In the systemic administration control arm, ventricular arrhythmias were also significantly increased.¹²

Increased inflammatory states appear to correlate with an increase in sympathetic tone and ventricular arrhythmias.¹² In an animal study, direct injection of the proinflammatory factor IL-1Β into the LSG not only resulted in increased inflammation, but aggravated cardiac sympathetic remodeling. This led to a decreased effective refractory period and action potential duration, leading to an increased maximal slope of the restitution curve and higher occurrence of ventricular arrhythmias.⁴¹ Shi et al demonstrated that paraventricular nucleus microinjection with TNF-α and IL-1Β also enhanced the cardiac sympathetic afferent reflex, showing that these proinflammatory cytokines not only upregulate the inflammatory response, but can also have excitatory effects that stimulate sympathetic activity and have the potential to be proarrhythmic.^19,42 Local and systemic administration of the gut microbe-derived TMAO increased the expression of IL-1Β and TNF-α, thus implicating the microbiome as a potential mediator of the inflammatory response and as another potential pathway for increased ventricular arrhythmias.¹²

The N-methyl-d-aspartate receptor (NMDAR) is found in multiple organs—including the heart—but more specifically in the conducting system and myocardium.43,44 Research has discovered an upregulation of NMDARs in the setting of cardiac sympathetic hyperinnervation in rat models both with healed myocardial necrotic injury and without. The infusion of their ligand, NMDA, provoked ventricular tachycardia and ventricular fibrillation in rat models with sympathetic hyperinnervation and healed myocardial necrotic injury.⁴⁵ Another study found that NMDAR activation provoked ventricular arrhythmias, but also prolonged repolarization and induced electrical instability.⁴⁶ Proinflammatory markers have been shown to upregulate the expression of NMDARs; more importantly, NMDAR expression has been shown to be significantly increased in the setting of TMAO administration.^12,47,48

5-HT also appears to have a substantial association with ventricular arrhythmias in addition to atrial arrhythmias. el-Mahdy demonstrated in anesthetized rats with acute coronary ligation that systemic doses of 5-HT represented a significant dose-dependent increase in the duration of ventricular tachycardia and ventricular fibrillation, while also increasing the number of ventricular ectopic beats.⁴⁹ Certain gut microorganisms are known to produce 5-HT, including those in the genera Streptococcus, Escherichia, and Enterococcus.²² Additionally, oral ingestion of the Bifidobacterium infantis increased plasma levels of tryptophan in rat models.²¹ The gut microbiome may have significant effects on plasma serotonin levels, and thus have the potential to alter the risk for ventricular arrhythmias.

The deleterious effects of the gut microbiome have been documented. However, it appears to have potential protective effects, and several studies point to the possible mechanisms of this beneficial interaction. Propionate is a SCFA microorganism produced by gut microbial fermentation.⁵⁰ In a rat model study, Zhou et al found that infusion of sodium propionate significantly reduced ventricular arrhythmias during acute myocardial ischemia or burst stimulation, thus confirming cardioprotective effects.^50,51

Proposed mechanisms for reduced susceptibility to ventricular arrhythmias with propionate infusion include parasympathetic activation via the gut-brain axis, anti-inflammatory pathways, and improved cardiac electrophysiology instability.⁵⁰ In addition butyrate has been found to reduce inflammation and myocardial hypertrophy. Jiang et al demonstrated in rats postmyocardial infarction that butyrate promoted expression of anti-inflammatory M2 macrophage markers, decreased expressions of nerve growth factor and norepinephrine, and decreased the density of nerve fibers for growth-associated protein-43 and tyrosine hydroxylase. The cumulative impact of butyrate led to suppression of inflammation and the inhibition of sympathetic neural remodeling, ultimately resulting in improved cardiac function and reduction in ventricular arrhythmias after myocardial infarction.⁵²

Gut bacteria-derived acetate-mediated reduction in cardiac fibrosis may be another mechanism for the effects on ventricular arrhythmias. Cardiac fibrosis and scar are established as the primary substrate for reentrant ventricular arrhythmias seen in various cardiomyopathies.

Future Directions

The microbiome residing in the human gut has a significant impact on cardiac arrhythmias, the details of which remain unknown. A likely bidirectional relationship exists in which the gut microbiome may affect arrhythmogenesis and in turn be affected by cardiac arrhythmias. The mechanisms of action are not well understood, but likely involve the autonomic nervous system, inflammation, and metabolic pathways.

The gut microbiome is a complex collection of heterogenous microorganisms that have dramatic effects on the human body. Additional research is necessary to identify further associations and causations of gut microorganisms with various human body processes, as well as cardiovascular disease. The microbiome has been shown to directly and indirectly influence the development of different disease states, including the cardiovascular system and cardiac arrhythmias. Several pathways have been proposed through which the gut microbiome can potentially affect cardiac arrhythmogenesis. There are likely several mechanisms simultaneously in operation. Understanding the role of human gut microbiome in the genesis of cardiac arrhythmias not only may improve our understanding of arrhythmias, but also may result in novel treatment options. This could potentially lead to the development of therapeutic options and strategies to modulate the gut microbiome to help detect, prevent, and treat cardiac arrhythmias.

The extensive surface of the gastrointestinal tract presents an interface between the human body and its environment. Residing within the intestinal lumen, ingested food and various microorganisms are an essential aspect of this relationship. The trillions of microorganisms, primarily commensal bacteria hosted by the human gut, constitute the human gut microbiome.

There is growing evidence that the human gut microbiome plays a role in maintaining normal body function and homeostasis.¹ Research, such as the National Institute of Health Microbiome Project, is helping to show the impact of gut microorganisms and their negative influence on metabolic diseases and chronic inflammatory disorders.^2-5 An imbalance in the microbiota, known as dysbiosis, has been associated with metabolic and cardiovascular diseases (CVD), including hypertension, diabetes mellitus, obesity, and coronary artery disease (CAD). Gut dysbiosis has also been associated with cardiac arrhythmias, including atrial fibrillation (AF) and ventricular arrhythmias (Figure).^6-12

Whether gut dysbiosis is a cause or effect of the human disease process is unclear. While further research is warranted, some evidence of causation has been found. In 2018, Yoshida et al demonstrated an association between patients with CAD who had a significantly lower burden of the gut bacteria species Bacteroides vulgatus and Bacteroides dorei compared to that of patients without CAD. The study found that administration of these Bacteroides species reduced atherosclerotic lesion formation in atherosclerosis-prone mice.¹³ If altering gut microbial composition can affect the disease process, it may indicate a causative role for gut dysbiosis in disease pathogenesis. Furthermore, this finding also suggests agents may be used to alter the gut microbiome and potentially prevent and treat diseases. An altered gut microbiome may serve as an early marker for human disease, aiding in timely diagnosis and institution of disease-modifying treatments.

This review outlines the broad relationship of the pathways and intermediaries that may be involved in mediating the interaction between the gut microbiome and cardiac arrhythmias based on rapidly increasing evidence. A comprehensive search among PubMed and Google Scholar databases was conducted to find articles relevant to the topic.

Potential Intermediaries

Potential pathways for how the gut microbiome and cardiovascular system interact are subjects of active research. However, recent research may point to potential mechanisms of the association between the systems. The gut microbiome may influence human physiology through 3 principal routes: the autonomic nervous system, inflammatory pathways, and metabolic processes.

Autonomic Nervous System

The concept of bidirectional communication between the gut and central nervous system, known as the microbiota-gut-brain axis, is widely accepted.¹⁴ Proposed mediators of this interaction include the vagus nerve, the sympathetic nervous system, and the hypothalamic-pituitary-adrenal axis; cytokines produced by the immune system, tryptophan metabolism, and the production of short-chain fatty acids (SCFAs).^15,16

The gut microbiome appears to have a direct impact on the autonomic nervous system, through which it can influence cardiovascular function. Muller et al described how the gut microbiome modulated gut-extrinsic sympathetic neurons and that the depletion of gut microbiota led to activation of both brainstem sensory nuclei and efferent sympathetic premotor glutamatergic neurons.¹⁶ Meng et al found that systemic injection of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) led to significantly increased activity in the paraventricular nucleus, a hypothalamic structure essential to the central autonomic network. Their study demonstrated that systemic TMAO also led to increased left stellate ganglion (LSG) activity, a known contributor to cardiac sympathetic tone.¹²

Inflammatory Pathways

Inflammatory responses are another pathway for the gut microbiome to influence the cardiovascular system. SCFAs are a set of gut microbial metabolites produced in the colon by bacterial fermentation and decomposition of resistant starches and dietary fibers.¹⁷ These metabolites are increasingly recognized for their role in modulating disease processes, including cardiac disease. Aguilar et al found that the progression of atherosclerosis was slowed in apolipoprotein E (Apo-E) knockout mice by a chow diet supplemented with butyrate, a SCFA, suggesting it is an atheroprotective therapeutic agent. Less adhesion and migration of macrophages, reduced inflammation, improved plaque stability, and lowered atherosclerosis progression.¹⁸ Wei et al demonstrated in animal models that direct microinjection of the proinflammatory factors interleukin (IL)-1Β and tumor necrosis factor (TNF)-αdirectly into the subfornical organ increased heart rate, mean blood pressure, and renal sympathetic nerve activity.¹⁹

Metabolic Processes

Serotonin (5-HT), a metabolite of tryptophan, is a neurotransmitter that regulates many bodily functions and plays a significant role in the microbiota-brain gut axis.²⁰ Oral ingestion of the bacterial species Bifidobacterium infantis increased plasma tryptophan in rat models.²¹ Additionally, many other microorganisms, including species of Candida, Streptococcus, Escherichia, and Enterococcus are known to produce 5-HT.²² While a relationship between the gut microbiome and plasma 5-HT has been established, interactions between 5-HT and the cardiovascular system are complex. Research has shown that stimulation of 5-HT_1A receptors produces bradycardic and vasopressor effects, while stimulation of the 5-HT₂ receptor induces vasoconstriction and tachycardia.²³

A high-fiber diet can lower the incidence of hypertension, although the mechanisms are not clear. One potential reason could be alteration in gut bacteria, as a diet high in fiber has been shown to increase the prevalence of acetate-producing bacteria.²⁴

Atherosclerosis

Research investigating the relationship of the gut microbiome with arrhythmias is in its early stages; however, the connection of the gut microbiome and atherosclerosis is more established.²⁵ Contemporary studies have shown various gut microorganisms associated with atherosclerosis.²⁶ Jie et al reported that patients with atherosclerotic cardiovascular disease had increased Enterobacteriaceae loads and oral cavity-associated bacteria with lower levels of butyrate producing bacteria when compared with healthy controls.²⁷ In addition, microbial metabolites such as TMAO appear to promote atherosclerosis by increasing vascular inflammation and platelet reactivity.²⁶ Researchers are investigating the modulation of these associations to help reduce atherosclerotic burden. Kasahara et al found that Roseburia intestinalis could reduce atherosclerotic disease in mice through the production of butyrate.²⁸ Roberts et al established that administration of TMAO inhibitors reduced TMAO levels while reducing thrombus formation without observable toxicity or increased bleeding risk.²⁹

Atrial Arrhythmias

The gut microbiome can also specifically affect cardiac arrhythmogenesis, and multiple studies suggest possible mediators of this interaction. Certain gut microbiome derived metabolites like TMAO may have a role in promoting AF.³⁰ Other gut microbial metabolites like lipopolysaccharides and indoxyl sulfate are implicated in atrial electrical instability.^31,32 Microbe-derived free fatty acids such as palmitic acid and adrenic acid can precipitate arrhythmogenesis. ^33,34 Preponderances of certain gut bacteria like Ruminococcus, Streptococcus, and Enterococcus, as well as reductions of Faecalibacterium, Alistipes, Oscillibacter, and Bilophila have been detected in patients with AF.⁸ Tabata et al found that certain clusters of bacterial groups led by Ruminococcus species seem to show higher prevalence in patients with AF, whereas the genus Enterobacter was significantly lower compared with control subjects. That study also noted that gut microbial composition is affected by diet and antacid use.³⁵ Gut microbiome-derived serotonin may be another mediator for AF, which may be related to the fact that 5-HT₄ receptors are present in atrial tissue.³⁶

Ventricular Arrhythmias

A critical component to the development of malignant ventricular arrhythmias is an imbalance in autonomic tone; in particular, the overactivation of the sympathetic nervous system.³⁷ Animal models have shown that augmentation of the sympathetic nervous system plays an essential role in the subsequent development of ventricular arrhythmias. ³⁸ Several studies have established the LSG as an important component of the cardiac sympathetic nervous system pathway. ^38,39 Ablation of the LSG has been shown to effectively reduce the burden of malignant arrhythmias, further pointing toward the role of excess sympathetic activity.^37,39 Stellate ganglion denervation has become an established method for managing life-threatening ventricular arrhythmias.⁴⁰

Gut metabolites may have significant effects on cardiac sympathetic activity. Meng et al investigated the effect of TMAO on the LSG in animals and its overall effect on the incidence of ventricular arrhythmias under ischemic conditions. To fully explore this interaction, they examined the effect of TMAO on LSG function though 2 mechanisms: local administration of TMAO within the LSG and systemic administration of TMAO leading to activation of the central sympathetic nervous system. In both protocols, left anterior descending coronary artery occlusion was performed after TMAO administration. Injection of TMAO directly into the LSG was found to significantly increase the cardiac sympathetic tone and incidence of ventricular arrhythmias. In the systemic administration control arm, ventricular arrhythmias were also significantly increased.¹²

Increased inflammatory states appear to correlate with an increase in sympathetic tone and ventricular arrhythmias.¹² In an animal study, direct injection of the proinflammatory factor IL-1Β into the LSG not only resulted in increased inflammation, but aggravated cardiac sympathetic remodeling. This led to a decreased effective refractory period and action potential duration, leading to an increased maximal slope of the restitution curve and higher occurrence of ventricular arrhythmias.⁴¹ Shi et al demonstrated that paraventricular nucleus microinjection with TNF-α and IL-1Β also enhanced the cardiac sympathetic afferent reflex, showing that these proinflammatory cytokines not only upregulate the inflammatory response, but can also have excitatory effects that stimulate sympathetic activity and have the potential to be proarrhythmic.^19,42 Local and systemic administration of the gut microbe-derived TMAO increased the expression of IL-1Β and TNF-α, thus implicating the microbiome as a potential mediator of the inflammatory response and as another potential pathway for increased ventricular arrhythmias.¹²

The N-methyl-d-aspartate receptor (NMDAR) is found in multiple organs—including the heart—but more specifically in the conducting system and myocardium.43,44 Research has discovered an upregulation of NMDARs in the setting of cardiac sympathetic hyperinnervation in rat models both with healed myocardial necrotic injury and without. The infusion of their ligand, NMDA, provoked ventricular tachycardia and ventricular fibrillation in rat models with sympathetic hyperinnervation and healed myocardial necrotic injury.⁴⁵ Another study found that NMDAR activation provoked ventricular arrhythmias, but also prolonged repolarization and induced electrical instability.⁴⁶ Proinflammatory markers have been shown to upregulate the expression of NMDARs; more importantly, NMDAR expression has been shown to be significantly increased in the setting of TMAO administration.^12,47,48

5-HT also appears to have a substantial association with ventricular arrhythmias in addition to atrial arrhythmias. el-Mahdy demonstrated in anesthetized rats with acute coronary ligation that systemic doses of 5-HT represented a significant dose-dependent increase in the duration of ventricular tachycardia and ventricular fibrillation, while also increasing the number of ventricular ectopic beats.⁴⁹ Certain gut microorganisms are known to produce 5-HT, including those in the genera Streptococcus, Escherichia, and Enterococcus.²² Additionally, oral ingestion of the Bifidobacterium infantis increased plasma levels of tryptophan in rat models.²¹ The gut microbiome may have significant effects on plasma serotonin levels, and thus have the potential to alter the risk for ventricular arrhythmias.

The deleterious effects of the gut microbiome have been documented. However, it appears to have potential protective effects, and several studies point to the possible mechanisms of this beneficial interaction. Propionate is a SCFA microorganism produced by gut microbial fermentation.⁵⁰ In a rat model study, Zhou et al found that infusion of sodium propionate significantly reduced ventricular arrhythmias during acute myocardial ischemia or burst stimulation, thus confirming cardioprotective effects.^50,51

Proposed mechanisms for reduced susceptibility to ventricular arrhythmias with propionate infusion include parasympathetic activation via the gut-brain axis, anti-inflammatory pathways, and improved cardiac electrophysiology instability.⁵⁰ In addition butyrate has been found to reduce inflammation and myocardial hypertrophy. Jiang et al demonstrated in rats postmyocardial infarction that butyrate promoted expression of anti-inflammatory M2 macrophage markers, decreased expressions of nerve growth factor and norepinephrine, and decreased the density of nerve fibers for growth-associated protein-43 and tyrosine hydroxylase. The cumulative impact of butyrate led to suppression of inflammation and the inhibition of sympathetic neural remodeling, ultimately resulting in improved cardiac function and reduction in ventricular arrhythmias after myocardial infarction.⁵²

Gut bacteria-derived acetate-mediated reduction in cardiac fibrosis may be another mechanism for the effects on ventricular arrhythmias. Cardiac fibrosis and scar are established as the primary substrate for reentrant ventricular arrhythmias seen in various cardiomyopathies.

Future Directions

The microbiome residing in the human gut has a significant impact on cardiac arrhythmias, the details of which remain unknown. A likely bidirectional relationship exists in which the gut microbiome may affect arrhythmogenesis and in turn be affected by cardiac arrhythmias. The mechanisms of action are not well understood, but likely involve the autonomic nervous system, inflammation, and metabolic pathways.

The gut microbiome is a complex collection of heterogenous microorganisms that have dramatic effects on the human body. Additional research is necessary to identify further associations and causations of gut microorganisms with various human body processes, as well as cardiovascular disease. The microbiome has been shown to directly and indirectly influence the development of different disease states, including the cardiovascular system and cardiac arrhythmias. Several pathways have been proposed through which the gut microbiome can potentially affect cardiac arrhythmogenesis. There are likely several mechanisms simultaneously in operation. Understanding the role of human gut microbiome in the genesis of cardiac arrhythmias not only may improve our understanding of arrhythmias, but also may result in novel treatment options. This could potentially lead to the development of therapeutic options and strategies to modulate the gut microbiome to help detect, prevent, and treat cardiac arrhythmias.

The extensive surface of the gastrointestinal tract presents an interface between the human body and its environment. Residing within the intestinal lumen, ingested food and various microorganisms are an essential aspect of this relationship. The trillions of microorganisms, primarily commensal bacteria hosted by the human gut, constitute the human gut microbiome.

There is growing evidence that the human gut microbiome plays a role in maintaining normal body function and homeostasis.¹ Research, such as the National Institute of Health Microbiome Project, is helping to show the impact of gut microorganisms and their negative influence on metabolic diseases and chronic inflammatory disorders.^2-5 An imbalance in the microbiota, known as dysbiosis, has been associated with metabolic and cardiovascular diseases (CVD), including hypertension, diabetes mellitus, obesity, and coronary artery disease (CAD). Gut dysbiosis has also been associated with cardiac arrhythmias, including atrial fibrillation (AF) and ventricular arrhythmias (Figure).^6-12

Whether gut dysbiosis is a cause or effect of the human disease process is unclear. While further research is warranted, some evidence of causation has been found. In 2018, Yoshida et al demonstrated an association between patients with CAD who had a significantly lower burden of the gut bacteria species Bacteroides vulgatus and Bacteroides dorei compared to that of patients without CAD. The study found that administration of these Bacteroides species reduced atherosclerotic lesion formation in atherosclerosis-prone mice.¹³ If altering gut microbial composition can affect the disease process, it may indicate a causative role for gut dysbiosis in disease pathogenesis. Furthermore, this finding also suggests agents may be used to alter the gut microbiome and potentially prevent and treat diseases. An altered gut microbiome may serve as an early marker for human disease, aiding in timely diagnosis and institution of disease-modifying treatments.

This review outlines the broad relationship of the pathways and intermediaries that may be involved in mediating the interaction between the gut microbiome and cardiac arrhythmias based on rapidly increasing evidence. A comprehensive search among PubMed and Google Scholar databases was conducted to find articles relevant to the topic.

Potential Intermediaries

Potential pathways for how the gut microbiome and cardiovascular system interact are subjects of active research. However, recent research may point to potential mechanisms of the association between the systems. The gut microbiome may influence human physiology through 3 principal routes: the autonomic nervous system, inflammatory pathways, and metabolic processes.

Autonomic Nervous System

The concept of bidirectional communication between the gut and central nervous system, known as the microbiota-gut-brain axis, is widely accepted.¹⁴ Proposed mediators of this interaction include the vagus nerve, the sympathetic nervous system, and the hypothalamic-pituitary-adrenal axis; cytokines produced by the immune system, tryptophan metabolism, and the production of short-chain fatty acids (SCFAs).^15,16

The gut microbiome appears to have a direct impact on the autonomic nervous system, through which it can influence cardiovascular function. Muller et al described how the gut microbiome modulated gut-extrinsic sympathetic neurons and that the depletion of gut microbiota led to activation of both brainstem sensory nuclei and efferent sympathetic premotor glutamatergic neurons.¹⁶ Meng et al found that systemic injection of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) led to significantly increased activity in the paraventricular nucleus, a hypothalamic structure essential to the central autonomic network. Their study demonstrated that systemic TMAO also led to increased left stellate ganglion (LSG) activity, a known contributor to cardiac sympathetic tone.¹²

Inflammatory Pathways

Inflammatory responses are another pathway for the gut microbiome to influence the cardiovascular system. SCFAs are a set of gut microbial metabolites produced in the colon by bacterial fermentation and decomposition of resistant starches and dietary fibers.¹⁷ These metabolites are increasingly recognized for their role in modulating disease processes, including cardiac disease. Aguilar et al found that the progression of atherosclerosis was slowed in apolipoprotein E (Apo-E) knockout mice by a chow diet supplemented with butyrate, a SCFA, suggesting it is an atheroprotective therapeutic agent. Less adhesion and migration of macrophages, reduced inflammation, improved plaque stability, and lowered atherosclerosis progression.¹⁸ Wei et al demonstrated in animal models that direct microinjection of the proinflammatory factors interleukin (IL)-1Β and tumor necrosis factor (TNF)-αdirectly into the subfornical organ increased heart rate, mean blood pressure, and renal sympathetic nerve activity.¹⁹

Metabolic Processes

Serotonin (5-HT), a metabolite of tryptophan, is a neurotransmitter that regulates many bodily functions and plays a significant role in the microbiota-brain gut axis.²⁰ Oral ingestion of the bacterial species Bifidobacterium infantis increased plasma tryptophan in rat models.²¹ Additionally, many other microorganisms, including species of Candida, Streptococcus, Escherichia, and Enterococcus are known to produce 5-HT.²² While a relationship between the gut microbiome and plasma 5-HT has been established, interactions between 5-HT and the cardiovascular system are complex. Research has shown that stimulation of 5-HT_1A receptors produces bradycardic and vasopressor effects, while stimulation of the 5-HT₂ receptor induces vasoconstriction and tachycardia.²³

A high-fiber diet can lower the incidence of hypertension, although the mechanisms are not clear. One potential reason could be alteration in gut bacteria, as a diet high in fiber has been shown to increase the prevalence of acetate-producing bacteria.²⁴

Atherosclerosis

Research investigating the relationship of the gut microbiome with arrhythmias is in its early stages; however, the connection of the gut microbiome and atherosclerosis is more established.²⁵ Contemporary studies have shown various gut microorganisms associated with atherosclerosis.²⁶ Jie et al reported that patients with atherosclerotic cardiovascular disease had increased Enterobacteriaceae loads and oral cavity-associated bacteria with lower levels of butyrate producing bacteria when compared with healthy controls.²⁷ In addition, microbial metabolites such as TMAO appear to promote atherosclerosis by increasing vascular inflammation and platelet reactivity.²⁶ Researchers are investigating the modulation of these associations to help reduce atherosclerotic burden. Kasahara et al found that Roseburia intestinalis could reduce atherosclerotic disease in mice through the production of butyrate.²⁸ Roberts et al established that administration of TMAO inhibitors reduced TMAO levels while reducing thrombus formation without observable toxicity or increased bleeding risk.²⁹

Atrial Arrhythmias

The gut microbiome can also specifically affect cardiac arrhythmogenesis, and multiple studies suggest possible mediators of this interaction. Certain gut microbiome derived metabolites like TMAO may have a role in promoting AF.³⁰ Other gut microbial metabolites like lipopolysaccharides and indoxyl sulfate are implicated in atrial electrical instability.^31,32 Microbe-derived free fatty acids such as palmitic acid and adrenic acid can precipitate arrhythmogenesis. ^33,34 Preponderances of certain gut bacteria like Ruminococcus, Streptococcus, and Enterococcus, as well as reductions of Faecalibacterium, Alistipes, Oscillibacter, and Bilophila have been detected in patients with AF.⁸ Tabata et al found that certain clusters of bacterial groups led by Ruminococcus species seem to show higher prevalence in patients with AF, whereas the genus Enterobacter was significantly lower compared with control subjects. That study also noted that gut microbial composition is affected by diet and antacid use.³⁵ Gut microbiome-derived serotonin may be another mediator for AF, which may be related to the fact that 5-HT₄ receptors are present in atrial tissue.³⁶

Ventricular Arrhythmias

A critical component to the development of malignant ventricular arrhythmias is an imbalance in autonomic tone; in particular, the overactivation of the sympathetic nervous system.³⁷ Animal models have shown that augmentation of the sympathetic nervous system plays an essential role in the subsequent development of ventricular arrhythmias. ³⁸ Several studies have established the LSG as an important component of the cardiac sympathetic nervous system pathway. ^38,39 Ablation of the LSG has been shown to effectively reduce the burden of malignant arrhythmias, further pointing toward the role of excess sympathetic activity.^37,39 Stellate ganglion denervation has become an established method for managing life-threatening ventricular arrhythmias.⁴⁰

Gut metabolites may have significant effects on cardiac sympathetic activity. Meng et al investigated the effect of TMAO on the LSG in animals and its overall effect on the incidence of ventricular arrhythmias under ischemic conditions. To fully explore this interaction, they examined the effect of TMAO on LSG function though 2 mechanisms: local administration of TMAO within the LSG and systemic administration of TMAO leading to activation of the central sympathetic nervous system. In both protocols, left anterior descending coronary artery occlusion was performed after TMAO administration. Injection of TMAO directly into the LSG was found to significantly increase the cardiac sympathetic tone and incidence of ventricular arrhythmias. In the systemic administration control arm, ventricular arrhythmias were also significantly increased.¹²

Increased inflammatory states appear to correlate with an increase in sympathetic tone and ventricular arrhythmias.¹² In an animal study, direct injection of the proinflammatory factor IL-1Β into the LSG not only resulted in increased inflammation, but aggravated cardiac sympathetic remodeling. This led to a decreased effective refractory period and action potential duration, leading to an increased maximal slope of the restitution curve and higher occurrence of ventricular arrhythmias.⁴¹ Shi et al demonstrated that paraventricular nucleus microinjection with TNF-α and IL-1Β also enhanced the cardiac sympathetic afferent reflex, showing that these proinflammatory cytokines not only upregulate the inflammatory response, but can also have excitatory effects that stimulate sympathetic activity and have the potential to be proarrhythmic.^19,42 Local and systemic administration of the gut microbe-derived TMAO increased the expression of IL-1Β and TNF-α, thus implicating the microbiome as a potential mediator of the inflammatory response and as another potential pathway for increased ventricular arrhythmias.¹²

The N-methyl-d-aspartate receptor (NMDAR) is found in multiple organs—including the heart—but more specifically in the conducting system and myocardium.43,44 Research has discovered an upregulation of NMDARs in the setting of cardiac sympathetic hyperinnervation in rat models both with healed myocardial necrotic injury and without. The infusion of their ligand, NMDA, provoked ventricular tachycardia and ventricular fibrillation in rat models with sympathetic hyperinnervation and healed myocardial necrotic injury.⁴⁵ Another study found that NMDAR activation provoked ventricular arrhythmias, but also prolonged repolarization and induced electrical instability.⁴⁶ Proinflammatory markers have been shown to upregulate the expression of NMDARs; more importantly, NMDAR expression has been shown to be significantly increased in the setting of TMAO administration.^12,47,48

5-HT also appears to have a substantial association with ventricular arrhythmias in addition to atrial arrhythmias. el-Mahdy demonstrated in anesthetized rats with acute coronary ligation that systemic doses of 5-HT represented a significant dose-dependent increase in the duration of ventricular tachycardia and ventricular fibrillation, while also increasing the number of ventricular ectopic beats.⁴⁹ Certain gut microorganisms are known to produce 5-HT, including those in the genera Streptococcus, Escherichia, and Enterococcus.²² Additionally, oral ingestion of the Bifidobacterium infantis increased plasma levels of tryptophan in rat models.²¹ The gut microbiome may have significant effects on plasma serotonin levels, and thus have the potential to alter the risk for ventricular arrhythmias.

The deleterious effects of the gut microbiome have been documented. However, it appears to have potential protective effects, and several studies point to the possible mechanisms of this beneficial interaction. Propionate is a SCFA microorganism produced by gut microbial fermentation.⁵⁰ In a rat model study, Zhou et al found that infusion of sodium propionate significantly reduced ventricular arrhythmias during acute myocardial ischemia or burst stimulation, thus confirming cardioprotective effects.^50,51

Proposed mechanisms for reduced susceptibility to ventricular arrhythmias with propionate infusion include parasympathetic activation via the gut-brain axis, anti-inflammatory pathways, and improved cardiac electrophysiology instability.⁵⁰ In addition butyrate has been found to reduce inflammation and myocardial hypertrophy. Jiang et al demonstrated in rats postmyocardial infarction that butyrate promoted expression of anti-inflammatory M2 macrophage markers, decreased expressions of nerve growth factor and norepinephrine, and decreased the density of nerve fibers for growth-associated protein-43 and tyrosine hydroxylase. The cumulative impact of butyrate led to suppression of inflammation and the inhibition of sympathetic neural remodeling, ultimately resulting in improved cardiac function and reduction in ventricular arrhythmias after myocardial infarction.⁵²

Gut bacteria-derived acetate-mediated reduction in cardiac fibrosis may be another mechanism for the effects on ventricular arrhythmias. Cardiac fibrosis and scar are established as the primary substrate for reentrant ventricular arrhythmias seen in various cardiomyopathies.

Future Directions

The microbiome residing in the human gut has a significant impact on cardiac arrhythmias, the details of which remain unknown. A likely bidirectional relationship exists in which the gut microbiome may affect arrhythmogenesis and in turn be affected by cardiac arrhythmias. The mechanisms of action are not well understood, but likely involve the autonomic nervous system, inflammation, and metabolic pathways.

The gut microbiome is a complex collection of heterogenous microorganisms that have dramatic effects on the human body. Additional research is necessary to identify further associations and causations of gut microorganisms with various human body processes, as well as cardiovascular disease. The microbiome has been shown to directly and indirectly influence the development of different disease states, including the cardiovascular system and cardiac arrhythmias. Several pathways have been proposed through which the gut microbiome can potentially affect cardiac arrhythmogenesis. There are likely several mechanisms simultaneously in operation. Understanding the role of human gut microbiome in the genesis of cardiac arrhythmias not only may improve our understanding of arrhythmias, but also may result in novel treatment options. This could potentially lead to the development of therapeutic options and strategies to modulate the gut microbiome to help detect, prevent, and treat cardiac arrhythmias.