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Stratifying diagnostic cut-off values of tumor markers based on genetic variants may improve detection of pancreatic cancer, according to investigators.

Stratification had the greatest positive impact on accuracy of carbohydrate antigen 19-9 (CA19-9), reported lead author Toshiya Abe, MD, PhD, of Johns Hopkins Hospital, Baltimore, and colleagues.

“Despite the evidence that genetic factors influence tumor marker levels, the potential utility of using a genetic test to improve the interpretation of tumor markers has drawn limited attention,” the investigators wrote in Clinical Gastroenterology and Hepatology.

And improvements are needed, the investigators noted, particularly for early cancer detection in high-risk individuals.

“[T]he toughest hurdle for a pancreatic cancer detection blood test is the detection of stage I disease,” the investigators wrote. “Cancers generally shed biomarkers in proportion to their size, and small stage I pancreatic cancers shed fewer diagnostic biomarkers into the circulation, making diagnosis more difficult.”

Although a 2016 study by Dr. Guopei Luo and colleagues demonstrated that diagnostic accuracy of CA19-9 could be improved via genotyping, tumor marker performance was not characterized by high-specificity cut-off values, which the present study aimed to do.

The control group included 504 high-risk individuals who were prospectively enrolled in the Cancer of the Pancreas Screening (CAPS) studies from 2002 to 2018, while the case group included 245 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent resection at Johns Hopkins from 2010 to 2017.

The control group was randomly divided into discovery and validation sets in order to achieve 99% specificity cut-off values, which were used to measure sensitivity in the case group. According to the investigators, high-specificity cut-off values are necessary for surveillance of asymptomatic high-risk individuals in order to minimize false-positive results.

In all patients, tumor markers and genotype were analyzed. Tumor markers included carcinoembryonic antigen (CEA), CA19-9, and cancer antigen 125 (CA-125). Genotyping included 16 single-nucleotide polymorphisms (SNPs) in 9 genes, including FUT2 and FUT3, which are known to influence levels of CA19-9.

In contrast with previous findings, which identified three relevant subgroups of FUT2/FUT3, the present study found that four distinct subgroups were significantly associated with CA19-9 levels: FUT3-null, FUT3+/-, FUT3+/+, and FUT2-null.

When CA19-9 cut-off levels were stratified by these four subgroups and applied to the 245 patients with pancreatic cancer, the investigators achieved a sensitivity of 60.8%, compared with 52.7% without stratification. The new cut-off values led to reclassification of 28 (11.4%) patients with pancreatic cancer, including 24 who switched from negative to positive, and 4 who switched from positive to negative.

Sensitivity of the SNP-adjusted CA19-9 test was improved to 66.4% when used exclusively in patients with functional FUT3 genes. Conversely, sensitivity was markedly lower, at 36.7%, when the test was used for patients with stage I disease.

While CA19-9 testing was notably improved by SNP-based stratification, results from CEA and CA-125 testing were more modest. Standard CEA testing had a sensitivity of 13.8%, compared with 15.9% when cut-off values were stratified by FUT2 status and ABO blood group. Similarly, modifying CA-125 values based on SNPs in GAL3ST2 raised sensitivity from 15.5% to 17.6%.

Although combining SNP-modified tumor marker results did increase overall sensitivity to as high as 66.1%, this also reduced specificity to as low as 95.4%

Still, Dr. Abe and colleagues suggested that the findings demonstrate proof of concept.

“Our results show that a tumor marker SNP test can improve the diagnostic accuracy of CA19-9 and, to a lesser extent, CEA and CA-125, but further work is needed to improve the diagnostic accuracy of our panel for the detection of early-stage pancreatic cancer,” they concluded.

The investigators also suggested that the technique could have value for surveillance of ovarian cancer; however, again, they emphasized the need for more research.The study was funded by the National Institutes of Health, Susan Wojcicki and Dennis Troper, the Pancreatic Cancer Action Network, and others. The investigators reported no conflicts of interest.

SOURCE: Abe T et al. Clin Gastro Hepatol. 2019 Oct 29. doi: 10.1016/j.cgh.2019.10.036.

Stratifying diagnostic cut-off values of tumor markers based on genetic variants may improve detection of pancreatic cancer, according to investigators.

Stratification had the greatest positive impact on accuracy of carbohydrate antigen 19-9 (CA19-9), reported lead author Toshiya Abe, MD, PhD, of Johns Hopkins Hospital, Baltimore, and colleagues.

“Despite the evidence that genetic factors influence tumor marker levels, the potential utility of using a genetic test to improve the interpretation of tumor markers has drawn limited attention,” the investigators wrote in Clinical Gastroenterology and Hepatology.

And improvements are needed, the investigators noted, particularly for early cancer detection in high-risk individuals.

“[T]he toughest hurdle for a pancreatic cancer detection blood test is the detection of stage I disease,” the investigators wrote. “Cancers generally shed biomarkers in proportion to their size, and small stage I pancreatic cancers shed fewer diagnostic biomarkers into the circulation, making diagnosis more difficult.”

Although a 2016 study by Dr. Guopei Luo and colleagues demonstrated that diagnostic accuracy of CA19-9 could be improved via genotyping, tumor marker performance was not characterized by high-specificity cut-off values, which the present study aimed to do.

The control group included 504 high-risk individuals who were prospectively enrolled in the Cancer of the Pancreas Screening (CAPS) studies from 2002 to 2018, while the case group included 245 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent resection at Johns Hopkins from 2010 to 2017.

The control group was randomly divided into discovery and validation sets in order to achieve 99% specificity cut-off values, which were used to measure sensitivity in the case group. According to the investigators, high-specificity cut-off values are necessary for surveillance of asymptomatic high-risk individuals in order to minimize false-positive results.

In all patients, tumor markers and genotype were analyzed. Tumor markers included carcinoembryonic antigen (CEA), CA19-9, and cancer antigen 125 (CA-125). Genotyping included 16 single-nucleotide polymorphisms (SNPs) in 9 genes, including FUT2 and FUT3, which are known to influence levels of CA19-9.

In contrast with previous findings, which identified three relevant subgroups of FUT2/FUT3, the present study found that four distinct subgroups were significantly associated with CA19-9 levels: FUT3-null, FUT3+/-, FUT3+/+, and FUT2-null.

When CA19-9 cut-off levels were stratified by these four subgroups and applied to the 245 patients with pancreatic cancer, the investigators achieved a sensitivity of 60.8%, compared with 52.7% without stratification. The new cut-off values led to reclassification of 28 (11.4%) patients with pancreatic cancer, including 24 who switched from negative to positive, and 4 who switched from positive to negative.

Sensitivity of the SNP-adjusted CA19-9 test was improved to 66.4% when used exclusively in patients with functional FUT3 genes. Conversely, sensitivity was markedly lower, at 36.7%, when the test was used for patients with stage I disease.

While CA19-9 testing was notably improved by SNP-based stratification, results from CEA and CA-125 testing were more modest. Standard CEA testing had a sensitivity of 13.8%, compared with 15.9% when cut-off values were stratified by FUT2 status and ABO blood group. Similarly, modifying CA-125 values based on SNPs in GAL3ST2 raised sensitivity from 15.5% to 17.6%.

Although combining SNP-modified tumor marker results did increase overall sensitivity to as high as 66.1%, this also reduced specificity to as low as 95.4%

Still, Dr. Abe and colleagues suggested that the findings demonstrate proof of concept.

“Our results show that a tumor marker SNP test can improve the diagnostic accuracy of CA19-9 and, to a lesser extent, CEA and CA-125, but further work is needed to improve the diagnostic accuracy of our panel for the detection of early-stage pancreatic cancer,” they concluded.

The investigators also suggested that the technique could have value for surveillance of ovarian cancer; however, again, they emphasized the need for more research.The study was funded by the National Institutes of Health, Susan Wojcicki and Dennis Troper, the Pancreatic Cancer Action Network, and others. The investigators reported no conflicts of interest.

SOURCE: Abe T et al. Clin Gastro Hepatol. 2019 Oct 29. doi: 10.1016/j.cgh.2019.10.036.

Stratifying diagnostic cut-off values of tumor markers based on genetic variants may improve detection of pancreatic cancer, according to investigators.

Stratification had the greatest positive impact on accuracy of carbohydrate antigen 19-9 (CA19-9), reported lead author Toshiya Abe, MD, PhD, of Johns Hopkins Hospital, Baltimore, and colleagues.

“Despite the evidence that genetic factors influence tumor marker levels, the potential utility of using a genetic test to improve the interpretation of tumor markers has drawn limited attention,” the investigators wrote in Clinical Gastroenterology and Hepatology.

And improvements are needed, the investigators noted, particularly for early cancer detection in high-risk individuals.

“[T]he toughest hurdle for a pancreatic cancer detection blood test is the detection of stage I disease,” the investigators wrote. “Cancers generally shed biomarkers in proportion to their size, and small stage I pancreatic cancers shed fewer diagnostic biomarkers into the circulation, making diagnosis more difficult.”

Although a 2016 study by Dr. Guopei Luo and colleagues demonstrated that diagnostic accuracy of CA19-9 could be improved via genotyping, tumor marker performance was not characterized by high-specificity cut-off values, which the present study aimed to do.

The control group included 504 high-risk individuals who were prospectively enrolled in the Cancer of the Pancreas Screening (CAPS) studies from 2002 to 2018, while the case group included 245 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent resection at Johns Hopkins from 2010 to 2017.

The control group was randomly divided into discovery and validation sets in order to achieve 99% specificity cut-off values, which were used to measure sensitivity in the case group. According to the investigators, high-specificity cut-off values are necessary for surveillance of asymptomatic high-risk individuals in order to minimize false-positive results.

In all patients, tumor markers and genotype were analyzed. Tumor markers included carcinoembryonic antigen (CEA), CA19-9, and cancer antigen 125 (CA-125). Genotyping included 16 single-nucleotide polymorphisms (SNPs) in 9 genes, including FUT2 and FUT3, which are known to influence levels of CA19-9.

In contrast with previous findings, which identified three relevant subgroups of FUT2/FUT3, the present study found that four distinct subgroups were significantly associated with CA19-9 levels: FUT3-null, FUT3+/-, FUT3+/+, and FUT2-null.

When CA19-9 cut-off levels were stratified by these four subgroups and applied to the 245 patients with pancreatic cancer, the investigators achieved a sensitivity of 60.8%, compared with 52.7% without stratification. The new cut-off values led to reclassification of 28 (11.4%) patients with pancreatic cancer, including 24 who switched from negative to positive, and 4 who switched from positive to negative.

Sensitivity of the SNP-adjusted CA19-9 test was improved to 66.4% when used exclusively in patients with functional FUT3 genes. Conversely, sensitivity was markedly lower, at 36.7%, when the test was used for patients with stage I disease.

While CA19-9 testing was notably improved by SNP-based stratification, results from CEA and CA-125 testing were more modest. Standard CEA testing had a sensitivity of 13.8%, compared with 15.9% when cut-off values were stratified by FUT2 status and ABO blood group. Similarly, modifying CA-125 values based on SNPs in GAL3ST2 raised sensitivity from 15.5% to 17.6%.

Although combining SNP-modified tumor marker results did increase overall sensitivity to as high as 66.1%, this also reduced specificity to as low as 95.4%

Still, Dr. Abe and colleagues suggested that the findings demonstrate proof of concept.

“Our results show that a tumor marker SNP test can improve the diagnostic accuracy of CA19-9 and, to a lesser extent, CEA and CA-125, but further work is needed to improve the diagnostic accuracy of our panel for the detection of early-stage pancreatic cancer,” they concluded.

The investigators also suggested that the technique could have value for surveillance of ovarian cancer; however, again, they emphasized the need for more research.The study was funded by the National Institutes of Health, Susan Wojcicki and Dennis Troper, the Pancreatic Cancer Action Network, and others. The investigators reported no conflicts of interest.

SOURCE: Abe T et al. Clin Gastro Hepatol. 2019 Oct 29. doi: 10.1016/j.cgh.2019.10.036.

Adolescents who undergo metabolic bariatric surgery may require long-term nutrient monitoring and supplementation to prevent nutritional deficiencies, according to investigators.

In a 5-year prospective study, more than a quarter of the participants who underwent vertical sleeve gastrectomy (VSG) developed two or more nutritional deficiencies, reported lead author Stavra A. Xanthakos, MD, of the Cincinnati Children’s Hospital Medical Center, and colleagues.

“Although prevalence of nutritional deficiencies has been estimated largely from adult cohorts, bariatric surgery is an increasingly accepted treatment for severe obesity in youth,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Yet, lower adherence to supplementation and anticipated longer lifespan with altered gastrointestinal physiology may increase risk of adverse nutritional outcomes in these youth.”

Previous research has suggested that teens may be at higher risk for nutritional deficiencies, but these studies were largely retrospective, or when prospective, lacked sufficient long-term follow-up, analysis of comprehensive patient factors, or inclusion of VSG, which is now the predominant technique in the field, the investigators noted.

“Our study is the first to assess comparative nutritional outcomes in adolescents after both VSG and gastric bypass,” they wrote.

The study involved 226 participants aged 13-19 years who underwent either Roux-en-Y gastric bypass (n = 161) or VSG (n = 67) at five tertiary-care centers in the United States during 2007-2012.

Six months after surgery, at 12 months, and on an annual basis thereafter, the investigators gathered clinical data and measured participant serum levels of ferritin; transferrin; albumin; parathyroid hormone; C-reactive protein; and vitamins A, D, B₁, B₁₂, and folate. Analyses also included sex, age, ethnicity, race, household demographics, weight, height, comorbidities, and body mass index (BMI).

The majority of participants were female (75%) and white (72%). At baseline, mean BMI and age were 52.7 kg/m² and 16.5 years, respectively. After 5 years, mean body mass index decreased 23% without a significant difference between procedures.

Generally, nutritional deficiencies occurred earlier and were more common after gastric bypass, although both procedures were ultimately associated with increased risks.

In the gastric bypass group, 59% of participants had two or more nutritional deficiencies at 5 years, and 19% had three more deficiencies, which represented increased rates of fivefold and sixfold, respectively, which the investigators described as “striking.” In the VSG group, 27% of patients had two or more nutritional deficiencies at 5 years; while this fourfold increase was not statistically significant, the investigators suggested that it indicated “a lower, but not negligible, nutritional risk.”

Hypoferritinemia was particularly common in both groups, with rates at year 5 of 71% and 45% among patients who underwent gastric bypass and VSG, respectively.

“Our results now provide critical evidence that VSG does in fact carry significantly lower nutritional risk than Roux-en-Y gastric bypass, but can still worsen iron status,” the investigators wrote.

The investigators also highlighted a nonsignificant increase in the incidence of vitamin B₁₂ deficiency among patients who underwent gastric bypass, with rates increasing from 0.6% at baseline to 11.5% at 5 years.

“Vitamin B₁₂ status likewise worsened disproportionately after [gastric bypass], despite similar trajectories of weight loss after VSG,” the investigators wrote. “This suggests that the differential risk is caused by anatomic and physiological differences between procedures, rather than weight loss alone.”

Beyond surgery type, risk factors for nutritional deficiency included inadequate supplement intake, pregnancy, weight regain, and black race.

“Our findings underscore the importance of long-term nutritional monitoring in adolescents after bariatric surgery and the need to examine impact on health outcomes and quality of life as these youth advance into adulthood, including systematic assessment of anemia and bone health,” the investigators concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Courcoulas reported grant support from Allurion.

SOURCE: Xanthakos SA et al. Clin Gastro Hepatol. 2019 Nov 6. doi: 10.1016/j.cgh.2019.10.048.

Adolescents who undergo metabolic bariatric surgery may require long-term nutrient monitoring and supplementation to prevent nutritional deficiencies, according to investigators.

In a 5-year prospective study, more than a quarter of the participants who underwent vertical sleeve gastrectomy (VSG) developed two or more nutritional deficiencies, reported lead author Stavra A. Xanthakos, MD, of the Cincinnati Children’s Hospital Medical Center, and colleagues.

“Although prevalence of nutritional deficiencies has been estimated largely from adult cohorts, bariatric surgery is an increasingly accepted treatment for severe obesity in youth,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Yet, lower adherence to supplementation and anticipated longer lifespan with altered gastrointestinal physiology may increase risk of adverse nutritional outcomes in these youth.”

Previous research has suggested that teens may be at higher risk for nutritional deficiencies, but these studies were largely retrospective, or when prospective, lacked sufficient long-term follow-up, analysis of comprehensive patient factors, or inclusion of VSG, which is now the predominant technique in the field, the investigators noted.

“Our study is the first to assess comparative nutritional outcomes in adolescents after both VSG and gastric bypass,” they wrote.

The study involved 226 participants aged 13-19 years who underwent either Roux-en-Y gastric bypass (n = 161) or VSG (n = 67) at five tertiary-care centers in the United States during 2007-2012.

Six months after surgery, at 12 months, and on an annual basis thereafter, the investigators gathered clinical data and measured participant serum levels of ferritin; transferrin; albumin; parathyroid hormone; C-reactive protein; and vitamins A, D, B₁, B₁₂, and folate. Analyses also included sex, age, ethnicity, race, household demographics, weight, height, comorbidities, and body mass index (BMI).

The majority of participants were female (75%) and white (72%). At baseline, mean BMI and age were 52.7 kg/m² and 16.5 years, respectively. After 5 years, mean body mass index decreased 23% without a significant difference between procedures.

Generally, nutritional deficiencies occurred earlier and were more common after gastric bypass, although both procedures were ultimately associated with increased risks.

In the gastric bypass group, 59% of participants had two or more nutritional deficiencies at 5 years, and 19% had three more deficiencies, which represented increased rates of fivefold and sixfold, respectively, which the investigators described as “striking.” In the VSG group, 27% of patients had two or more nutritional deficiencies at 5 years; while this fourfold increase was not statistically significant, the investigators suggested that it indicated “a lower, but not negligible, nutritional risk.”

Hypoferritinemia was particularly common in both groups, with rates at year 5 of 71% and 45% among patients who underwent gastric bypass and VSG, respectively.

“Our results now provide critical evidence that VSG does in fact carry significantly lower nutritional risk than Roux-en-Y gastric bypass, but can still worsen iron status,” the investigators wrote.

The investigators also highlighted a nonsignificant increase in the incidence of vitamin B₁₂ deficiency among patients who underwent gastric bypass, with rates increasing from 0.6% at baseline to 11.5% at 5 years.

“Vitamin B₁₂ status likewise worsened disproportionately after [gastric bypass], despite similar trajectories of weight loss after VSG,” the investigators wrote. “This suggests that the differential risk is caused by anatomic and physiological differences between procedures, rather than weight loss alone.”

Beyond surgery type, risk factors for nutritional deficiency included inadequate supplement intake, pregnancy, weight regain, and black race.

“Our findings underscore the importance of long-term nutritional monitoring in adolescents after bariatric surgery and the need to examine impact on health outcomes and quality of life as these youth advance into adulthood, including systematic assessment of anemia and bone health,” the investigators concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Courcoulas reported grant support from Allurion.

SOURCE: Xanthakos SA et al. Clin Gastro Hepatol. 2019 Nov 6. doi: 10.1016/j.cgh.2019.10.048.

Adolescents who undergo metabolic bariatric surgery may require long-term nutrient monitoring and supplementation to prevent nutritional deficiencies, according to investigators.

In a 5-year prospective study, more than a quarter of the participants who underwent vertical sleeve gastrectomy (VSG) developed two or more nutritional deficiencies, reported lead author Stavra A. Xanthakos, MD, of the Cincinnati Children’s Hospital Medical Center, and colleagues.

“Although prevalence of nutritional deficiencies has been estimated largely from adult cohorts, bariatric surgery is an increasingly accepted treatment for severe obesity in youth,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Yet, lower adherence to supplementation and anticipated longer lifespan with altered gastrointestinal physiology may increase risk of adverse nutritional outcomes in these youth.”

Previous research has suggested that teens may be at higher risk for nutritional deficiencies, but these studies were largely retrospective, or when prospective, lacked sufficient long-term follow-up, analysis of comprehensive patient factors, or inclusion of VSG, which is now the predominant technique in the field, the investigators noted.

“Our study is the first to assess comparative nutritional outcomes in adolescents after both VSG and gastric bypass,” they wrote.

The study involved 226 participants aged 13-19 years who underwent either Roux-en-Y gastric bypass (n = 161) or VSG (n = 67) at five tertiary-care centers in the United States during 2007-2012.

Six months after surgery, at 12 months, and on an annual basis thereafter, the investigators gathered clinical data and measured participant serum levels of ferritin; transferrin; albumin; parathyroid hormone; C-reactive protein; and vitamins A, D, B₁, B₁₂, and folate. Analyses also included sex, age, ethnicity, race, household demographics, weight, height, comorbidities, and body mass index (BMI).

The majority of participants were female (75%) and white (72%). At baseline, mean BMI and age were 52.7 kg/m² and 16.5 years, respectively. After 5 years, mean body mass index decreased 23% without a significant difference between procedures.

Generally, nutritional deficiencies occurred earlier and were more common after gastric bypass, although both procedures were ultimately associated with increased risks.

In the gastric bypass group, 59% of participants had two or more nutritional deficiencies at 5 years, and 19% had three more deficiencies, which represented increased rates of fivefold and sixfold, respectively, which the investigators described as “striking.” In the VSG group, 27% of patients had two or more nutritional deficiencies at 5 years; while this fourfold increase was not statistically significant, the investigators suggested that it indicated “a lower, but not negligible, nutritional risk.”

Hypoferritinemia was particularly common in both groups, with rates at year 5 of 71% and 45% among patients who underwent gastric bypass and VSG, respectively.

“Our results now provide critical evidence that VSG does in fact carry significantly lower nutritional risk than Roux-en-Y gastric bypass, but can still worsen iron status,” the investigators wrote.

The investigators also highlighted a nonsignificant increase in the incidence of vitamin B₁₂ deficiency among patients who underwent gastric bypass, with rates increasing from 0.6% at baseline to 11.5% at 5 years.

“Vitamin B₁₂ status likewise worsened disproportionately after [gastric bypass], despite similar trajectories of weight loss after VSG,” the investigators wrote. “This suggests that the differential risk is caused by anatomic and physiological differences between procedures, rather than weight loss alone.”

Beyond surgery type, risk factors for nutritional deficiency included inadequate supplement intake, pregnancy, weight regain, and black race.

“Our findings underscore the importance of long-term nutritional monitoring in adolescents after bariatric surgery and the need to examine impact on health outcomes and quality of life as these youth advance into adulthood, including systematic assessment of anemia and bone health,” the investigators concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Courcoulas reported grant support from Allurion.

SOURCE: Xanthakos SA et al. Clin Gastro Hepatol. 2019 Nov 6. doi: 10.1016/j.cgh.2019.10.048.

For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.

Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.

“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.

The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).

Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.

Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.

“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.

Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).

“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.

Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.

“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”

The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.

“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.

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

SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.

For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.

Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.

“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.

The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).

Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.

Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.

“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.

Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).

“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.

Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.

“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”

The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.

“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.

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

SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.

For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.

Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.

“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.

The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).

Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.

Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.

“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.

Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).

“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.

Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.

“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”

The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.

“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.

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

SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.

During parturient transmission of gut bacteria from mothers to infants, the dominant maternal source of bacteria is rectal, according to investigators.

This challenges the hypothesis that exposure to the birth canal explains major differences in gut bacteria between infants born vaginally and those born via C-section, reported Moran Yassour, PhD, of Hebrew University in Jerusalem.

“It’s not how and if you entered the birth canal, but rather how you exited it,” Dr. Yassour said during a presentation at the annual Gut Microbiota for Health World Summit.

According to Dr. Yassour, a number of investigators have evaluated vertical transmission of gut bacteria from mothers to newborns, but most began collecting data a week or more after birth, potentially missing critical information.

“We wanted to generate large-scale, paired, longitudinal data, which means that we had [samples from] both mothers and children, and we wanted to start at birth,” Dr. Yassour said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

Dr. Yassour explained that newborns delivered vaginally often exhibit Bacteroides in their gut, whereas babies born via C-section do not exhibit these bacteria until 6-18 months of age; however, the vaginal microbiome typically lacks Bacteroides, making the birth canal an unlikely source. This disconnect served as the impetus for the present investigation, Dr. Yassour said.

The study, which is available as a preprint, involved 73 mothers and their infants. To determine the impact of birth canal exposure, the investigators compared gut bacteria of infants born vaginally with those born via pre-labor C-section (no exposure to the birth canal), and those born via post-labor C-section (exposure to the birth canal).

Initial results were surprising, Dr. Yassour said, as 54% of babies delivered via C-section had Bacteroides in their stool during the first week. But in the second week, 94% of the C-section group lacked Bacteroides, which aligns with characteristic findings and suggests failure of colonization, rather than complete lack of exposure.

Out of the 24 infants with persistent Bacteroides colonization, 22 (92%) were born vaginally, compared with 2 (8%) born via pre-labor C-section, and none born via post-labor C-section. This pattern was maintained in a multivariate analysis that accounted for antibiotic use and exposure to formula, both of which are more common among mothers that give birth via C-section.

The investigators also conducted a strain-level analysis of mothers and infants using metagenomic sequencing. Across all time points, 90% of matched maternal-infant strains were detected in babies delivered vaginally.

“[W]e found evidence for mother-to-child transmission of rectal rather than vaginal strains,” the investigators wrote. “These results challenge birth canal exposure as the dominant factor in infant gut microbiome establishment and implicate colonization efficiency rather than exposure as a dictating factor of the newborn gut microbiome composition.”

Dr. Yassour said that these findings may have an immediate effect on clinical practice.

“People have reported the practice of smearing babies that were born by C-section with vaginal fluids in the sense of trying to recapitulate the microbial signature that we find in kids born vaginally,” Dr. Yassour said. “But it’s probably not the vaginal fluid that we need to smear; it’s probably the proximity to the rectum and the bowel movements that happen during delivery ... and that is what’s causing this initial seeding from mother to child.”

Dr. Yassour disclosed no conflicts of interest.

SOURCE: Yassour M et al. GMFH 2020.

During parturient transmission of gut bacteria from mothers to infants, the dominant maternal source of bacteria is rectal, according to investigators.

This challenges the hypothesis that exposure to the birth canal explains major differences in gut bacteria between infants born vaginally and those born via C-section, reported Moran Yassour, PhD, of Hebrew University in Jerusalem.

“It’s not how and if you entered the birth canal, but rather how you exited it,” Dr. Yassour said during a presentation at the annual Gut Microbiota for Health World Summit.

According to Dr. Yassour, a number of investigators have evaluated vertical transmission of gut bacteria from mothers to newborns, but most began collecting data a week or more after birth, potentially missing critical information.

“We wanted to generate large-scale, paired, longitudinal data, which means that we had [samples from] both mothers and children, and we wanted to start at birth,” Dr. Yassour said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

Dr. Yassour explained that newborns delivered vaginally often exhibit Bacteroides in their gut, whereas babies born via C-section do not exhibit these bacteria until 6-18 months of age; however, the vaginal microbiome typically lacks Bacteroides, making the birth canal an unlikely source. This disconnect served as the impetus for the present investigation, Dr. Yassour said.

The study, which is available as a preprint, involved 73 mothers and their infants. To determine the impact of birth canal exposure, the investigators compared gut bacteria of infants born vaginally with those born via pre-labor C-section (no exposure to the birth canal), and those born via post-labor C-section (exposure to the birth canal).

Initial results were surprising, Dr. Yassour said, as 54% of babies delivered via C-section had Bacteroides in their stool during the first week. But in the second week, 94% of the C-section group lacked Bacteroides, which aligns with characteristic findings and suggests failure of colonization, rather than complete lack of exposure.

Out of the 24 infants with persistent Bacteroides colonization, 22 (92%) were born vaginally, compared with 2 (8%) born via pre-labor C-section, and none born via post-labor C-section. This pattern was maintained in a multivariate analysis that accounted for antibiotic use and exposure to formula, both of which are more common among mothers that give birth via C-section.

The investigators also conducted a strain-level analysis of mothers and infants using metagenomic sequencing. Across all time points, 90% of matched maternal-infant strains were detected in babies delivered vaginally.

“[W]e found evidence for mother-to-child transmission of rectal rather than vaginal strains,” the investigators wrote. “These results challenge birth canal exposure as the dominant factor in infant gut microbiome establishment and implicate colonization efficiency rather than exposure as a dictating factor of the newborn gut microbiome composition.”

Dr. Yassour said that these findings may have an immediate effect on clinical practice.

“People have reported the practice of smearing babies that were born by C-section with vaginal fluids in the sense of trying to recapitulate the microbial signature that we find in kids born vaginally,” Dr. Yassour said. “But it’s probably not the vaginal fluid that we need to smear; it’s probably the proximity to the rectum and the bowel movements that happen during delivery ... and that is what’s causing this initial seeding from mother to child.”

Dr. Yassour disclosed no conflicts of interest.

SOURCE: Yassour M et al. GMFH 2020.

During parturient transmission of gut bacteria from mothers to infants, the dominant maternal source of bacteria is rectal, according to investigators.

This challenges the hypothesis that exposure to the birth canal explains major differences in gut bacteria between infants born vaginally and those born via C-section, reported Moran Yassour, PhD, of Hebrew University in Jerusalem.

“It’s not how and if you entered the birth canal, but rather how you exited it,” Dr. Yassour said during a presentation at the annual Gut Microbiota for Health World Summit.

According to Dr. Yassour, a number of investigators have evaluated vertical transmission of gut bacteria from mothers to newborns, but most began collecting data a week or more after birth, potentially missing critical information.

“We wanted to generate large-scale, paired, longitudinal data, which means that we had [samples from] both mothers and children, and we wanted to start at birth,” Dr. Yassour said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

Dr. Yassour explained that newborns delivered vaginally often exhibit Bacteroides in their gut, whereas babies born via C-section do not exhibit these bacteria until 6-18 months of age; however, the vaginal microbiome typically lacks Bacteroides, making the birth canal an unlikely source. This disconnect served as the impetus for the present investigation, Dr. Yassour said.

The study, which is available as a preprint, involved 73 mothers and their infants. To determine the impact of birth canal exposure, the investigators compared gut bacteria of infants born vaginally with those born via pre-labor C-section (no exposure to the birth canal), and those born via post-labor C-section (exposure to the birth canal).

Initial results were surprising, Dr. Yassour said, as 54% of babies delivered via C-section had Bacteroides in their stool during the first week. But in the second week, 94% of the C-section group lacked Bacteroides, which aligns with characteristic findings and suggests failure of colonization, rather than complete lack of exposure.

Out of the 24 infants with persistent Bacteroides colonization, 22 (92%) were born vaginally, compared with 2 (8%) born via pre-labor C-section, and none born via post-labor C-section. This pattern was maintained in a multivariate analysis that accounted for antibiotic use and exposure to formula, both of which are more common among mothers that give birth via C-section.

The investigators also conducted a strain-level analysis of mothers and infants using metagenomic sequencing. Across all time points, 90% of matched maternal-infant strains were detected in babies delivered vaginally.

“[W]e found evidence for mother-to-child transmission of rectal rather than vaginal strains,” the investigators wrote. “These results challenge birth canal exposure as the dominant factor in infant gut microbiome establishment and implicate colonization efficiency rather than exposure as a dictating factor of the newborn gut microbiome composition.”

Dr. Yassour said that these findings may have an immediate effect on clinical practice.

“People have reported the practice of smearing babies that were born by C-section with vaginal fluids in the sense of trying to recapitulate the microbial signature that we find in kids born vaginally,” Dr. Yassour said. “But it’s probably not the vaginal fluid that we need to smear; it’s probably the proximity to the rectum and the bowel movements that happen during delivery ... and that is what’s causing this initial seeding from mother to child.”

Dr. Yassour disclosed no conflicts of interest.

SOURCE: Yassour M et al. GMFH 2020.

Differences in metabolism of levodopa between patients with Parkinson’s disease may be caused by variations in gut bacteria, according to investigators.

Specifically, patients with a higher abundance of Enterococcus faecalis may be converting levodopa into dopamine via decarboxylation before it can cross the blood-brain barrier, reported Emily P. Balskus, PhD, of Harvard University in Cambridge, Mass.

Although existing decarboxylase inhibitors, such as carbidopa, can reduce metabolism of levodopa by host enzymes, these drugs are unable to inhibit the enzymatic activity of E. faecalis in the gut, Dr. Balskus said at the annual Gut Microbiota for Health World Summit, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

“[Carbidopa] is actually completely ineffective at inhibiting decarboxylation in human fecal suspension,” Dr. Balskus said, referring to research led by PhD student Vayu Maini Rekdal. “We think that this could indicate that patients who are taking carbidopa are not inhibiting any bacterial metabolism that they may have.”

While previous research showed that E. faecalis could decarboxylate levodopa, Dr. Balskus and colleagues linked this process with the tyrosine decarboxylase gene (TyrDC), and showed that the of abundance E. faecalis and TyrDC correlate with levodopa metabolism.

Unlike the human enzyme responsible for decarboxylation of levodopa, the E. faecalis enzyme preferentially binds with L-tyrosine. This could explain why existing decarboxylase inhibitors have little impact on decarboxylation in the gut, Dr. Balskus said.

She also noted that this unique characteristic may open doors to new therapeutics. In the lab, Dr. Balskus and colleagues tested a decarboxylase inhibitor that resembled L-tyrosine, (S)-alpha-fluoromethyltyrosine (AFMT). Indeed, AFMT completely inhibited of decarboxylation of levodopa in both E. faecalis cells and complex human microbiome samples.

“We think this is pretty exciting,” Dr. Balskus said.

Early animal studies support this enthusiasm, as germ-free mice colonized with E. faecalis maintain higher serum levels of levodopa with concurrent administration of AFMT.

“We think that this could indicate that a promising way to improve levodopa therapy for Parkinson’s patients would be to develop compounds that inhibit bacterial drug metabolism activity,” Dr. Balskus said.

Concluding her presentation, Dr. Balskus emphasized the importance of a biochemical approach to microbiome research. “Studying enzymes opens up new, exciting opportunities for microbiome manipulation. We can design or develop inhibitors of enzymes, use those inhibitors as tools to study the roles of individual metabolic activities, and potentially use them as therapeutics. We are very excited about the possibility of treating or preventing human disease not just by manipulating processes in our own cells, but by targeting activities in the microbiota.”

Dr. Balskus reported funding from HHMI, the Bill and Melinda Gates Foundation, the David and Lucile Packard Foundation, and Merck.

Differences in metabolism of levodopa between patients with Parkinson’s disease may be caused by variations in gut bacteria, according to investigators.

Specifically, patients with a higher abundance of Enterococcus faecalis may be converting levodopa into dopamine via decarboxylation before it can cross the blood-brain barrier, reported Emily P. Balskus, PhD, of Harvard University in Cambridge, Mass.

Although existing decarboxylase inhibitors, such as carbidopa, can reduce metabolism of levodopa by host enzymes, these drugs are unable to inhibit the enzymatic activity of E. faecalis in the gut, Dr. Balskus said at the annual Gut Microbiota for Health World Summit, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

“[Carbidopa] is actually completely ineffective at inhibiting decarboxylation in human fecal suspension,” Dr. Balskus said, referring to research led by PhD student Vayu Maini Rekdal. “We think that this could indicate that patients who are taking carbidopa are not inhibiting any bacterial metabolism that they may have.”

While previous research showed that E. faecalis could decarboxylate levodopa, Dr. Balskus and colleagues linked this process with the tyrosine decarboxylase gene (TyrDC), and showed that the of abundance E. faecalis and TyrDC correlate with levodopa metabolism.

Unlike the human enzyme responsible for decarboxylation of levodopa, the E. faecalis enzyme preferentially binds with L-tyrosine. This could explain why existing decarboxylase inhibitors have little impact on decarboxylation in the gut, Dr. Balskus said.

She also noted that this unique characteristic may open doors to new therapeutics. In the lab, Dr. Balskus and colleagues tested a decarboxylase inhibitor that resembled L-tyrosine, (S)-alpha-fluoromethyltyrosine (AFMT). Indeed, AFMT completely inhibited of decarboxylation of levodopa in both E. faecalis cells and complex human microbiome samples.

“We think this is pretty exciting,” Dr. Balskus said.

Early animal studies support this enthusiasm, as germ-free mice colonized with E. faecalis maintain higher serum levels of levodopa with concurrent administration of AFMT.

“We think that this could indicate that a promising way to improve levodopa therapy for Parkinson’s patients would be to develop compounds that inhibit bacterial drug metabolism activity,” Dr. Balskus said.

Concluding her presentation, Dr. Balskus emphasized the importance of a biochemical approach to microbiome research. “Studying enzymes opens up new, exciting opportunities for microbiome manipulation. We can design or develop inhibitors of enzymes, use those inhibitors as tools to study the roles of individual metabolic activities, and potentially use them as therapeutics. We are very excited about the possibility of treating or preventing human disease not just by manipulating processes in our own cells, but by targeting activities in the microbiota.”

Dr. Balskus reported funding from HHMI, the Bill and Melinda Gates Foundation, the David and Lucile Packard Foundation, and Merck.

Differences in metabolism of levodopa between patients with Parkinson’s disease may be caused by variations in gut bacteria, according to investigators.

Specifically, patients with a higher abundance of Enterococcus faecalis may be converting levodopa into dopamine via decarboxylation before it can cross the blood-brain barrier, reported Emily P. Balskus, PhD, of Harvard University in Cambridge, Mass.

Although existing decarboxylase inhibitors, such as carbidopa, can reduce metabolism of levodopa by host enzymes, these drugs are unable to inhibit the enzymatic activity of E. faecalis in the gut, Dr. Balskus said at the annual Gut Microbiota for Health World Summit, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

“[Carbidopa] is actually completely ineffective at inhibiting decarboxylation in human fecal suspension,” Dr. Balskus said, referring to research led by PhD student Vayu Maini Rekdal. “We think that this could indicate that patients who are taking carbidopa are not inhibiting any bacterial metabolism that they may have.”

While previous research showed that E. faecalis could decarboxylate levodopa, Dr. Balskus and colleagues linked this process with the tyrosine decarboxylase gene (TyrDC), and showed that the of abundance E. faecalis and TyrDC correlate with levodopa metabolism.

Unlike the human enzyme responsible for decarboxylation of levodopa, the E. faecalis enzyme preferentially binds with L-tyrosine. This could explain why existing decarboxylase inhibitors have little impact on decarboxylation in the gut, Dr. Balskus said.

She also noted that this unique characteristic may open doors to new therapeutics. In the lab, Dr. Balskus and colleagues tested a decarboxylase inhibitor that resembled L-tyrosine, (S)-alpha-fluoromethyltyrosine (AFMT). Indeed, AFMT completely inhibited of decarboxylation of levodopa in both E. faecalis cells and complex human microbiome samples.

“We think this is pretty exciting,” Dr. Balskus said.

Early animal studies support this enthusiasm, as germ-free mice colonized with E. faecalis maintain higher serum levels of levodopa with concurrent administration of AFMT.

“We think that this could indicate that a promising way to improve levodopa therapy for Parkinson’s patients would be to develop compounds that inhibit bacterial drug metabolism activity,” Dr. Balskus said.

Concluding her presentation, Dr. Balskus emphasized the importance of a biochemical approach to microbiome research. “Studying enzymes opens up new, exciting opportunities for microbiome manipulation. We can design or develop inhibitors of enzymes, use those inhibitors as tools to study the roles of individual metabolic activities, and potentially use them as therapeutics. We are very excited about the possibility of treating or preventing human disease not just by manipulating processes in our own cells, but by targeting activities in the microbiota.”

Dr. Balskus reported funding from HHMI, the Bill and Melinda Gates Foundation, the David and Lucile Packard Foundation, and Merck.

Fecal microbiota transplantation (FMT) appears safe and effective for treating recurrent Clostridioides difficile infection in patients with inflammatory bowel disease (IBD), according to an ongoing prospective trial.

Most patients were cured of C. difficile after one fecal transplant, reported Jessica Allegretti, MD, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.

“[For patients without IBD], fecal microbiota transplantation has been shown to be very effective for the treatment of recurrent C. diff,” Dr. Allegretti said at the annual Gut Microbiota for Health World Summit.

But similar data for patients with IBD are scarce, and this knowledge gap has high clinical relevance, Dr. Allegretti said. She noted that C. difficile infections are eight times more common among patients with IBD, and risk of recurrence is increased 4.5-fold.

According to Dr. Allegretti, three small clinical trials have tested FMT for treating recurrent C. difficile infections in patients with IBD.

“[These studies were] somewhat prospective, but [data] mainly retrospectively collected, as they relied heavily on chart review for the assessment of IBD disease activity,” she said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility..

Across the trials, C. difficile infection cure rates were comparable with non-IBD cohorts; but disease flare rates ranged from 17.9% to 54%, which raised concern that FMT may trigger inflammation.

To investigate further, Dr. Allegretti and her colleagues designed a prospective trial that is set to enroll 50 patients with IBD. Among 37 patients treated to date, a slight majority were women (56.8%), about one-third had Crohn’s disease (37.8%), and two-thirds had ulcerative colitis (62.2%). The average baseline calprotectin level, which measures inflammation in the intestines, was 1,804.8 microg/g of feces, which is far above the upper limit of 50 microg/g.

“This is a very inflamed patient population,” Dr. Allegretti said.

Out of these 37 patients, 34 (92%) were cured of C. difficile infection after only one fecal transplant, and the remaining three patients were cured after a second FMT.

“They all did very well,” Dr. Allegretti said.

Concerning IBD clinical scores, all patients with Crohn’s disease either had unchanged or improved disease. Among those with ulcerative colitis, almost all had unchanged or improved disease, except for one patient who had a de novo flare.

Early microbiome analyses showed patients had increased alpha diversity and richness after FMT that was sustained through week 12. Because only three patients had recurrence, numbers were too small to generate predictive data based on relative abundance.

Dr. Allegretti continued her presentation with a review of FMT for IBD in general.

“For Crohn’s disease, the role [of microbiome manipulation] seems a bit more clear,” Dr. Allegretti said, considering multiple effective treatments that alter gut flora, such as antibiotics.

In contrast, the role for microbiome manipulation in treating ulcerative colitis “has remained a bit unclear,” she said. Although some probiotics appear effective for treating mild disease, other microbiome-altering treatments, such as diversion of fecal stream, antibiotics, and bowel rest, have fallen short.

Still, pooled data from four randomized clinical trials showed that FMT led to remission in 28% of patients with ulcerative colitis, compared with 9% who receive placebo.

“You may be thinking that seems a bit underwhelming compared to the 90% or so cure rate we get for C. diff trials,” Dr. Allegretti said. “However, if you look at our other biologic trials in IBD, 28% puts FMT on par with our other IBD therapies.”

According to Dr. Allegretti, at least three stool-based, FMT-like therapeutics are poised to become commercially available in the next few years for the treatment of C. difficile infection, including broad- and narrow-spectrum enema bags and oral capsules.

“I certainly think we will start to see off-label usage in our IBD patients, and we will start to have an easier and more systemic way of utilizing these microbiome-based therapies,” Dr. Allegretti said. “They will be coming to market, and when they do, whether or not we are allowed to still do traditional FMT in its current form remains unseen. The FDA may not allow us to do that in the future when we have an FDA-approved product.”Dr. Allegretti disclosed relationships with Merck, Openbiome, Finch Therapeutics, and others.

[email protected]

Fecal microbiota transplantation (FMT) appears safe and effective for treating recurrent Clostridioides difficile infection in patients with inflammatory bowel disease (IBD), according to an ongoing prospective trial.

Most patients were cured of C. difficile after one fecal transplant, reported Jessica Allegretti, MD, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.

“[For patients without IBD], fecal microbiota transplantation has been shown to be very effective for the treatment of recurrent C. diff,” Dr. Allegretti said at the annual Gut Microbiota for Health World Summit.

But similar data for patients with IBD are scarce, and this knowledge gap has high clinical relevance, Dr. Allegretti said. She noted that C. difficile infections are eight times more common among patients with IBD, and risk of recurrence is increased 4.5-fold.

According to Dr. Allegretti, three small clinical trials have tested FMT for treating recurrent C. difficile infections in patients with IBD.

“[These studies were] somewhat prospective, but [data] mainly retrospectively collected, as they relied heavily on chart review for the assessment of IBD disease activity,” she said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility..

Across the trials, C. difficile infection cure rates were comparable with non-IBD cohorts; but disease flare rates ranged from 17.9% to 54%, which raised concern that FMT may trigger inflammation.

To investigate further, Dr. Allegretti and her colleagues designed a prospective trial that is set to enroll 50 patients with IBD. Among 37 patients treated to date, a slight majority were women (56.8%), about one-third had Crohn’s disease (37.8%), and two-thirds had ulcerative colitis (62.2%). The average baseline calprotectin level, which measures inflammation in the intestines, was 1,804.8 microg/g of feces, which is far above the upper limit of 50 microg/g.

“This is a very inflamed patient population,” Dr. Allegretti said.

Out of these 37 patients, 34 (92%) were cured of C. difficile infection after only one fecal transplant, and the remaining three patients were cured after a second FMT.

“They all did very well,” Dr. Allegretti said.

Concerning IBD clinical scores, all patients with Crohn’s disease either had unchanged or improved disease. Among those with ulcerative colitis, almost all had unchanged or improved disease, except for one patient who had a de novo flare.

Early microbiome analyses showed patients had increased alpha diversity and richness after FMT that was sustained through week 12. Because only three patients had recurrence, numbers were too small to generate predictive data based on relative abundance.

Dr. Allegretti continued her presentation with a review of FMT for IBD in general.

“For Crohn’s disease, the role [of microbiome manipulation] seems a bit more clear,” Dr. Allegretti said, considering multiple effective treatments that alter gut flora, such as antibiotics.

In contrast, the role for microbiome manipulation in treating ulcerative colitis “has remained a bit unclear,” she said. Although some probiotics appear effective for treating mild disease, other microbiome-altering treatments, such as diversion of fecal stream, antibiotics, and bowel rest, have fallen short.

Still, pooled data from four randomized clinical trials showed that FMT led to remission in 28% of patients with ulcerative colitis, compared with 9% who receive placebo.

“You may be thinking that seems a bit underwhelming compared to the 90% or so cure rate we get for C. diff trials,” Dr. Allegretti said. “However, if you look at our other biologic trials in IBD, 28% puts FMT on par with our other IBD therapies.”

According to Dr. Allegretti, at least three stool-based, FMT-like therapeutics are poised to become commercially available in the next few years for the treatment of C. difficile infection, including broad- and narrow-spectrum enema bags and oral capsules.

“I certainly think we will start to see off-label usage in our IBD patients, and we will start to have an easier and more systemic way of utilizing these microbiome-based therapies,” Dr. Allegretti said. “They will be coming to market, and when they do, whether or not we are allowed to still do traditional FMT in its current form remains unseen. The FDA may not allow us to do that in the future when we have an FDA-approved product.”Dr. Allegretti disclosed relationships with Merck, Openbiome, Finch Therapeutics, and others.

[email protected]

Fecal microbiota transplantation (FMT) appears safe and effective for treating recurrent Clostridioides difficile infection in patients with inflammatory bowel disease (IBD), according to an ongoing prospective trial.

Most patients were cured of C. difficile after one fecal transplant, reported Jessica Allegretti, MD, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.

“[For patients without IBD], fecal microbiota transplantation has been shown to be very effective for the treatment of recurrent C. diff,” Dr. Allegretti said at the annual Gut Microbiota for Health World Summit.

But similar data for patients with IBD are scarce, and this knowledge gap has high clinical relevance, Dr. Allegretti said. She noted that C. difficile infections are eight times more common among patients with IBD, and risk of recurrence is increased 4.5-fold.

According to Dr. Allegretti, three small clinical trials have tested FMT for treating recurrent C. difficile infections in patients with IBD.

“[These studies were] somewhat prospective, but [data] mainly retrospectively collected, as they relied heavily on chart review for the assessment of IBD disease activity,” she said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility..

Across the trials, C. difficile infection cure rates were comparable with non-IBD cohorts; but disease flare rates ranged from 17.9% to 54%, which raised concern that FMT may trigger inflammation.

To investigate further, Dr. Allegretti and her colleagues designed a prospective trial that is set to enroll 50 patients with IBD. Among 37 patients treated to date, a slight majority were women (56.8%), about one-third had Crohn’s disease (37.8%), and two-thirds had ulcerative colitis (62.2%). The average baseline calprotectin level, which measures inflammation in the intestines, was 1,804.8 microg/g of feces, which is far above the upper limit of 50 microg/g.

“This is a very inflamed patient population,” Dr. Allegretti said.

Out of these 37 patients, 34 (92%) were cured of C. difficile infection after only one fecal transplant, and the remaining three patients were cured after a second FMT.

“They all did very well,” Dr. Allegretti said.

Concerning IBD clinical scores, all patients with Crohn’s disease either had unchanged or improved disease. Among those with ulcerative colitis, almost all had unchanged or improved disease, except for one patient who had a de novo flare.

Early microbiome analyses showed patients had increased alpha diversity and richness after FMT that was sustained through week 12. Because only three patients had recurrence, numbers were too small to generate predictive data based on relative abundance.

Dr. Allegretti continued her presentation with a review of FMT for IBD in general.

“For Crohn’s disease, the role [of microbiome manipulation] seems a bit more clear,” Dr. Allegretti said, considering multiple effective treatments that alter gut flora, such as antibiotics.

In contrast, the role for microbiome manipulation in treating ulcerative colitis “has remained a bit unclear,” she said. Although some probiotics appear effective for treating mild disease, other microbiome-altering treatments, such as diversion of fecal stream, antibiotics, and bowel rest, have fallen short.

Still, pooled data from four randomized clinical trials showed that FMT led to remission in 28% of patients with ulcerative colitis, compared with 9% who receive placebo.

“You may be thinking that seems a bit underwhelming compared to the 90% or so cure rate we get for C. diff trials,” Dr. Allegretti said. “However, if you look at our other biologic trials in IBD, 28% puts FMT on par with our other IBD therapies.”

According to Dr. Allegretti, at least three stool-based, FMT-like therapeutics are poised to become commercially available in the next few years for the treatment of C. difficile infection, including broad- and narrow-spectrum enema bags and oral capsules.

“I certainly think we will start to see off-label usage in our IBD patients, and we will start to have an easier and more systemic way of utilizing these microbiome-based therapies,” Dr. Allegretti said. “They will be coming to market, and when they do, whether or not we are allowed to still do traditional FMT in its current form remains unseen. The FDA may not allow us to do that in the future when we have an FDA-approved product.”Dr. Allegretti disclosed relationships with Merck, Openbiome, Finch Therapeutics, and others.

[email protected]

Patients with COVID-19 may be at risk for liver injury, but mechanisms of damage remain unclear, according to investigators.

Proposed mechanisms include direct virus-induced effects, immune-induced damage due to excessive inflammatory responses, and drug-induced injury, reported lead author Ling Xu of Huazhong University of Science and Technology, Wuhan, China, and colleagues.

“From a clinical perspective, in addition to actively dealing with the primary disease caused by coronavirus infection, attention should also be paid to monitor the occurrence of liver injury, and to the application of drugs which may induce liver damage,” the investigators wrote in Liver International. “Patients with liver damage are advised to be treated with drugs that could both protect liver functions and inhibit inflammatory responses, such as ammonium glycyrrhizinate, which may, in turn, accelerate the process of disease recovery.”

The review of liver injury associated with major pathogenic coronaviruses included severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emergent SARS-CoV-2, which causes COVID-19.

In cases of COVID-19, reported incidence of liver injury ranges from 15% to 53%, based on elevations of alanine transaminase (ALT) and aspartate aminotransferase (AST), along with slightly elevated bilirubin levels. In severe cases, albumin decreases have also been documented.

Liver injury appears to be significantly more common among those with severe infection. In one cohort of 82 patients who died from COVID-19, the incidence of liver injury was 78%, while another study of 36 nonsurvivors reported a rate of 58%.

According to the investigators, both bile duct epithelial cells and liver cells express angiotensin converting enzyme II (ACE2), which is an entry receptor for SARS-CoV-2; however, expression of ACE2 in bile duct cells is “much higher” than in liver cells, and comparable with alveolar type 2 cells in the lungs.

“Bile duct epithelial cells are known to play important roles in liver regeneration and immune response,” the investigators noted.

Beyond direct- and immune-induced effects of COVID-19, postmortem findings suggest that drug-induced liver injury may also be a possibility, with a number of theoretical culprits, including antibiotics, steroids, and antivirals. Although the investigators emphasized that data are insufficient to pinpoint an exact agent, they highlighted a recent preprint study, which reported a significantly higher rate of lopinavir/ritonavir administration among patients with abnormal liver function, compared with those who had normal liver function (56.1% vs. 25%; P = .009).

“Drug-induced liver injury during the treatment of coronavirus infection should not be ignored and needs to be carefully investigated,” the investigators concluded.

Fundamental Research Funds for the Central Universities supported the work. The investigators reported no conflicts of interest.

SOURCE: Xu L et al. Liver Int. 2020 Mar 14. doi: 10.1111/liv.14435.

Patients with COVID-19 may be at risk for liver injury, but mechanisms of damage remain unclear, according to investigators.

Proposed mechanisms include direct virus-induced effects, immune-induced damage due to excessive inflammatory responses, and drug-induced injury, reported lead author Ling Xu of Huazhong University of Science and Technology, Wuhan, China, and colleagues.

“From a clinical perspective, in addition to actively dealing with the primary disease caused by coronavirus infection, attention should also be paid to monitor the occurrence of liver injury, and to the application of drugs which may induce liver damage,” the investigators wrote in Liver International. “Patients with liver damage are advised to be treated with drugs that could both protect liver functions and inhibit inflammatory responses, such as ammonium glycyrrhizinate, which may, in turn, accelerate the process of disease recovery.”

The review of liver injury associated with major pathogenic coronaviruses included severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emergent SARS-CoV-2, which causes COVID-19.

In cases of COVID-19, reported incidence of liver injury ranges from 15% to 53%, based on elevations of alanine transaminase (ALT) and aspartate aminotransferase (AST), along with slightly elevated bilirubin levels. In severe cases, albumin decreases have also been documented.

Liver injury appears to be significantly more common among those with severe infection. In one cohort of 82 patients who died from COVID-19, the incidence of liver injury was 78%, while another study of 36 nonsurvivors reported a rate of 58%.

According to the investigators, both bile duct epithelial cells and liver cells express angiotensin converting enzyme II (ACE2), which is an entry receptor for SARS-CoV-2; however, expression of ACE2 in bile duct cells is “much higher” than in liver cells, and comparable with alveolar type 2 cells in the lungs.

“Bile duct epithelial cells are known to play important roles in liver regeneration and immune response,” the investigators noted.

Beyond direct- and immune-induced effects of COVID-19, postmortem findings suggest that drug-induced liver injury may also be a possibility, with a number of theoretical culprits, including antibiotics, steroids, and antivirals. Although the investigators emphasized that data are insufficient to pinpoint an exact agent, they highlighted a recent preprint study, which reported a significantly higher rate of lopinavir/ritonavir administration among patients with abnormal liver function, compared with those who had normal liver function (56.1% vs. 25%; P = .009).

“Drug-induced liver injury during the treatment of coronavirus infection should not be ignored and needs to be carefully investigated,” the investigators concluded.

Fundamental Research Funds for the Central Universities supported the work. The investigators reported no conflicts of interest.

SOURCE: Xu L et al. Liver Int. 2020 Mar 14. doi: 10.1111/liv.14435.

Patients with COVID-19 may be at risk for liver injury, but mechanisms of damage remain unclear, according to investigators.

Proposed mechanisms include direct virus-induced effects, immune-induced damage due to excessive inflammatory responses, and drug-induced injury, reported lead author Ling Xu of Huazhong University of Science and Technology, Wuhan, China, and colleagues.

“From a clinical perspective, in addition to actively dealing with the primary disease caused by coronavirus infection, attention should also be paid to monitor the occurrence of liver injury, and to the application of drugs which may induce liver damage,” the investigators wrote in Liver International. “Patients with liver damage are advised to be treated with drugs that could both protect liver functions and inhibit inflammatory responses, such as ammonium glycyrrhizinate, which may, in turn, accelerate the process of disease recovery.”

The review of liver injury associated with major pathogenic coronaviruses included severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emergent SARS-CoV-2, which causes COVID-19.

In cases of COVID-19, reported incidence of liver injury ranges from 15% to 53%, based on elevations of alanine transaminase (ALT) and aspartate aminotransferase (AST), along with slightly elevated bilirubin levels. In severe cases, albumin decreases have also been documented.

Liver injury appears to be significantly more common among those with severe infection. In one cohort of 82 patients who died from COVID-19, the incidence of liver injury was 78%, while another study of 36 nonsurvivors reported a rate of 58%.

According to the investigators, both bile duct epithelial cells and liver cells express angiotensin converting enzyme II (ACE2), which is an entry receptor for SARS-CoV-2; however, expression of ACE2 in bile duct cells is “much higher” than in liver cells, and comparable with alveolar type 2 cells in the lungs.

“Bile duct epithelial cells are known to play important roles in liver regeneration and immune response,” the investigators noted.

Beyond direct- and immune-induced effects of COVID-19, postmortem findings suggest that drug-induced liver injury may also be a possibility, with a number of theoretical culprits, including antibiotics, steroids, and antivirals. Although the investigators emphasized that data are insufficient to pinpoint an exact agent, they highlighted a recent preprint study, which reported a significantly higher rate of lopinavir/ritonavir administration among patients with abnormal liver function, compared with those who had normal liver function (56.1% vs. 25%; P = .009).

“Drug-induced liver injury during the treatment of coronavirus infection should not be ignored and needs to be carefully investigated,” the investigators concluded.

Fundamental Research Funds for the Central Universities supported the work. The investigators reported no conflicts of interest.

SOURCE: Xu L et al. Liver Int. 2020 Mar 14. doi: 10.1111/liv.14435.

Patients with diabetes may have an increased risk of developing coronavirus infection (COVID-19), along with increased risks of morbidity and mortality, according to researchers writing in Diabetes & Metabolic Syndrome.

Although relevant clinical data remain scarce, patients with diabetes should take extra precautions to avoid infection and, if infected, may require special care, reported Ritesh Gupta, MD, of Fortis C-DOC Hospital, New Delhi, and colleagues.

“The disease severity [with COVID-19] has varied from mild, self-limiting, flu-like illness to fulminant pneumonia, respiratory failure, and death,” the authors wrote.

As of March 16, 2020, the World Health Organization reported 167,515 confirmed cases of COVID-19 and 6,606 deaths from around the world, with a mortality rate of 3.9%. But the actual mortality rate may be lower, the authors suggested, because a study involving more than 1,000 confirmed cases reported a mortality rate of 1.4%.

“Considering that the number of unreported and unconfirmed cases is likely to be much higher than the reported cases, the actual mortality may be less than 1%, which is similar to that of severe seasonal influenza,” the authors said, in reference to an editorial by Anthony S. Fauci, MD, and colleagues in the New England Journal of Medicine. In addition, they noted, mortality rates may vary by region.

The largest study relevant to patients with diabetes, which involved 72,314 cases of COVID-19, showed that patients with diabetes had a threefold higher mortality rate than did those without diabetes (7.3% vs. 2.3%, respectively). These figures were reported by the Chinese Centre for Disease Control and Prevention.

However, data from smaller cohorts with diabetes and COVID-19 have yielded mixed results. For instance, one study, involving 140 patients from Wuhan, suggested that diabetes was not a risk factor for severe disease, and in an analysis of 11 studies reporting on laboratory abnormalities in patients with a diagnosis of COVID-19, raised blood sugar levels or diabetes were not mentioned among the predictors of severe disease.

“Our knowledge about the prevalence of COVID-19 and disease course in people with diabetes will evolve as more detailed analyses are carried out,” the authors wrote. “For now, it is reasonable to assume that people with diabetes are at increased risk of developing infection. Coexisting heart disease, kidney disease, advanced age, and frailty are likely to further increase the severity of disease.”
 

Prevention first

“It is important that people with diabetes maintain good glycemic control, because it might help in reducing the risk of infection and the severity,” the authors wrote.

In addition to more frequent monitoring of blood glucose levels, they recommended other preventive measures, such as getting adequate nutrition, exercising, and being current with vaccinations for influenza and pneumonia. The latter, they said, may also reduce the risk of secondary bacterial pneumonia after a respiratory viral infection.

In regard to nutrition, adequate protein intake is important and “any deficiencies of minerals and vitamins need to be taken care of,” they advised. Likewise, exercise is known to improve immunity and should continue, but they suggest avoiding gyms and swimming pools.

For patients with coexisting heart and/or kidney disease, they also recommended efforts to stabilize cardiac/renal status.

In addition, the general preventive measures, such as regular and thorough hand washing with soap and water, practicing good respiratory hygiene by sneezing and coughing into a bent elbow or a facial tissue, and avoiding contact with anyone who is infected, should be observed.

As with other patients with chronic diseases that are managed long-term medications, patients with diabetes should always ensure that they have a sufficient supply of their medications and refills, if possible.
 

After a diagnosis

If patients with diabetes develop COVID-19, then home management may still be possible, wrote the authors, who recommended basic treatment measures such as maintaining hydration and managing symptoms with acetaminophen and steam inhalation, and home isolation for 14 days or until the symptoms resolve.

In the event of hyperglycemia with fever in patients with type 1 diabetes, blood glucose and urinary ketones should be monitored often. “Frequent changes in dosage and correctional bolus may be required to maintain normoglycemia,” they cautioned.

Concerning diabetic drug regimens, they suggest patients avoid antihyperglycemic agents that can cause volume depletion or hypoglycemia and, if necessary, that they reduce oral antidiabetic drugs and follow sick-day guidelines.

For hospitalized patients, the investigators strengthened that statement, advising that oral agents need to be stopped, particularly sodium-glucose cotransporter 2 inhibitors and metformin. “Insulin is the preferred agent for control of hyperglycemia in hospitalized sick patients,” they wrote.

Untested therapies

The authors also discussed a range of untested therapies that may help fight COVID-19, such as antiviral drugs (such as lopinavir and ritonavir), zinc nanoparticles, and vitamin C. Supplementing those recommendations, Dr. Gupta and colleagues provided a concise review of COVID-19 epidemiology and extant data relevant to patients with diabetes.

The investigators reported no conflicts of interest.

SOURCE: Gupta et al. Diabetes Metab Syndr. 2020;14(3):211-12.

Patients with diabetes may have an increased risk of developing coronavirus infection (COVID-19), along with increased risks of morbidity and mortality, according to researchers writing in Diabetes & Metabolic Syndrome.

Although relevant clinical data remain scarce, patients with diabetes should take extra precautions to avoid infection and, if infected, may require special care, reported Ritesh Gupta, MD, of Fortis C-DOC Hospital, New Delhi, and colleagues.

“The disease severity [with COVID-19] has varied from mild, self-limiting, flu-like illness to fulminant pneumonia, respiratory failure, and death,” the authors wrote.

As of March 16, 2020, the World Health Organization reported 167,515 confirmed cases of COVID-19 and 6,606 deaths from around the world, with a mortality rate of 3.9%. But the actual mortality rate may be lower, the authors suggested, because a study involving more than 1,000 confirmed cases reported a mortality rate of 1.4%.

“Considering that the number of unreported and unconfirmed cases is likely to be much higher than the reported cases, the actual mortality may be less than 1%, which is similar to that of severe seasonal influenza,” the authors said, in reference to an editorial by Anthony S. Fauci, MD, and colleagues in the New England Journal of Medicine. In addition, they noted, mortality rates may vary by region.

The largest study relevant to patients with diabetes, which involved 72,314 cases of COVID-19, showed that patients with diabetes had a threefold higher mortality rate than did those without diabetes (7.3% vs. 2.3%, respectively). These figures were reported by the Chinese Centre for Disease Control and Prevention.

However, data from smaller cohorts with diabetes and COVID-19 have yielded mixed results. For instance, one study, involving 140 patients from Wuhan, suggested that diabetes was not a risk factor for severe disease, and in an analysis of 11 studies reporting on laboratory abnormalities in patients with a diagnosis of COVID-19, raised blood sugar levels or diabetes were not mentioned among the predictors of severe disease.

“Our knowledge about the prevalence of COVID-19 and disease course in people with diabetes will evolve as more detailed analyses are carried out,” the authors wrote. “For now, it is reasonable to assume that people with diabetes are at increased risk of developing infection. Coexisting heart disease, kidney disease, advanced age, and frailty are likely to further increase the severity of disease.”
 

Prevention first

“It is important that people with diabetes maintain good glycemic control, because it might help in reducing the risk of infection and the severity,” the authors wrote.

In addition to more frequent monitoring of blood glucose levels, they recommended other preventive measures, such as getting adequate nutrition, exercising, and being current with vaccinations for influenza and pneumonia. The latter, they said, may also reduce the risk of secondary bacterial pneumonia after a respiratory viral infection.

In regard to nutrition, adequate protein intake is important and “any deficiencies of minerals and vitamins need to be taken care of,” they advised. Likewise, exercise is known to improve immunity and should continue, but they suggest avoiding gyms and swimming pools.

For patients with coexisting heart and/or kidney disease, they also recommended efforts to stabilize cardiac/renal status.

In addition, the general preventive measures, such as regular and thorough hand washing with soap and water, practicing good respiratory hygiene by sneezing and coughing into a bent elbow or a facial tissue, and avoiding contact with anyone who is infected, should be observed.

As with other patients with chronic diseases that are managed long-term medications, patients with diabetes should always ensure that they have a sufficient supply of their medications and refills, if possible.
 

After a diagnosis

If patients with diabetes develop COVID-19, then home management may still be possible, wrote the authors, who recommended basic treatment measures such as maintaining hydration and managing symptoms with acetaminophen and steam inhalation, and home isolation for 14 days or until the symptoms resolve.

In the event of hyperglycemia with fever in patients with type 1 diabetes, blood glucose and urinary ketones should be monitored often. “Frequent changes in dosage and correctional bolus may be required to maintain normoglycemia,” they cautioned.

Concerning diabetic drug regimens, they suggest patients avoid antihyperglycemic agents that can cause volume depletion or hypoglycemia and, if necessary, that they reduce oral antidiabetic drugs and follow sick-day guidelines.

For hospitalized patients, the investigators strengthened that statement, advising that oral agents need to be stopped, particularly sodium-glucose cotransporter 2 inhibitors and metformin. “Insulin is the preferred agent for control of hyperglycemia in hospitalized sick patients,” they wrote.

Untested therapies

The authors also discussed a range of untested therapies that may help fight COVID-19, such as antiviral drugs (such as lopinavir and ritonavir), zinc nanoparticles, and vitamin C. Supplementing those recommendations, Dr. Gupta and colleagues provided a concise review of COVID-19 epidemiology and extant data relevant to patients with diabetes.

The investigators reported no conflicts of interest.

SOURCE: Gupta et al. Diabetes Metab Syndr. 2020;14(3):211-12.

Patients with diabetes may have an increased risk of developing coronavirus infection (COVID-19), along with increased risks of morbidity and mortality, according to researchers writing in Diabetes & Metabolic Syndrome.

Although relevant clinical data remain scarce, patients with diabetes should take extra precautions to avoid infection and, if infected, may require special care, reported Ritesh Gupta, MD, of Fortis C-DOC Hospital, New Delhi, and colleagues.

“The disease severity [with COVID-19] has varied from mild, self-limiting, flu-like illness to fulminant pneumonia, respiratory failure, and death,” the authors wrote.

As of March 16, 2020, the World Health Organization reported 167,515 confirmed cases of COVID-19 and 6,606 deaths from around the world, with a mortality rate of 3.9%. But the actual mortality rate may be lower, the authors suggested, because a study involving more than 1,000 confirmed cases reported a mortality rate of 1.4%.

“Considering that the number of unreported and unconfirmed cases is likely to be much higher than the reported cases, the actual mortality may be less than 1%, which is similar to that of severe seasonal influenza,” the authors said, in reference to an editorial by Anthony S. Fauci, MD, and colleagues in the New England Journal of Medicine. In addition, they noted, mortality rates may vary by region.

The largest study relevant to patients with diabetes, which involved 72,314 cases of COVID-19, showed that patients with diabetes had a threefold higher mortality rate than did those without diabetes (7.3% vs. 2.3%, respectively). These figures were reported by the Chinese Centre for Disease Control and Prevention.

However, data from smaller cohorts with diabetes and COVID-19 have yielded mixed results. For instance, one study, involving 140 patients from Wuhan, suggested that diabetes was not a risk factor for severe disease, and in an analysis of 11 studies reporting on laboratory abnormalities in patients with a diagnosis of COVID-19, raised blood sugar levels or diabetes were not mentioned among the predictors of severe disease.

“Our knowledge about the prevalence of COVID-19 and disease course in people with diabetes will evolve as more detailed analyses are carried out,” the authors wrote. “For now, it is reasonable to assume that people with diabetes are at increased risk of developing infection. Coexisting heart disease, kidney disease, advanced age, and frailty are likely to further increase the severity of disease.”
 

Prevention first

“It is important that people with diabetes maintain good glycemic control, because it might help in reducing the risk of infection and the severity,” the authors wrote.

In addition to more frequent monitoring of blood glucose levels, they recommended other preventive measures, such as getting adequate nutrition, exercising, and being current with vaccinations for influenza and pneumonia. The latter, they said, may also reduce the risk of secondary bacterial pneumonia after a respiratory viral infection.

In regard to nutrition, adequate protein intake is important and “any deficiencies of minerals and vitamins need to be taken care of,” they advised. Likewise, exercise is known to improve immunity and should continue, but they suggest avoiding gyms and swimming pools.

For patients with coexisting heart and/or kidney disease, they also recommended efforts to stabilize cardiac/renal status.

In addition, the general preventive measures, such as regular and thorough hand washing with soap and water, practicing good respiratory hygiene by sneezing and coughing into a bent elbow or a facial tissue, and avoiding contact with anyone who is infected, should be observed.

As with other patients with chronic diseases that are managed long-term medications, patients with diabetes should always ensure that they have a sufficient supply of their medications and refills, if possible.
 

After a diagnosis

If patients with diabetes develop COVID-19, then home management may still be possible, wrote the authors, who recommended basic treatment measures such as maintaining hydration and managing symptoms with acetaminophen and steam inhalation, and home isolation for 14 days or until the symptoms resolve.

In the event of hyperglycemia with fever in patients with type 1 diabetes, blood glucose and urinary ketones should be monitored often. “Frequent changes in dosage and correctional bolus may be required to maintain normoglycemia,” they cautioned.

Concerning diabetic drug regimens, they suggest patients avoid antihyperglycemic agents that can cause volume depletion or hypoglycemia and, if necessary, that they reduce oral antidiabetic drugs and follow sick-day guidelines.

For hospitalized patients, the investigators strengthened that statement, advising that oral agents need to be stopped, particularly sodium-glucose cotransporter 2 inhibitors and metformin. “Insulin is the preferred agent for control of hyperglycemia in hospitalized sick patients,” they wrote.

Untested therapies

The authors also discussed a range of untested therapies that may help fight COVID-19, such as antiviral drugs (such as lopinavir and ritonavir), zinc nanoparticles, and vitamin C. Supplementing those recommendations, Dr. Gupta and colleagues provided a concise review of COVID-19 epidemiology and extant data relevant to patients with diabetes.

The investigators reported no conflicts of interest.

SOURCE: Gupta et al. Diabetes Metab Syndr. 2020;14(3):211-12.

Phase 3 clinical trials for cancer are underreporting safety and efficacy data for elderly patients, according to a systematic review of 159 articles.

Roughly 40% of articles reporting efficacy data and 9% of articles reporting safety data had results stratified by age, Karlynn BrintzenhofeSzoc, PhD, of the University of Cincinnati, and colleagues noted in the Journal of Geriatric Oncology.

“Results of our systematic review suggest that there is inadequate reporting of treatment efficacy and adverse events as well as discrepancies as to how older age is defined, considered, and reported,” the investigators wrote. “This sparse and varied reporting critically limits the evidence base for treating older patients with cancer.”

This study was inspired by the American Society of Clinical Oncology, which turned a spotlight on the age-specific data shortage in 2015, when it published a statement that called for inclusion of more elderly patients in cancer trials (J Clin Oncol. 2015 Nov 10;33[32]:3826-33).

According to Tammy Hshieh, MD, a geriatrician at Dana-Farber Cancer Institute in Boston, data for elderly patients with cancer are needed more than ever.

“Cancer care has become, increasingly, a field where precision medicine is at its strongest,” Dr. Hshieh said in an interview. “[Oncologists] have a lot of data on patients that allow them to tailor their care to each individual patient’s profile, and so the fact that there is not a lot of evidence looking at toxicities and side effects for older patients makes it basically harder for oncologists to practice evidence-based medicine for this vulnerable but growing population.” This leads to poorer and more variable outcomes, Dr. Hshieh said. When data aren’t available, clinicians must rely on experience and recognize that patient age isn’t as simple as date of birth.

“Oncologists looking at older patients really have to trust their gestalt and their experience in determining how to provide the best care for their older patients,” she said. “They have to look at the chronological age of the patient and try to determine whether that actually matches more of what we’re saying is the physiological age of the patient and use that to guide their treatment.”
 

Study details

The study included phase 3 clinical trials of adult cancer patients that were conducted from mid-2016 through mid-2017. After identifying 929 manuscripts, the investigators removed duplicates and those that did not meet criteria. This left 159 articles published in 36 journals and covering 25 cancer types.

Of the 159 articles, 73.6% included age-specific medians (in addition to age means), and 47.2% had data stratified by age.

Efficacy was often reported (96.2%), but only 39.9% of articles specified age when describing effectiveness. Although most articles (84.9%) included safety data, only 8.9% had safety findings stratified by age.

In article discussion sections, age was mentioned infrequently in relation to treatment efficacy (13.8%) and rarely in relation to complications and adverse events (5.7%).Beyond underreporting of age-specific data, the investigators found that age categories themselves may be an area in need of improvement.“When outcomes pertaining to older adults were reported, the results were inconsistent as evidenced by the array of age distributions and varying categorization of ‘older adults,’” the investigators wrote. “There is a significant and timely need to design all clinical trials to include older adults and utilize a broad array of geriatric-specific outcomes.” Dr. Hshieh said these findings are concerning, but the study itself suggests the medical community is making efforts to correct the data shortage.“It was actually an important study, even though the results are a little discouraging,” Dr. Hshieh said. “What I’m hoping is that [these findings], combined with all the other literature that’s starting to come out about the need for more research in older patients with cancer, is going to be an impetus for us to do more research, and to be more open to treating older patients, and not to be afraid to confront this head on.”When asked about strategies for managing elderly patients, Dr. Hshieh first recommended the 2018 ASCO Guideline for Geriatric Oncology (J Clin Oncol. 2018 Aug 1;36[22]:2326-47).

“It’s very well written,” she said. “It is clear and user-friendly.”

Dr. Hshieh also offered some simple principles that may help guide clinical decision making.“I’m thinking of three things that an oncologist in the community would want to look at when they see an older patient and they’re trying to determine their treatment plan,” she said. “I would say [the oncologist] should look at [the patient’s] function; their psychosocial status, which includes mood and the support that they have in the community; and cognition.”

Dr. Hshieh and the study authors reported no conflicts of interest.

SOURCE: BrintzenhofeSzoc K et al. J Geriatr Oncol. 2020 Jan 10. pii: S1879-4068(19)30501-6.

Phase 3 clinical trials for cancer are underreporting safety and efficacy data for elderly patients, according to a systematic review of 159 articles.

Roughly 40% of articles reporting efficacy data and 9% of articles reporting safety data had results stratified by age, Karlynn BrintzenhofeSzoc, PhD, of the University of Cincinnati, and colleagues noted in the Journal of Geriatric Oncology.

“Results of our systematic review suggest that there is inadequate reporting of treatment efficacy and adverse events as well as discrepancies as to how older age is defined, considered, and reported,” the investigators wrote. “This sparse and varied reporting critically limits the evidence base for treating older patients with cancer.”

This study was inspired by the American Society of Clinical Oncology, which turned a spotlight on the age-specific data shortage in 2015, when it published a statement that called for inclusion of more elderly patients in cancer trials (J Clin Oncol. 2015 Nov 10;33[32]:3826-33).

According to Tammy Hshieh, MD, a geriatrician at Dana-Farber Cancer Institute in Boston, data for elderly patients with cancer are needed more than ever.

“Cancer care has become, increasingly, a field where precision medicine is at its strongest,” Dr. Hshieh said in an interview. “[Oncologists] have a lot of data on patients that allow them to tailor their care to each individual patient’s profile, and so the fact that there is not a lot of evidence looking at toxicities and side effects for older patients makes it basically harder for oncologists to practice evidence-based medicine for this vulnerable but growing population.” This leads to poorer and more variable outcomes, Dr. Hshieh said. When data aren’t available, clinicians must rely on experience and recognize that patient age isn’t as simple as date of birth.

“Oncologists looking at older patients really have to trust their gestalt and their experience in determining how to provide the best care for their older patients,” she said. “They have to look at the chronological age of the patient and try to determine whether that actually matches more of what we’re saying is the physiological age of the patient and use that to guide their treatment.”
 

Study details

The study included phase 3 clinical trials of adult cancer patients that were conducted from mid-2016 through mid-2017. After identifying 929 manuscripts, the investigators removed duplicates and those that did not meet criteria. This left 159 articles published in 36 journals and covering 25 cancer types.

Of the 159 articles, 73.6% included age-specific medians (in addition to age means), and 47.2% had data stratified by age.

Efficacy was often reported (96.2%), but only 39.9% of articles specified age when describing effectiveness. Although most articles (84.9%) included safety data, only 8.9% had safety findings stratified by age.

In article discussion sections, age was mentioned infrequently in relation to treatment efficacy (13.8%) and rarely in relation to complications and adverse events (5.7%).Beyond underreporting of age-specific data, the investigators found that age categories themselves may be an area in need of improvement.“When outcomes pertaining to older adults were reported, the results were inconsistent as evidenced by the array of age distributions and varying categorization of ‘older adults,’” the investigators wrote. “There is a significant and timely need to design all clinical trials to include older adults and utilize a broad array of geriatric-specific outcomes.” Dr. Hshieh said these findings are concerning, but the study itself suggests the medical community is making efforts to correct the data shortage.“It was actually an important study, even though the results are a little discouraging,” Dr. Hshieh said. “What I’m hoping is that [these findings], combined with all the other literature that’s starting to come out about the need for more research in older patients with cancer, is going to be an impetus for us to do more research, and to be more open to treating older patients, and not to be afraid to confront this head on.”When asked about strategies for managing elderly patients, Dr. Hshieh first recommended the 2018 ASCO Guideline for Geriatric Oncology (J Clin Oncol. 2018 Aug 1;36[22]:2326-47).

“It’s very well written,” she said. “It is clear and user-friendly.”

Dr. Hshieh also offered some simple principles that may help guide clinical decision making.“I’m thinking of three things that an oncologist in the community would want to look at when they see an older patient and they’re trying to determine their treatment plan,” she said. “I would say [the oncologist] should look at [the patient’s] function; their psychosocial status, which includes mood and the support that they have in the community; and cognition.”

Dr. Hshieh and the study authors reported no conflicts of interest.

SOURCE: BrintzenhofeSzoc K et al. J Geriatr Oncol. 2020 Jan 10. pii: S1879-4068(19)30501-6.

Phase 3 clinical trials for cancer are underreporting safety and efficacy data for elderly patients, according to a systematic review of 159 articles.

Roughly 40% of articles reporting efficacy data and 9% of articles reporting safety data had results stratified by age, Karlynn BrintzenhofeSzoc, PhD, of the University of Cincinnati, and colleagues noted in the Journal of Geriatric Oncology.

“Results of our systematic review suggest that there is inadequate reporting of treatment efficacy and adverse events as well as discrepancies as to how older age is defined, considered, and reported,” the investigators wrote. “This sparse and varied reporting critically limits the evidence base for treating older patients with cancer.”

This study was inspired by the American Society of Clinical Oncology, which turned a spotlight on the age-specific data shortage in 2015, when it published a statement that called for inclusion of more elderly patients in cancer trials (J Clin Oncol. 2015 Nov 10;33[32]:3826-33).

According to Tammy Hshieh, MD, a geriatrician at Dana-Farber Cancer Institute in Boston, data for elderly patients with cancer are needed more than ever.

“Cancer care has become, increasingly, a field where precision medicine is at its strongest,” Dr. Hshieh said in an interview. “[Oncologists] have a lot of data on patients that allow them to tailor their care to each individual patient’s profile, and so the fact that there is not a lot of evidence looking at toxicities and side effects for older patients makes it basically harder for oncologists to practice evidence-based medicine for this vulnerable but growing population.” This leads to poorer and more variable outcomes, Dr. Hshieh said. When data aren’t available, clinicians must rely on experience and recognize that patient age isn’t as simple as date of birth.

“Oncologists looking at older patients really have to trust their gestalt and their experience in determining how to provide the best care for their older patients,” she said. “They have to look at the chronological age of the patient and try to determine whether that actually matches more of what we’re saying is the physiological age of the patient and use that to guide their treatment.”
 

Study details

The study included phase 3 clinical trials of adult cancer patients that were conducted from mid-2016 through mid-2017. After identifying 929 manuscripts, the investigators removed duplicates and those that did not meet criteria. This left 159 articles published in 36 journals and covering 25 cancer types.

Of the 159 articles, 73.6% included age-specific medians (in addition to age means), and 47.2% had data stratified by age.

Efficacy was often reported (96.2%), but only 39.9% of articles specified age when describing effectiveness. Although most articles (84.9%) included safety data, only 8.9% had safety findings stratified by age.

In article discussion sections, age was mentioned infrequently in relation to treatment efficacy (13.8%) and rarely in relation to complications and adverse events (5.7%).Beyond underreporting of age-specific data, the investigators found that age categories themselves may be an area in need of improvement.“When outcomes pertaining to older adults were reported, the results were inconsistent as evidenced by the array of age distributions and varying categorization of ‘older adults,’” the investigators wrote. “There is a significant and timely need to design all clinical trials to include older adults and utilize a broad array of geriatric-specific outcomes.” Dr. Hshieh said these findings are concerning, but the study itself suggests the medical community is making efforts to correct the data shortage.“It was actually an important study, even though the results are a little discouraging,” Dr. Hshieh said. “What I’m hoping is that [these findings], combined with all the other literature that’s starting to come out about the need for more research in older patients with cancer, is going to be an impetus for us to do more research, and to be more open to treating older patients, and not to be afraid to confront this head on.”When asked about strategies for managing elderly patients, Dr. Hshieh first recommended the 2018 ASCO Guideline for Geriatric Oncology (J Clin Oncol. 2018 Aug 1;36[22]:2326-47).

“It’s very well written,” she said. “It is clear and user-friendly.”

Dr. Hshieh also offered some simple principles that may help guide clinical decision making.“I’m thinking of three things that an oncologist in the community would want to look at when they see an older patient and they’re trying to determine their treatment plan,” she said. “I would say [the oncologist] should look at [the patient’s] function; their psychosocial status, which includes mood and the support that they have in the community; and cognition.”

Dr. Hshieh and the study authors reported no conflicts of interest.

SOURCE: BrintzenhofeSzoc K et al. J Geriatr Oncol. 2020 Jan 10. pii: S1879-4068(19)30501-6.

Microbiome studies should be correcting statistics to account for proton pump inhibitor (PPI) use, according to a leading expert.

After antibiotics, PPIs are the leading cause of microbiome variance in both research and general populations, and these alterations could have a range of consequences, reported Rinse K. Weersma, MD, PhD, of the University of Groningen (the Netherlands).

About 20% of people are taking a PPI, Dr. Weersma said at the annual Gut Microbiota for Health World Summit, noting that, in countries such as the United States and the United Kingdom, this figure may be higher.

“There’s chronic use of proton pump inhibitors in the population on a massive scale,” Dr. Weersma said.

To complicate matters, estimates suggest that 25%-70% of people who are taking PPIs have no appropriate indication. While this issue is partly because of increasing over-the-counter usage, physicians are also contributing to the problem by prescribing PPIs without adequate follow-up.

“The number of people using proton pump inhibitors is steadily increasing,” Dr. Weersma said. “The number of people getting them prescribed is relatively stable. The problem is, we never stop.”

According to Dr. Weersma, a growing body of research shows that PPI use may increase the risk of developing other conditions. Although many of these relationships are correlative, some are now widely accepted as causal. Most notable and clinically relevant, Dr. Weersma said, are enteric infections. Clostridioides difficile–associated diarrhea, for instance, is 65% more common among PPI users.

While the mechanisms behind this susceptibility to infection are uncertain, Dr. Weersma suggested that the most likely cause is “oralization” of the gut microbiome caused by loss of the acid barrier, which introduces upper gastrointestinal bacteria, or oral bacteria, into the lower intestines.

Perhaps more relevant to clinical trials, PPIs may also influence the safety and efficacy of drugs.

“There is a lot of interaction between the gut microbiome and a lot of drugs,” Dr. Weersma said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “We really don’t know a lot about this at the moment.”

He went on to explain that bidirectional interactions between drugs and the microbiome may actually present clinical opportunities.

“This is a field that people currently call pharmacomicrobiomics,” Dr. Weersma said. “This is very intriguing, of course, because everyone knows about pharmacogenomics ... which lets you stratify your patients, but you cannot intervene; you cannot change your genetic background to increase efficacy or avoid toxicity. But in fact, with the microbiome, we could modulate the microbiome and improve bioavailability, for example.”

Conversely, Dr. Weersma pointed out that PPI use may be interfering with drug efficacy to a life-altering degree.

He cited a recent study by Chalabi and colleagues, which found that PPI use affected responses to immune checkpoint inhibitors (Ann Oncol. 2020 Jan 16. doi: 10.1016/j.annonc.2020.01.006). Among 169 patients with lung cancer who were treated with atezolizumab, overall survival was significantly lower in PPI users (9.6 vs. 14.5 months; P = .001).

A number of other clinical implications are also possible, Dr. Weersma said, although these require further investigation. For example, a 2019 study by Stark and colleagues suggested that childhood use of PPIs may increase obesity risk.

“[There are] no microbiome data here,” Dr. Weersma said, “but it makes you think.”

While considering the downsides of PPIs, Dr. Weersma also emphasized their importance in clinical practice. “[Proton pump inhibitors] are very great drugs. They are cheap, they are safe, they are very effective. So if you have evidence-based indications to use proton pump inhibitors, you should definitely use them and not stop them.”

Dr. Weersma called for responsible use of PPIs, and suggested that clinicians need to prepare for pushback from patients, who, after stopping PPIs, may experience a temporary resurgence of symptoms because of acid rebound.

“You have to make them aware [of acid rebound],” Dr. Weersma said. “Say: ‘Wait 2 or 3 weeks and this rebound is gone.’ We should say that way, way, way more often.”

But clinicians shouldn’t bear the burden of responsible usage alone, Dr. Weersma said.

“There’s a role for clinicians, patients, and regulatory bodies also, to think about the massive use of proton pump inhibitors now and in the future.”

In the discussion that followed the presentation, a summit attendee brought up the realities of clinical practice before PPIs, when patients frequently had gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory use. In response, Dr. Weersma again emphasized that PPIs play a critical role for many patients. After once more encouraging responsible use, Dr. Weersma expressed concern about the risks involved in conveying his message; not only to the medical community, but also to the general public.

“This is a very difficult message [to deliver],” Dr. Weersma said. “In the Netherlands this was taken up by the media and the news, so my email inbox exploded. It’s difficult to get this nuance right.”

Dr. Weersma disclosed relationships with Takeda, Johnson & Johnson, Ferring, and others.

Microbiome studies should be correcting statistics to account for proton pump inhibitor (PPI) use, according to a leading expert.

After antibiotics, PPIs are the leading cause of microbiome variance in both research and general populations, and these alterations could have a range of consequences, reported Rinse K. Weersma, MD, PhD, of the University of Groningen (the Netherlands).

About 20% of people are taking a PPI, Dr. Weersma said at the annual Gut Microbiota for Health World Summit, noting that, in countries such as the United States and the United Kingdom, this figure may be higher.

“There’s chronic use of proton pump inhibitors in the population on a massive scale,” Dr. Weersma said.

To complicate matters, estimates suggest that 25%-70% of people who are taking PPIs have no appropriate indication. While this issue is partly because of increasing over-the-counter usage, physicians are also contributing to the problem by prescribing PPIs without adequate follow-up.

“The number of people using proton pump inhibitors is steadily increasing,” Dr. Weersma said. “The number of people getting them prescribed is relatively stable. The problem is, we never stop.”

According to Dr. Weersma, a growing body of research shows that PPI use may increase the risk of developing other conditions. Although many of these relationships are correlative, some are now widely accepted as causal. Most notable and clinically relevant, Dr. Weersma said, are enteric infections. Clostridioides difficile–associated diarrhea, for instance, is 65% more common among PPI users.

While the mechanisms behind this susceptibility to infection are uncertain, Dr. Weersma suggested that the most likely cause is “oralization” of the gut microbiome caused by loss of the acid barrier, which introduces upper gastrointestinal bacteria, or oral bacteria, into the lower intestines.

Perhaps more relevant to clinical trials, PPIs may also influence the safety and efficacy of drugs.

“There is a lot of interaction between the gut microbiome and a lot of drugs,” Dr. Weersma said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “We really don’t know a lot about this at the moment.”

He went on to explain that bidirectional interactions between drugs and the microbiome may actually present clinical opportunities.

“This is a field that people currently call pharmacomicrobiomics,” Dr. Weersma said. “This is very intriguing, of course, because everyone knows about pharmacogenomics ... which lets you stratify your patients, but you cannot intervene; you cannot change your genetic background to increase efficacy or avoid toxicity. But in fact, with the microbiome, we could modulate the microbiome and improve bioavailability, for example.”

Conversely, Dr. Weersma pointed out that PPI use may be interfering with drug efficacy to a life-altering degree.

He cited a recent study by Chalabi and colleagues, which found that PPI use affected responses to immune checkpoint inhibitors (Ann Oncol. 2020 Jan 16. doi: 10.1016/j.annonc.2020.01.006). Among 169 patients with lung cancer who were treated with atezolizumab, overall survival was significantly lower in PPI users (9.6 vs. 14.5 months; P = .001).

A number of other clinical implications are also possible, Dr. Weersma said, although these require further investigation. For example, a 2019 study by Stark and colleagues suggested that childhood use of PPIs may increase obesity risk.

“[There are] no microbiome data here,” Dr. Weersma said, “but it makes you think.”

While considering the downsides of PPIs, Dr. Weersma also emphasized their importance in clinical practice. “[Proton pump inhibitors] are very great drugs. They are cheap, they are safe, they are very effective. So if you have evidence-based indications to use proton pump inhibitors, you should definitely use them and not stop them.”

Dr. Weersma called for responsible use of PPIs, and suggested that clinicians need to prepare for pushback from patients, who, after stopping PPIs, may experience a temporary resurgence of symptoms because of acid rebound.

“You have to make them aware [of acid rebound],” Dr. Weersma said. “Say: ‘Wait 2 or 3 weeks and this rebound is gone.’ We should say that way, way, way more often.”

But clinicians shouldn’t bear the burden of responsible usage alone, Dr. Weersma said.

“There’s a role for clinicians, patients, and regulatory bodies also, to think about the massive use of proton pump inhibitors now and in the future.”

In the discussion that followed the presentation, a summit attendee brought up the realities of clinical practice before PPIs, when patients frequently had gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory use. In response, Dr. Weersma again emphasized that PPIs play a critical role for many patients. After once more encouraging responsible use, Dr. Weersma expressed concern about the risks involved in conveying his message; not only to the medical community, but also to the general public.

“This is a very difficult message [to deliver],” Dr. Weersma said. “In the Netherlands this was taken up by the media and the news, so my email inbox exploded. It’s difficult to get this nuance right.”

Dr. Weersma disclosed relationships with Takeda, Johnson & Johnson, Ferring, and others.

Microbiome studies should be correcting statistics to account for proton pump inhibitor (PPI) use, according to a leading expert.

After antibiotics, PPIs are the leading cause of microbiome variance in both research and general populations, and these alterations could have a range of consequences, reported Rinse K. Weersma, MD, PhD, of the University of Groningen (the Netherlands).

About 20% of people are taking a PPI, Dr. Weersma said at the annual Gut Microbiota for Health World Summit, noting that, in countries such as the United States and the United Kingdom, this figure may be higher.

“There’s chronic use of proton pump inhibitors in the population on a massive scale,” Dr. Weersma said.

To complicate matters, estimates suggest that 25%-70% of people who are taking PPIs have no appropriate indication. While this issue is partly because of increasing over-the-counter usage, physicians are also contributing to the problem by prescribing PPIs without adequate follow-up.

“The number of people using proton pump inhibitors is steadily increasing,” Dr. Weersma said. “The number of people getting them prescribed is relatively stable. The problem is, we never stop.”

According to Dr. Weersma, a growing body of research shows that PPI use may increase the risk of developing other conditions. Although many of these relationships are correlative, some are now widely accepted as causal. Most notable and clinically relevant, Dr. Weersma said, are enteric infections. Clostridioides difficile–associated diarrhea, for instance, is 65% more common among PPI users.

While the mechanisms behind this susceptibility to infection are uncertain, Dr. Weersma suggested that the most likely cause is “oralization” of the gut microbiome caused by loss of the acid barrier, which introduces upper gastrointestinal bacteria, or oral bacteria, into the lower intestines.

Perhaps more relevant to clinical trials, PPIs may also influence the safety and efficacy of drugs.

“There is a lot of interaction between the gut microbiome and a lot of drugs,” Dr. Weersma said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “We really don’t know a lot about this at the moment.”

He went on to explain that bidirectional interactions between drugs and the microbiome may actually present clinical opportunities.

“This is a field that people currently call pharmacomicrobiomics,” Dr. Weersma said. “This is very intriguing, of course, because everyone knows about pharmacogenomics ... which lets you stratify your patients, but you cannot intervene; you cannot change your genetic background to increase efficacy or avoid toxicity. But in fact, with the microbiome, we could modulate the microbiome and improve bioavailability, for example.”

Conversely, Dr. Weersma pointed out that PPI use may be interfering with drug efficacy to a life-altering degree.

He cited a recent study by Chalabi and colleagues, which found that PPI use affected responses to immune checkpoint inhibitors (Ann Oncol. 2020 Jan 16. doi: 10.1016/j.annonc.2020.01.006). Among 169 patients with lung cancer who were treated with atezolizumab, overall survival was significantly lower in PPI users (9.6 vs. 14.5 months; P = .001).

A number of other clinical implications are also possible, Dr. Weersma said, although these require further investigation. For example, a 2019 study by Stark and colleagues suggested that childhood use of PPIs may increase obesity risk.

“[There are] no microbiome data here,” Dr. Weersma said, “but it makes you think.”

While considering the downsides of PPIs, Dr. Weersma also emphasized their importance in clinical practice. “[Proton pump inhibitors] are very great drugs. They are cheap, they are safe, they are very effective. So if you have evidence-based indications to use proton pump inhibitors, you should definitely use them and not stop them.”

Dr. Weersma called for responsible use of PPIs, and suggested that clinicians need to prepare for pushback from patients, who, after stopping PPIs, may experience a temporary resurgence of symptoms because of acid rebound.

“You have to make them aware [of acid rebound],” Dr. Weersma said. “Say: ‘Wait 2 or 3 weeks and this rebound is gone.’ We should say that way, way, way more often.”

But clinicians shouldn’t bear the burden of responsible usage alone, Dr. Weersma said.

“There’s a role for clinicians, patients, and regulatory bodies also, to think about the massive use of proton pump inhibitors now and in the future.”

In the discussion that followed the presentation, a summit attendee brought up the realities of clinical practice before PPIs, when patients frequently had gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory use. In response, Dr. Weersma again emphasized that PPIs play a critical role for many patients. After once more encouraging responsible use, Dr. Weersma expressed concern about the risks involved in conveying his message; not only to the medical community, but also to the general public.

“This is a very difficult message [to deliver],” Dr. Weersma said. “In the Netherlands this was taken up by the media and the news, so my email inbox exploded. It’s difficult to get this nuance right.”

Dr. Weersma disclosed relationships with Takeda, Johnson & Johnson, Ferring, and others.