Jim Kling

In a phase 2 trial in eosinophilic gastritis and duodenitis, an anti–Siglec-8 antibody greatly reduced populations of eosinophilic cells, and also led to improved symptoms. The sponsoring company, Alkalos, is currently conducting a phase 3 trial in eosinophilic gastritis or duodenitis and a phase 2-3 trial in eosinophilic esophagitis.

The news is welcome to clinicians who treat these rare conditions, since the only current treatment option is steroids. This is particularly challenging because most patients with these conditions present in their 30s and 40s, according to Carol Semrad, MD, professor of medicine at the University of Chicago, who was asked to comment on the study. She noted that the study’s results were impressive, but it will take a phase 3 trial to convince. It’s also unclear if the clinical benefit tracks with the impressive reduction seen in eosinophil count. “There’s somewhat of a disconnect between symptom reduction and reduction of the eosinophil counts. Sometimes just blocking the inflammation [isn’t enough]. Maybe there is other damage to the bowel.”

Still, “it looks like they have a proof of concept that it’s very effective at blocking the eosinophils and mast cells that are thought to be causing eosinophilic gastritis and duodenitis in human disease. That, along with improvement in symptoms, is highly promising, given that we have no other treatment beside steroids,” said Dr. Semrad.

The research, led by Evan S. Dellon, MD, MPH, of the University of North Carolina at Chapel Hill, and Ikuo Hirano, MD, of Northwestern University, Chicago, appeared in the New England Journal of Medicine.

The antibody (lirentelimab) targets sialic acid–binding immunoglobulin-like lectin 8 (Siglec-8), which is an inhibitory receptor found on mature eosinophils and mast cells, and expressed at low levels on basophils. The antibody reduces eosinophil population through natural killer cell-mediated cellular cytotoxicity and apoptosis, and other antibodies against the same target have been shown to inhibit activation of mast cells.

At 22 sites across the United States, researchers randomized 65 adults with active, uncontrolled eosinophilic gastritis or eosinophilic duodenitis, or both, to receive four monthly low doses (0.3, 1, 1, and 1 mg/kg) or high-dose lirentelimab (0.3, 1, 3, and 3 mg/kg), or placebo. A total of 10 patients had gastritis, 25 had duodenitis, and 30 had both.

In the intention-to-treat analysis, there was a mean 86% reduction in eosinophil count in patients in the treatment groups, compared with a 9% increase in controls (P < .001). In the per-protocol analysis, there was a 95% reduction versus a 10% increase (P < .001). Of treated patients, 95% had a gastrointestinal eosinophil count of 6 or fewer per high-powered field, compared with 0% in the placebo group.

In the intention-to-treat analysis, 63% of treated patients experienced a treatment response, defined as at least a 30% reduction in total symptom score and at least a 75% reduction in eosinophil count. About 5% of patients had a response in the placebo group (P < .001). The mean percentage change in total symptom score was –48 versus –22 in the placebo group (P = .004). In the per-protocol analysis, 69% responded versus 5% (P < .001). The mean percentage change in total symptom score was –53 versus –24 (P = .001).

91% of patients in the treatment groups experienced at least one adverse event, compared with 82% in the placebo group. About 60% in the treatment group had an infusion-related reaction versus 23% who received placebo; 93% of reactions were mild to moderate. Serious adverse events occurred in 9% of the treatment group and 14% of patients on placebo. The only serious adverse event thought to be related to the drug was a single grade 4 infusion-related event in the high-dose treatment group, which led to discontinuation of the drug and withdrawal from the trial. 86% of patients in the treatment group experienced transient lymphopenia, as did 47% of the placebo group, but there were no clinical consequences.

One potential concern with the therapy is the effect that long-term suppression of eosinophils and mast cells, and to a lesser extent basophils, could have on the immune system. Eosinophils are key to defenses against parasites, so that will need to be looked at in further studies, according to Dr. Semrad: “How is blocking those inflammatory cells going to impact gut function and the ability to fight off certain organisms? That’s going to be one of the real questions.”

The study was funded by Alkalos. Dr. Semrad has no relevant financial disclosures.

SOURCE: Dellon ES et al. N Engl J Med. 2020 Oct 22. doi: 10.1056/NEJMoa2012047.

In a phase 2 trial in eosinophilic gastritis and duodenitis, an anti–Siglec-8 antibody greatly reduced populations of eosinophilic cells, and also led to improved symptoms. The sponsoring company, Alkalos, is currently conducting a phase 3 trial in eosinophilic gastritis or duodenitis and a phase 2-3 trial in eosinophilic esophagitis.

The news is welcome to clinicians who treat these rare conditions, since the only current treatment option is steroids. This is particularly challenging because most patients with these conditions present in their 30s and 40s, according to Carol Semrad, MD, professor of medicine at the University of Chicago, who was asked to comment on the study. She noted that the study’s results were impressive, but it will take a phase 3 trial to convince. It’s also unclear if the clinical benefit tracks with the impressive reduction seen in eosinophil count. “There’s somewhat of a disconnect between symptom reduction and reduction of the eosinophil counts. Sometimes just blocking the inflammation [isn’t enough]. Maybe there is other damage to the bowel.”

Still, “it looks like they have a proof of concept that it’s very effective at blocking the eosinophils and mast cells that are thought to be causing eosinophilic gastritis and duodenitis in human disease. That, along with improvement in symptoms, is highly promising, given that we have no other treatment beside steroids,” said Dr. Semrad.

The research, led by Evan S. Dellon, MD, MPH, of the University of North Carolina at Chapel Hill, and Ikuo Hirano, MD, of Northwestern University, Chicago, appeared in the New England Journal of Medicine.

The antibody (lirentelimab) targets sialic acid–binding immunoglobulin-like lectin 8 (Siglec-8), which is an inhibitory receptor found on mature eosinophils and mast cells, and expressed at low levels on basophils. The antibody reduces eosinophil population through natural killer cell-mediated cellular cytotoxicity and apoptosis, and other antibodies against the same target have been shown to inhibit activation of mast cells.

At 22 sites across the United States, researchers randomized 65 adults with active, uncontrolled eosinophilic gastritis or eosinophilic duodenitis, or both, to receive four monthly low doses (0.3, 1, 1, and 1 mg/kg) or high-dose lirentelimab (0.3, 1, 3, and 3 mg/kg), or placebo. A total of 10 patients had gastritis, 25 had duodenitis, and 30 had both.

In the intention-to-treat analysis, there was a mean 86% reduction in eosinophil count in patients in the treatment groups, compared with a 9% increase in controls (P < .001). In the per-protocol analysis, there was a 95% reduction versus a 10% increase (P < .001). Of treated patients, 95% had a gastrointestinal eosinophil count of 6 or fewer per high-powered field, compared with 0% in the placebo group.

In the intention-to-treat analysis, 63% of treated patients experienced a treatment response, defined as at least a 30% reduction in total symptom score and at least a 75% reduction in eosinophil count. About 5% of patients had a response in the placebo group (P < .001). The mean percentage change in total symptom score was –48 versus –22 in the placebo group (P = .004). In the per-protocol analysis, 69% responded versus 5% (P < .001). The mean percentage change in total symptom score was –53 versus –24 (P = .001).

91% of patients in the treatment groups experienced at least one adverse event, compared with 82% in the placebo group. About 60% in the treatment group had an infusion-related reaction versus 23% who received placebo; 93% of reactions were mild to moderate. Serious adverse events occurred in 9% of the treatment group and 14% of patients on placebo. The only serious adverse event thought to be related to the drug was a single grade 4 infusion-related event in the high-dose treatment group, which led to discontinuation of the drug and withdrawal from the trial. 86% of patients in the treatment group experienced transient lymphopenia, as did 47% of the placebo group, but there were no clinical consequences.

One potential concern with the therapy is the effect that long-term suppression of eosinophils and mast cells, and to a lesser extent basophils, could have on the immune system. Eosinophils are key to defenses against parasites, so that will need to be looked at in further studies, according to Dr. Semrad: “How is blocking those inflammatory cells going to impact gut function and the ability to fight off certain organisms? That’s going to be one of the real questions.”

The study was funded by Alkalos. Dr. Semrad has no relevant financial disclosures.

SOURCE: Dellon ES et al. N Engl J Med. 2020 Oct 22. doi: 10.1056/NEJMoa2012047.

In a phase 2 trial in eosinophilic gastritis and duodenitis, an anti–Siglec-8 antibody greatly reduced populations of eosinophilic cells, and also led to improved symptoms. The sponsoring company, Alkalos, is currently conducting a phase 3 trial in eosinophilic gastritis or duodenitis and a phase 2-3 trial in eosinophilic esophagitis.

The news is welcome to clinicians who treat these rare conditions, since the only current treatment option is steroids. This is particularly challenging because most patients with these conditions present in their 30s and 40s, according to Carol Semrad, MD, professor of medicine at the University of Chicago, who was asked to comment on the study. She noted that the study’s results were impressive, but it will take a phase 3 trial to convince. It’s also unclear if the clinical benefit tracks with the impressive reduction seen in eosinophil count. “There’s somewhat of a disconnect between symptom reduction and reduction of the eosinophil counts. Sometimes just blocking the inflammation [isn’t enough]. Maybe there is other damage to the bowel.”

Still, “it looks like they have a proof of concept that it’s very effective at blocking the eosinophils and mast cells that are thought to be causing eosinophilic gastritis and duodenitis in human disease. That, along with improvement in symptoms, is highly promising, given that we have no other treatment beside steroids,” said Dr. Semrad.

The research, led by Evan S. Dellon, MD, MPH, of the University of North Carolina at Chapel Hill, and Ikuo Hirano, MD, of Northwestern University, Chicago, appeared in the New England Journal of Medicine.

The antibody (lirentelimab) targets sialic acid–binding immunoglobulin-like lectin 8 (Siglec-8), which is an inhibitory receptor found on mature eosinophils and mast cells, and expressed at low levels on basophils. The antibody reduces eosinophil population through natural killer cell-mediated cellular cytotoxicity and apoptosis, and other antibodies against the same target have been shown to inhibit activation of mast cells.

At 22 sites across the United States, researchers randomized 65 adults with active, uncontrolled eosinophilic gastritis or eosinophilic duodenitis, or both, to receive four monthly low doses (0.3, 1, 1, and 1 mg/kg) or high-dose lirentelimab (0.3, 1, 3, and 3 mg/kg), or placebo. A total of 10 patients had gastritis, 25 had duodenitis, and 30 had both.

In the intention-to-treat analysis, there was a mean 86% reduction in eosinophil count in patients in the treatment groups, compared with a 9% increase in controls (P < .001). In the per-protocol analysis, there was a 95% reduction versus a 10% increase (P < .001). Of treated patients, 95% had a gastrointestinal eosinophil count of 6 or fewer per high-powered field, compared with 0% in the placebo group.

In the intention-to-treat analysis, 63% of treated patients experienced a treatment response, defined as at least a 30% reduction in total symptom score and at least a 75% reduction in eosinophil count. About 5% of patients had a response in the placebo group (P < .001). The mean percentage change in total symptom score was –48 versus –22 in the placebo group (P = .004). In the per-protocol analysis, 69% responded versus 5% (P < .001). The mean percentage change in total symptom score was –53 versus –24 (P = .001).

91% of patients in the treatment groups experienced at least one adverse event, compared with 82% in the placebo group. About 60% in the treatment group had an infusion-related reaction versus 23% who received placebo; 93% of reactions were mild to moderate. Serious adverse events occurred in 9% of the treatment group and 14% of patients on placebo. The only serious adverse event thought to be related to the drug was a single grade 4 infusion-related event in the high-dose treatment group, which led to discontinuation of the drug and withdrawal from the trial. 86% of patients in the treatment group experienced transient lymphopenia, as did 47% of the placebo group, but there were no clinical consequences.

One potential concern with the therapy is the effect that long-term suppression of eosinophils and mast cells, and to a lesser extent basophils, could have on the immune system. Eosinophils are key to defenses against parasites, so that will need to be looked at in further studies, according to Dr. Semrad: “How is blocking those inflammatory cells going to impact gut function and the ability to fight off certain organisms? That’s going to be one of the real questions.”

The study was funded by Alkalos. Dr. Semrad has no relevant financial disclosures.

SOURCE: Dellon ES et al. N Engl J Med. 2020 Oct 22. doi: 10.1056/NEJMoa2012047.

A new analysis of the Swedish Obese Subjects (SOS) study shows that bariatric surgery is associated with about a 3-year increase in lifespan, compared with obese patients who do not undergo surgery. Still, surgery did not restore normal lifespan: Surgical patients’ lifespan remained less than that of a sample from the general Swedish population. The study follows other reports suggesting reduced mortality after bariatric surgery, but with a longer follow-up.

Whitestorm/ThinkStock

“These data add even more evidence to the growing literature showing that patients who undergo bariatric surgery experience a reduction in all-cause long-term mortality. In making decisions around bariatric surgical procedures and care, patients and their health care providers need to understand the trade-offs between improved weight, health, and longer-term survival versus the surgical risks and problems over time,” said Anita P. Courcoulas, MD, MPH, chief of minimally invasive bariatric and general surgery at the University of Pittsburgh Medical Center, said in an interview. Dr. Courcoulas was not involved in the study.

The results appeared in the New England Journal of Medicine.

The SOS study drew from 25 surgical departments and 480 primary health care centers in Sweden. The researchers examined data from 2,007 patients who underwent bariatric surgery between 1987 and 2001, and compared their outcomes to 2,040 matched controls. All were between age 37 and 60 years, with a body mass index (BMI) of at least 34 kg/m² for men and 38 for women. They also compared outcomes with 1,135 randomly sampled from the Swedish population registry.

Procedures included banding (18%), vertical banded gastroplasty (69%), and gastric bypass (13%). After an initial BMI reduction of about 11, the surgery group stabilized by year 8 at a BMI about 7 lower than baseline, and there was little change in BMI among controls.

After a mean follow-up of 24 years (interquartile range, 22-27 years), there were 10.7 deaths per 1,000 person-years in the surgery group, 13.2 among obese controls, and 5.2 in the general population (hazard ratio, 0.77 for surgery versus no surgery; P < .001). The general population had a lower mortality than nonsurgical controls (HR, 0.44; P < .001).

The surgery group had a higher median life expectancy than controls (median, 2.4 years; adjusted difference, 3.0 years; P < .001). The general population group had a median life expectancy that was 7.4 years higher than the control group (adjusted difference, 8.5 years; P < .001). The surgery group’s median life expectancy was still shorter than the general population reference (adjusted difference, 5.5 years; P < .001).

Cardiovascular disease risk was lower in the surgery group (HR, 0.70; 95% confidence interval, 0.57-0.85), as was risk of MI (HR, 0.51; 95% CI, 0.33-0.79), heart failure (HR, 0.52; 95% CI, 0.31-0.88), and stroke (HR, 0.45; 95% CI, 0.24-0.84). Cancer mortality was also lower (HR, 0.77; 95% CI, 0.61-0.96).

In the surgery group, causes of death that were elevated over the general population included cardiovascular causes (HR, 2.64; 95% CI, 1.78-3.91) and noncardiovascular causes, mainly infections; postsurgical complications; and factors such as alcoholism, suicide, or trauma (HR, 1.50; 95% CI, 1.18-1.91).

The study is limited by its retrospective nature, and because the surgical techniques used at the time are less effective than those used today, and could lead to weight gain over time. As a result, many patients who underwent surgery remained heavier than the general population. It’s also possible that negative health effects accumulated before surgery and persisted afterwards, according to Dr. Courcoulas.

The findings are likely generalizable to people with obesity, many of whom choose not to undergo bariatric surgery despite the potential benefits. “The population studied in SOS had a similar profile of underlying medical diseases to those groups who undergo bariatric surgery today and in the U.S. and around the world,” said Dr. Courcoulas.

The study was funded by the Swedish Research Council and others. Dr. Courcoulas has no relevant financial disclosures

SOURCE: Carlsson L et al. N Engl J Med. 2020 Oct 15. doi: 10.1056/NEJMoa2002449.

A new analysis of the Swedish Obese Subjects (SOS) study shows that bariatric surgery is associated with about a 3-year increase in lifespan, compared with obese patients who do not undergo surgery. Still, surgery did not restore normal lifespan: Surgical patients’ lifespan remained less than that of a sample from the general Swedish population. The study follows other reports suggesting reduced mortality after bariatric surgery, but with a longer follow-up.

Whitestorm/ThinkStock

“These data add even more evidence to the growing literature showing that patients who undergo bariatric surgery experience a reduction in all-cause long-term mortality. In making decisions around bariatric surgical procedures and care, patients and their health care providers need to understand the trade-offs between improved weight, health, and longer-term survival versus the surgical risks and problems over time,” said Anita P. Courcoulas, MD, MPH, chief of minimally invasive bariatric and general surgery at the University of Pittsburgh Medical Center, said in an interview. Dr. Courcoulas was not involved in the study.

The results appeared in the New England Journal of Medicine.

The SOS study drew from 25 surgical departments and 480 primary health care centers in Sweden. The researchers examined data from 2,007 patients who underwent bariatric surgery between 1987 and 2001, and compared their outcomes to 2,040 matched controls. All were between age 37 and 60 years, with a body mass index (BMI) of at least 34 kg/m² for men and 38 for women. They also compared outcomes with 1,135 randomly sampled from the Swedish population registry.

Procedures included banding (18%), vertical banded gastroplasty (69%), and gastric bypass (13%). After an initial BMI reduction of about 11, the surgery group stabilized by year 8 at a BMI about 7 lower than baseline, and there was little change in BMI among controls.

After a mean follow-up of 24 years (interquartile range, 22-27 years), there were 10.7 deaths per 1,000 person-years in the surgery group, 13.2 among obese controls, and 5.2 in the general population (hazard ratio, 0.77 for surgery versus no surgery; P < .001). The general population had a lower mortality than nonsurgical controls (HR, 0.44; P < .001).

The surgery group had a higher median life expectancy than controls (median, 2.4 years; adjusted difference, 3.0 years; P < .001). The general population group had a median life expectancy that was 7.4 years higher than the control group (adjusted difference, 8.5 years; P < .001). The surgery group’s median life expectancy was still shorter than the general population reference (adjusted difference, 5.5 years; P < .001).

Cardiovascular disease risk was lower in the surgery group (HR, 0.70; 95% confidence interval, 0.57-0.85), as was risk of MI (HR, 0.51; 95% CI, 0.33-0.79), heart failure (HR, 0.52; 95% CI, 0.31-0.88), and stroke (HR, 0.45; 95% CI, 0.24-0.84). Cancer mortality was also lower (HR, 0.77; 95% CI, 0.61-0.96).

In the surgery group, causes of death that were elevated over the general population included cardiovascular causes (HR, 2.64; 95% CI, 1.78-3.91) and noncardiovascular causes, mainly infections; postsurgical complications; and factors such as alcoholism, suicide, or trauma (HR, 1.50; 95% CI, 1.18-1.91).

The study is limited by its retrospective nature, and because the surgical techniques used at the time are less effective than those used today, and could lead to weight gain over time. As a result, many patients who underwent surgery remained heavier than the general population. It’s also possible that negative health effects accumulated before surgery and persisted afterwards, according to Dr. Courcoulas.

The findings are likely generalizable to people with obesity, many of whom choose not to undergo bariatric surgery despite the potential benefits. “The population studied in SOS had a similar profile of underlying medical diseases to those groups who undergo bariatric surgery today and in the U.S. and around the world,” said Dr. Courcoulas.

The study was funded by the Swedish Research Council and others. Dr. Courcoulas has no relevant financial disclosures

SOURCE: Carlsson L et al. N Engl J Med. 2020 Oct 15. doi: 10.1056/NEJMoa2002449.

A new analysis of the Swedish Obese Subjects (SOS) study shows that bariatric surgery is associated with about a 3-year increase in lifespan, compared with obese patients who do not undergo surgery. Still, surgery did not restore normal lifespan: Surgical patients’ lifespan remained less than that of a sample from the general Swedish population. The study follows other reports suggesting reduced mortality after bariatric surgery, but with a longer follow-up.

Whitestorm/ThinkStock

“These data add even more evidence to the growing literature showing that patients who undergo bariatric surgery experience a reduction in all-cause long-term mortality. In making decisions around bariatric surgical procedures and care, patients and their health care providers need to understand the trade-offs between improved weight, health, and longer-term survival versus the surgical risks and problems over time,” said Anita P. Courcoulas, MD, MPH, chief of minimally invasive bariatric and general surgery at the University of Pittsburgh Medical Center, said in an interview. Dr. Courcoulas was not involved in the study.

The results appeared in the New England Journal of Medicine.

The SOS study drew from 25 surgical departments and 480 primary health care centers in Sweden. The researchers examined data from 2,007 patients who underwent bariatric surgery between 1987 and 2001, and compared their outcomes to 2,040 matched controls. All were between age 37 and 60 years, with a body mass index (BMI) of at least 34 kg/m² for men and 38 for women. They also compared outcomes with 1,135 randomly sampled from the Swedish population registry.

Procedures included banding (18%), vertical banded gastroplasty (69%), and gastric bypass (13%). After an initial BMI reduction of about 11, the surgery group stabilized by year 8 at a BMI about 7 lower than baseline, and there was little change in BMI among controls.

After a mean follow-up of 24 years (interquartile range, 22-27 years), there were 10.7 deaths per 1,000 person-years in the surgery group, 13.2 among obese controls, and 5.2 in the general population (hazard ratio, 0.77 for surgery versus no surgery; P < .001). The general population had a lower mortality than nonsurgical controls (HR, 0.44; P < .001).

The surgery group had a higher median life expectancy than controls (median, 2.4 years; adjusted difference, 3.0 years; P < .001). The general population group had a median life expectancy that was 7.4 years higher than the control group (adjusted difference, 8.5 years; P < .001). The surgery group’s median life expectancy was still shorter than the general population reference (adjusted difference, 5.5 years; P < .001).

Cardiovascular disease risk was lower in the surgery group (HR, 0.70; 95% confidence interval, 0.57-0.85), as was risk of MI (HR, 0.51; 95% CI, 0.33-0.79), heart failure (HR, 0.52; 95% CI, 0.31-0.88), and stroke (HR, 0.45; 95% CI, 0.24-0.84). Cancer mortality was also lower (HR, 0.77; 95% CI, 0.61-0.96).

In the surgery group, causes of death that were elevated over the general population included cardiovascular causes (HR, 2.64; 95% CI, 1.78-3.91) and noncardiovascular causes, mainly infections; postsurgical complications; and factors such as alcoholism, suicide, or trauma (HR, 1.50; 95% CI, 1.18-1.91).

The study is limited by its retrospective nature, and because the surgical techniques used at the time are less effective than those used today, and could lead to weight gain over time. As a result, many patients who underwent surgery remained heavier than the general population. It’s also possible that negative health effects accumulated before surgery and persisted afterwards, according to Dr. Courcoulas.

The findings are likely generalizable to people with obesity, many of whom choose not to undergo bariatric surgery despite the potential benefits. “The population studied in SOS had a similar profile of underlying medical diseases to those groups who undergo bariatric surgery today and in the U.S. and around the world,” said Dr. Courcoulas.

The study was funded by the Swedish Research Council and others. Dr. Courcoulas has no relevant financial disclosures

SOURCE: Carlsson L et al. N Engl J Med. 2020 Oct 15. doi: 10.1056/NEJMoa2002449.

New developments in treatment of neuromyelitis optica spectrum disorder (NMOSD) have opened up options for disease treatment in pediatric patients, but have led to some uncertainty and confusion as well.

At the2020 CNS-ICNA Conjoint Meeting, held virtually this year, presenters discussed some of the challenges of differential diagnosis and treatment choice in pediatric NMOSD, which is easily confused with multiple sclerosis.

NMOSD used to be considered a monophasic disease restricted to the optic nerve and spinal cord, but is now known to affect other regions of the central nervous system and to relapse in some patients.
 

Diagnosis

The disease is often mediated by antibodies to the aquaporin-4 (AQP-4) water channel, but about 30% of adult patients lack the antibody, and AQP-4 seronegativity is more common in the pediatric population. Another common antibody found in 40%–50% of children with NMOSD targets myelin oligodendrocyte glycoprotein (MOG).

It is important to be aware that false negatives can occur in serology assays, and false positives are common, particularly in ELISA assays, Silvia N. Tenembaum, MD, said during her presentation. For those reasons, serology is not enough for a diagnosis. “Patients should also have compatible symptoms and MRI findings,” said Dr. Tenembaum, director of the pediatric neuroimmunology program at National Pediatric Hospital in Buenos Aires.

According to international consensus criteria, to be diagnosed with NMOSD, AQP-4 seropositive patients should also have at least one core clinical symptom: optic neuritis, acute myelitis, area postrema syndrome, other acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, or symptomatic cerebral syndrome. AQP-4 seronegative patients or with unknown status should have at least two core symptoms, one of which must be optic neuritis, acute myelitis, or area postrema syndrome. Both conventional MRI and advanced new techniques are important for achieving differential diagnosis.

The most common symptom in children is optic neuritis, which occurs in 50%-70% of patients. Cerebral syndromes with or without encephalopathy and large tumefactive white matter lesions are also common, according to Dr. Tenembaum.

There are many conditions that mimic the spinal cord and optic nerve symptoms of NMOSD, which must be ruled out. One example is optic myelopathy and vision loss from late-onset biotinylase deficiency. It is critical to rule that out because it is treatable with supplements. Optic neuropathy, papillitis, and papilledema can also resemble NMOSD.

It is critical to achieve an early diagnosis of NMOSD in children, because some MS drugs can worsen NMOSD, according to Thaís Armangue, MD, PhD, head of neuroimmunology at SJD Barcelona Children’s Hospital, who also presented at the session. She pointed out that the MOG antibody, while common in children, is also associated with many demyelinating diseases. Some 50%-60% of children with acute disseminated encephalomyelitis (ADEM) have high titers of MOG antibodies. Although early studies suggested that persistent anti-MOG antibodies were associated with risk of developing MS, more recent studies show it predicts a non-MS disease course, particularly at titers greater than 1:1280, according to Dr. Tenembaum. Persistent anti-MOG antibodies are also associated with relapsing disease, but it is associated with other syndromes besides NMOSD. “The probability is that [MOG antibodies are] useful, but they cannot guide chronic immunotherapy, because even monophasic patients can last maybe 12 months before they become MOG negative, and we cannot wait so many months” to determine treatment course, said Dr. Tenembaum.

For monophasic ADEM or NMOSD, there is no need for chronic treatment. But children with MS and recurrent NMOSD require early chronic immunotherapy because specific therapies have been shown to improve prognosis.
 

Acute treatment

When it comes to acute treatment of NMOSD, the goal is to suppress the inflammatory attack but also to minimize long-term damage and optimize long-term neurological function. “The potential for irreversible injury with an attack is very high, and cumulative disabilities in NMOSD can result directly from attacks,” E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children at the University of Toronto, said during her talk.

IV steroids are generally the first choice, with a preference for methylprednisolone. Pediatric patients that are MOG antibody positive usually respond better and more quickly than do adults, with rapid daily improvements in mobility, vomiting, and eyesight. Dr. Yeh recommends weaning good responders off steroids because AQP-4 positive patients are likely to relapse without a steroid wean, and antibody testing may be unavailable or results may be delayed. The wean can range from 4 weeks to 4-6 months, depending on antibody status, likelihood of AQP-4 positivity, and clinical parameters.

Inadequate responses are usually pretty evident. If there is only light perception by day 4 or 5, or paralyzed patients are nonambulatory and achieve only twitchy movements by that time, second-line therapies should be considered, including therapeutic plasma exchange (TPE) with 5-7 exchanges or intravenous immunoglobulins (IVIg).

Dr. Yeh called for quick treatment. Whatever you do, “please do it sooner rather than later if you think there’s no response [to steroids],” Dr. Yeh said.

TPE is the first choice, according to Dr. Yeh. “There seems to be a fair amount of information that suggests that if you’re having difficulty getting a response to steroids, TPE can make a difference in these patients,” she said. But in some cases TPE may not be available, and IVIg can be attempted first. If it achieves no or only marginal improvement, TPE can be attempted later, but it must be kept in mind that TPE conducted too soon could wash out IVIg. Patients who get much better on IVIg can undergo a steroid wean, and then be evaluated for prophylactic therapy, said Dr. Yeh.

The evidence for IVIg is limited, reflecting the difficulty of studying treatments in rare populations. Still, when TPE is not available and the patient is quite impaired, IVIg makes sense to try. “Absence of evidence does not mean that the therapy doesn’t work, and I don’t think we should throw out the baby with the bath water,” said Dr. Yeh.

Although IVIg treatment is generally well tolerated, there have been a few serious adverse events, such as anaphylactic shock and aseptic meningitis, according to Andrea Savransky, MD, a pediatrician at National Pediatric Hospital in Buenos Aires, who also spoke at the session. “I think it is important to weigh the benefits against the risk,” Dr. Savransky said. She noted that TPE should not be taken lightly. One study showed more complications in pediatric patients than in adult patients, and it must be performed in specialized centers.
 

Emerging treaments

Tanuja Chitnis, MD, director of the Partners Pediatric MS Center at Massachusetts General Hospital, Boston, discussed some of the emerging treatments for pediatric NMOSD. Rituximab has been associated with success in some retrospective studies, but dosing should be personalized. Dr. Chitnis reported that B cells can return before 6 months, so she monitors B cells beginning 2 months after induction, redosing after 4 or 5 months rather than 6 if B cells return.

Nevertheless, relapses can still occur after rituximab therapy. “There is room for additional therapies to address this gap,” said Dr. Chitnis. Three new antibodies have received approval for treatment of NMOSD in adults. These include the complement inhibitor eculizumab, the IL-6 receptor antibody satralizumab, and the anti-CD19 antibody inebilizumab. Phase 3 clinical trials in children have been conducted for eculizumab and are in the planning stage for inebilizumab, and pediatric patients were included in pivotal trials for satralizumab.

Eculizumab treatment resulted in a 94.2% reduction in relapse risk in AQP4-positive adults. Satralizumab showed a 79% reduction in relapse risk among AQP-4 positive subjects with NMOSD or neuromyelitis optica and a 34% reduction in those who were AQP-4 negative. The pediatric subgroup had similar levels of response to adults, though the numbers were too small for a subgroup analysis.

In AQP-4 positive patients, inebilizumab treatment yielded a 77% reduction in relapse rate. In all patients, there was a 73% reduction.

For MOG antibody-positive patients with AQP-4 negative disease, novel therapies are at earlier stages of development. Typical MS therapies such as interferon beta and glatiramer acetate don’t seem to be effective. Some that have shown signs of efficacy include azathioprine, mycophenylate mofetil, rituximab, and IVIg infusion, but the state of the field is not encouraging. “This is an observation now being studied in larger cohorts, but in general I have not found that there’s a very strong response to any of these therapies, possibly with the exception of IVIg,” said Dr. Chitnis.

Dr. Tenembaum has no relevant financial disclosures. Dr. Armangue has received speaking honoraria from Novartis and travel expenses for scientific meetings from Merck, Biogen, and Roche. Dr. Yeh is on the scientific advisory board of Juno Therapeutics and has received research support from Biogen. Dr. Chitnis advises Biogen-Idec, Novartis, and Alexion, serves on clinical trial advisory boards for Novartis and Sanofi Aventis, and has received research support from Verily, EMD Serono, and Novartis. Dr. Savransky has received honoraria from Genzyme de Argentina SA.

New developments in treatment of neuromyelitis optica spectrum disorder (NMOSD) have opened up options for disease treatment in pediatric patients, but have led to some uncertainty and confusion as well.

At the2020 CNS-ICNA Conjoint Meeting, held virtually this year, presenters discussed some of the challenges of differential diagnosis and treatment choice in pediatric NMOSD, which is easily confused with multiple sclerosis.

NMOSD used to be considered a monophasic disease restricted to the optic nerve and spinal cord, but is now known to affect other regions of the central nervous system and to relapse in some patients.
 

Diagnosis

The disease is often mediated by antibodies to the aquaporin-4 (AQP-4) water channel, but about 30% of adult patients lack the antibody, and AQP-4 seronegativity is more common in the pediatric population. Another common antibody found in 40%–50% of children with NMOSD targets myelin oligodendrocyte glycoprotein (MOG).

It is important to be aware that false negatives can occur in serology assays, and false positives are common, particularly in ELISA assays, Silvia N. Tenembaum, MD, said during her presentation. For those reasons, serology is not enough for a diagnosis. “Patients should also have compatible symptoms and MRI findings,” said Dr. Tenembaum, director of the pediatric neuroimmunology program at National Pediatric Hospital in Buenos Aires.

According to international consensus criteria, to be diagnosed with NMOSD, AQP-4 seropositive patients should also have at least one core clinical symptom: optic neuritis, acute myelitis, area postrema syndrome, other acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, or symptomatic cerebral syndrome. AQP-4 seronegative patients or with unknown status should have at least two core symptoms, one of which must be optic neuritis, acute myelitis, or area postrema syndrome. Both conventional MRI and advanced new techniques are important for achieving differential diagnosis.

The most common symptom in children is optic neuritis, which occurs in 50%-70% of patients. Cerebral syndromes with or without encephalopathy and large tumefactive white matter lesions are also common, according to Dr. Tenembaum.

There are many conditions that mimic the spinal cord and optic nerve symptoms of NMOSD, which must be ruled out. One example is optic myelopathy and vision loss from late-onset biotinylase deficiency. It is critical to rule that out because it is treatable with supplements. Optic neuropathy, papillitis, and papilledema can also resemble NMOSD.

It is critical to achieve an early diagnosis of NMOSD in children, because some MS drugs can worsen NMOSD, according to Thaís Armangue, MD, PhD, head of neuroimmunology at SJD Barcelona Children’s Hospital, who also presented at the session. She pointed out that the MOG antibody, while common in children, is also associated with many demyelinating diseases. Some 50%-60% of children with acute disseminated encephalomyelitis (ADEM) have high titers of MOG antibodies. Although early studies suggested that persistent anti-MOG antibodies were associated with risk of developing MS, more recent studies show it predicts a non-MS disease course, particularly at titers greater than 1:1280, according to Dr. Tenembaum. Persistent anti-MOG antibodies are also associated with relapsing disease, but it is associated with other syndromes besides NMOSD. “The probability is that [MOG antibodies are] useful, but they cannot guide chronic immunotherapy, because even monophasic patients can last maybe 12 months before they become MOG negative, and we cannot wait so many months” to determine treatment course, said Dr. Tenembaum.

For monophasic ADEM or NMOSD, there is no need for chronic treatment. But children with MS and recurrent NMOSD require early chronic immunotherapy because specific therapies have been shown to improve prognosis.
 

Acute treatment

When it comes to acute treatment of NMOSD, the goal is to suppress the inflammatory attack but also to minimize long-term damage and optimize long-term neurological function. “The potential for irreversible injury with an attack is very high, and cumulative disabilities in NMOSD can result directly from attacks,” E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children at the University of Toronto, said during her talk.

IV steroids are generally the first choice, with a preference for methylprednisolone. Pediatric patients that are MOG antibody positive usually respond better and more quickly than do adults, with rapid daily improvements in mobility, vomiting, and eyesight. Dr. Yeh recommends weaning good responders off steroids because AQP-4 positive patients are likely to relapse without a steroid wean, and antibody testing may be unavailable or results may be delayed. The wean can range from 4 weeks to 4-6 months, depending on antibody status, likelihood of AQP-4 positivity, and clinical parameters.

Inadequate responses are usually pretty evident. If there is only light perception by day 4 or 5, or paralyzed patients are nonambulatory and achieve only twitchy movements by that time, second-line therapies should be considered, including therapeutic plasma exchange (TPE) with 5-7 exchanges or intravenous immunoglobulins (IVIg).

Dr. Yeh called for quick treatment. Whatever you do, “please do it sooner rather than later if you think there’s no response [to steroids],” Dr. Yeh said.

TPE is the first choice, according to Dr. Yeh. “There seems to be a fair amount of information that suggests that if you’re having difficulty getting a response to steroids, TPE can make a difference in these patients,” she said. But in some cases TPE may not be available, and IVIg can be attempted first. If it achieves no or only marginal improvement, TPE can be attempted later, but it must be kept in mind that TPE conducted too soon could wash out IVIg. Patients who get much better on IVIg can undergo a steroid wean, and then be evaluated for prophylactic therapy, said Dr. Yeh.

The evidence for IVIg is limited, reflecting the difficulty of studying treatments in rare populations. Still, when TPE is not available and the patient is quite impaired, IVIg makes sense to try. “Absence of evidence does not mean that the therapy doesn’t work, and I don’t think we should throw out the baby with the bath water,” said Dr. Yeh.

Although IVIg treatment is generally well tolerated, there have been a few serious adverse events, such as anaphylactic shock and aseptic meningitis, according to Andrea Savransky, MD, a pediatrician at National Pediatric Hospital in Buenos Aires, who also spoke at the session. “I think it is important to weigh the benefits against the risk,” Dr. Savransky said. She noted that TPE should not be taken lightly. One study showed more complications in pediatric patients than in adult patients, and it must be performed in specialized centers.
 

Emerging treaments

Tanuja Chitnis, MD, director of the Partners Pediatric MS Center at Massachusetts General Hospital, Boston, discussed some of the emerging treatments for pediatric NMOSD. Rituximab has been associated with success in some retrospective studies, but dosing should be personalized. Dr. Chitnis reported that B cells can return before 6 months, so she monitors B cells beginning 2 months after induction, redosing after 4 or 5 months rather than 6 if B cells return.

Nevertheless, relapses can still occur after rituximab therapy. “There is room for additional therapies to address this gap,” said Dr. Chitnis. Three new antibodies have received approval for treatment of NMOSD in adults. These include the complement inhibitor eculizumab, the IL-6 receptor antibody satralizumab, and the anti-CD19 antibody inebilizumab. Phase 3 clinical trials in children have been conducted for eculizumab and are in the planning stage for inebilizumab, and pediatric patients were included in pivotal trials for satralizumab.

Eculizumab treatment resulted in a 94.2% reduction in relapse risk in AQP4-positive adults. Satralizumab showed a 79% reduction in relapse risk among AQP-4 positive subjects with NMOSD or neuromyelitis optica and a 34% reduction in those who were AQP-4 negative. The pediatric subgroup had similar levels of response to adults, though the numbers were too small for a subgroup analysis.

In AQP-4 positive patients, inebilizumab treatment yielded a 77% reduction in relapse rate. In all patients, there was a 73% reduction.

For MOG antibody-positive patients with AQP-4 negative disease, novel therapies are at earlier stages of development. Typical MS therapies such as interferon beta and glatiramer acetate don’t seem to be effective. Some that have shown signs of efficacy include azathioprine, mycophenylate mofetil, rituximab, and IVIg infusion, but the state of the field is not encouraging. “This is an observation now being studied in larger cohorts, but in general I have not found that there’s a very strong response to any of these therapies, possibly with the exception of IVIg,” said Dr. Chitnis.

Dr. Tenembaum has no relevant financial disclosures. Dr. Armangue has received speaking honoraria from Novartis and travel expenses for scientific meetings from Merck, Biogen, and Roche. Dr. Yeh is on the scientific advisory board of Juno Therapeutics and has received research support from Biogen. Dr. Chitnis advises Biogen-Idec, Novartis, and Alexion, serves on clinical trial advisory boards for Novartis and Sanofi Aventis, and has received research support from Verily, EMD Serono, and Novartis. Dr. Savransky has received honoraria from Genzyme de Argentina SA.

New developments in treatment of neuromyelitis optica spectrum disorder (NMOSD) have opened up options for disease treatment in pediatric patients, but have led to some uncertainty and confusion as well.

At the2020 CNS-ICNA Conjoint Meeting, held virtually this year, presenters discussed some of the challenges of differential diagnosis and treatment choice in pediatric NMOSD, which is easily confused with multiple sclerosis.

NMOSD used to be considered a monophasic disease restricted to the optic nerve and spinal cord, but is now known to affect other regions of the central nervous system and to relapse in some patients.
 

Diagnosis

The disease is often mediated by antibodies to the aquaporin-4 (AQP-4) water channel, but about 30% of adult patients lack the antibody, and AQP-4 seronegativity is more common in the pediatric population. Another common antibody found in 40%–50% of children with NMOSD targets myelin oligodendrocyte glycoprotein (MOG).

It is important to be aware that false negatives can occur in serology assays, and false positives are common, particularly in ELISA assays, Silvia N. Tenembaum, MD, said during her presentation. For those reasons, serology is not enough for a diagnosis. “Patients should also have compatible symptoms and MRI findings,” said Dr. Tenembaum, director of the pediatric neuroimmunology program at National Pediatric Hospital in Buenos Aires.

According to international consensus criteria, to be diagnosed with NMOSD, AQP-4 seropositive patients should also have at least one core clinical symptom: optic neuritis, acute myelitis, area postrema syndrome, other acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, or symptomatic cerebral syndrome. AQP-4 seronegative patients or with unknown status should have at least two core symptoms, one of which must be optic neuritis, acute myelitis, or area postrema syndrome. Both conventional MRI and advanced new techniques are important for achieving differential diagnosis.

The most common symptom in children is optic neuritis, which occurs in 50%-70% of patients. Cerebral syndromes with or without encephalopathy and large tumefactive white matter lesions are also common, according to Dr. Tenembaum.

There are many conditions that mimic the spinal cord and optic nerve symptoms of NMOSD, which must be ruled out. One example is optic myelopathy and vision loss from late-onset biotinylase deficiency. It is critical to rule that out because it is treatable with supplements. Optic neuropathy, papillitis, and papilledema can also resemble NMOSD.

It is critical to achieve an early diagnosis of NMOSD in children, because some MS drugs can worsen NMOSD, according to Thaís Armangue, MD, PhD, head of neuroimmunology at SJD Barcelona Children’s Hospital, who also presented at the session. She pointed out that the MOG antibody, while common in children, is also associated with many demyelinating diseases. Some 50%-60% of children with acute disseminated encephalomyelitis (ADEM) have high titers of MOG antibodies. Although early studies suggested that persistent anti-MOG antibodies were associated with risk of developing MS, more recent studies show it predicts a non-MS disease course, particularly at titers greater than 1:1280, according to Dr. Tenembaum. Persistent anti-MOG antibodies are also associated with relapsing disease, but it is associated with other syndromes besides NMOSD. “The probability is that [MOG antibodies are] useful, but they cannot guide chronic immunotherapy, because even monophasic patients can last maybe 12 months before they become MOG negative, and we cannot wait so many months” to determine treatment course, said Dr. Tenembaum.

For monophasic ADEM or NMOSD, there is no need for chronic treatment. But children with MS and recurrent NMOSD require early chronic immunotherapy because specific therapies have been shown to improve prognosis.
 

Acute treatment

When it comes to acute treatment of NMOSD, the goal is to suppress the inflammatory attack but also to minimize long-term damage and optimize long-term neurological function. “The potential for irreversible injury with an attack is very high, and cumulative disabilities in NMOSD can result directly from attacks,” E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children at the University of Toronto, said during her talk.

IV steroids are generally the first choice, with a preference for methylprednisolone. Pediatric patients that are MOG antibody positive usually respond better and more quickly than do adults, with rapid daily improvements in mobility, vomiting, and eyesight. Dr. Yeh recommends weaning good responders off steroids because AQP-4 positive patients are likely to relapse without a steroid wean, and antibody testing may be unavailable or results may be delayed. The wean can range from 4 weeks to 4-6 months, depending on antibody status, likelihood of AQP-4 positivity, and clinical parameters.

Inadequate responses are usually pretty evident. If there is only light perception by day 4 or 5, or paralyzed patients are nonambulatory and achieve only twitchy movements by that time, second-line therapies should be considered, including therapeutic plasma exchange (TPE) with 5-7 exchanges or intravenous immunoglobulins (IVIg).

Dr. Yeh called for quick treatment. Whatever you do, “please do it sooner rather than later if you think there’s no response [to steroids],” Dr. Yeh said.

TPE is the first choice, according to Dr. Yeh. “There seems to be a fair amount of information that suggests that if you’re having difficulty getting a response to steroids, TPE can make a difference in these patients,” she said. But in some cases TPE may not be available, and IVIg can be attempted first. If it achieves no or only marginal improvement, TPE can be attempted later, but it must be kept in mind that TPE conducted too soon could wash out IVIg. Patients who get much better on IVIg can undergo a steroid wean, and then be evaluated for prophylactic therapy, said Dr. Yeh.

The evidence for IVIg is limited, reflecting the difficulty of studying treatments in rare populations. Still, when TPE is not available and the patient is quite impaired, IVIg makes sense to try. “Absence of evidence does not mean that the therapy doesn’t work, and I don’t think we should throw out the baby with the bath water,” said Dr. Yeh.

Although IVIg treatment is generally well tolerated, there have been a few serious adverse events, such as anaphylactic shock and aseptic meningitis, according to Andrea Savransky, MD, a pediatrician at National Pediatric Hospital in Buenos Aires, who also spoke at the session. “I think it is important to weigh the benefits against the risk,” Dr. Savransky said. She noted that TPE should not be taken lightly. One study showed more complications in pediatric patients than in adult patients, and it must be performed in specialized centers.
 

Emerging treaments

Tanuja Chitnis, MD, director of the Partners Pediatric MS Center at Massachusetts General Hospital, Boston, discussed some of the emerging treatments for pediatric NMOSD. Rituximab has been associated with success in some retrospective studies, but dosing should be personalized. Dr. Chitnis reported that B cells can return before 6 months, so she monitors B cells beginning 2 months after induction, redosing after 4 or 5 months rather than 6 if B cells return.

Nevertheless, relapses can still occur after rituximab therapy. “There is room for additional therapies to address this gap,” said Dr. Chitnis. Three new antibodies have received approval for treatment of NMOSD in adults. These include the complement inhibitor eculizumab, the IL-6 receptor antibody satralizumab, and the anti-CD19 antibody inebilizumab. Phase 3 clinical trials in children have been conducted for eculizumab and are in the planning stage for inebilizumab, and pediatric patients were included in pivotal trials for satralizumab.

Eculizumab treatment resulted in a 94.2% reduction in relapse risk in AQP4-positive adults. Satralizumab showed a 79% reduction in relapse risk among AQP-4 positive subjects with NMOSD or neuromyelitis optica and a 34% reduction in those who were AQP-4 negative. The pediatric subgroup had similar levels of response to adults, though the numbers were too small for a subgroup analysis.

In AQP-4 positive patients, inebilizumab treatment yielded a 77% reduction in relapse rate. In all patients, there was a 73% reduction.

For MOG antibody-positive patients with AQP-4 negative disease, novel therapies are at earlier stages of development. Typical MS therapies such as interferon beta and glatiramer acetate don’t seem to be effective. Some that have shown signs of efficacy include azathioprine, mycophenylate mofetil, rituximab, and IVIg infusion, but the state of the field is not encouraging. “This is an observation now being studied in larger cohorts, but in general I have not found that there’s a very strong response to any of these therapies, possibly with the exception of IVIg,” said Dr. Chitnis.

Dr. Tenembaum has no relevant financial disclosures. Dr. Armangue has received speaking honoraria from Novartis and travel expenses for scientific meetings from Merck, Biogen, and Roche. Dr. Yeh is on the scientific advisory board of Juno Therapeutics and has received research support from Biogen. Dr. Chitnis advises Biogen-Idec, Novartis, and Alexion, serves on clinical trial advisory boards for Novartis and Sanofi Aventis, and has received research support from Verily, EMD Serono, and Novartis. Dr. Savransky has received honoraria from Genzyme de Argentina SA.

After almost 2 decades of progress, the global state of measles vaccination and measles mortality is deteriorating. Vaccine hesitancy, natural disasters, geopolitical disruptions, and most recently the COVID-19 pandemic have combined to undermine efforts, which had aimed to eradicate measles by this year.

One of the most serious concerns of measles infection is its long-term neurological complications, including the fatal subacute sclerosing panencephalitis (SSPE) and measles inclusion-body encephalitis (MIBE), which is usually seen in immune deficient children. Although some efforts are being made to determine which patients might be most vulnerable to these outcomes, and to treat them, the best approach is still prevention and vaccination, according to Banu Anlar, MD, of Hacettepe University, Ankara, Turkey, who spoke during a session at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

Worldwide vaccination strategies have slipped in recent years, leading to upticks in measles cases and vaccination rates. As a result, in 2018 the World Health Organization postponed its goal of eliminating measles by 2020. Future eradication goals will likely need to be modified, according to Anaita Udwadia Hegde MD, a pediatric neurologist in Mumbai, India, who also presented at the session.

After measles deaths dropped 74% between 2000 and 2010, coinciding with widespread increases in vaccination, the WHO felt emboldened to deal the disease a knockout blow. In 2010, it held a Global Technical Consultation to determine the feasibility of an eradication campaign, which concluded it should be possible by 2020. Several characteristics of measles made that a reasonable goal: It is passed only among humans, with no known animal reservoir; natural infection grants lifelong immunity; there is only one serotype; the virus is genetically stable; the vaccine is safe and leads to 95%-97% seroconversion after two doses, which provides long-term protection against known genotypes; the disease is easily recognized and tested for; and it had been successfully eliminated already in some regions of the world.

As of 2017, analyses showed that the vaccination program saved the lives of about 1.5 million children. That was a cause for celebration, but the goal of eradication has remained elusive. Vaccination rates have trailed targets. In 2018, UNICEF and WHO estimated that 86% of children globally received the first measles vaccine, unchanged from 2010 and below the goal of 95%. Only 69% of children received the second dose, below the goal of 80%. Four countries in Europe lost their measles elimination status in 2018.

Other attempts to eradicate diseases have met with mixed results. The only full success was smallpox, eliminated in 1977. Similar efforts with polio, malaria, guinea worm, and now measles have all come up short. Those failures could complicate future efforts because global agencies and donors may be leery of past failures because of potential harm to their reputations, according to Dr. Hegde.

Such programs require sustained financial commitment and political support as well as local trust. Nevertheless, they must continue for ethical reasons, said Dr. Hegde, but also for economic ones: Every $1 spent on vaccination programs saves $58 in future costs in low- and middle-income countries. Missed childhood vaccination also results in future vulnerable teenagers and young adults, and these populations are much harder to reach and can drive large outbreaks.

Several factors are contributing to the global regression in vaccine coverage, according to Kristen Feemster, MD, MPH, a pediatric infectious disease physician and the global director of medical affairs at Merck. Globalization has enabled the spread of the disease. Most cases in the United States are imported by travelers to countries where the disease is endemic. “Measles can happen anywhere in the world, and when it does it can travel and spread. If you have an unvaccinated traveler who is exposed to measles abroad, they can return home and spread it to anyone else who is unvaccinated or not otherwise immune. When we see cases they’ve been sporadic, but if you return to a community where immunization rates are low, you have the potential for more sustained spread,” Dr. Feemster said during her presentation.

Why are so many travelers unvaccinated? A key reason is that vaccine hesitance is growing. Most affected individuals involved in outbreaks are unvaccinated, usually by choice rather than for medical reasons. Concerns continue over the measles vaccine and autism, growing out of the debunked studies of Andrew Wakefield. In one example, a Somali community in Minnesota experienced a higher than usual number of autism cases and parents sought reasons to explain it. They discovered the supposed connection between vaccination and autism, and Wakefield himself met with a group of them. The result was a drop in vaccination and, in 2011 and 2017, sizable measles outbreaks.

2020 has of course brought a fresh challenge to measles vaccine with the COVID-19 pandemic, which has reduced access to health care and shifted scientific and health care interest away from measles and other vaccine-preventable diseases. On the positive side, social distancing, mask wearing, and restricted movement are likely reducing exposure to measles, but reduced vaccination rates are likely to result in future outbreaks. “There’s been a significant decrease in rates for routine immunizations globally, so there’s a potential for yet another resurgence of measles and other vaccine-preventable diseases,” said Dr. Feemster.

Dr. Feemster is an employee of Merck. Dr. Anlar and Dr. Hegde did not disclose any relevant financial relationships.

After almost 2 decades of progress, the global state of measles vaccination and measles mortality is deteriorating. Vaccine hesitancy, natural disasters, geopolitical disruptions, and most recently the COVID-19 pandemic have combined to undermine efforts, which had aimed to eradicate measles by this year.

One of the most serious concerns of measles infection is its long-term neurological complications, including the fatal subacute sclerosing panencephalitis (SSPE) and measles inclusion-body encephalitis (MIBE), which is usually seen in immune deficient children. Although some efforts are being made to determine which patients might be most vulnerable to these outcomes, and to treat them, the best approach is still prevention and vaccination, according to Banu Anlar, MD, of Hacettepe University, Ankara, Turkey, who spoke during a session at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

Worldwide vaccination strategies have slipped in recent years, leading to upticks in measles cases and vaccination rates. As a result, in 2018 the World Health Organization postponed its goal of eliminating measles by 2020. Future eradication goals will likely need to be modified, according to Anaita Udwadia Hegde MD, a pediatric neurologist in Mumbai, India, who also presented at the session.

After measles deaths dropped 74% between 2000 and 2010, coinciding with widespread increases in vaccination, the WHO felt emboldened to deal the disease a knockout blow. In 2010, it held a Global Technical Consultation to determine the feasibility of an eradication campaign, which concluded it should be possible by 2020. Several characteristics of measles made that a reasonable goal: It is passed only among humans, with no known animal reservoir; natural infection grants lifelong immunity; there is only one serotype; the virus is genetically stable; the vaccine is safe and leads to 95%-97% seroconversion after two doses, which provides long-term protection against known genotypes; the disease is easily recognized and tested for; and it had been successfully eliminated already in some regions of the world.

As of 2017, analyses showed that the vaccination program saved the lives of about 1.5 million children. That was a cause for celebration, but the goal of eradication has remained elusive. Vaccination rates have trailed targets. In 2018, UNICEF and WHO estimated that 86% of children globally received the first measles vaccine, unchanged from 2010 and below the goal of 95%. Only 69% of children received the second dose, below the goal of 80%. Four countries in Europe lost their measles elimination status in 2018.

Other attempts to eradicate diseases have met with mixed results. The only full success was smallpox, eliminated in 1977. Similar efforts with polio, malaria, guinea worm, and now measles have all come up short. Those failures could complicate future efforts because global agencies and donors may be leery of past failures because of potential harm to their reputations, according to Dr. Hegde.

Such programs require sustained financial commitment and political support as well as local trust. Nevertheless, they must continue for ethical reasons, said Dr. Hegde, but also for economic ones: Every $1 spent on vaccination programs saves $58 in future costs in low- and middle-income countries. Missed childhood vaccination also results in future vulnerable teenagers and young adults, and these populations are much harder to reach and can drive large outbreaks.

Several factors are contributing to the global regression in vaccine coverage, according to Kristen Feemster, MD, MPH, a pediatric infectious disease physician and the global director of medical affairs at Merck. Globalization has enabled the spread of the disease. Most cases in the United States are imported by travelers to countries where the disease is endemic. “Measles can happen anywhere in the world, and when it does it can travel and spread. If you have an unvaccinated traveler who is exposed to measles abroad, they can return home and spread it to anyone else who is unvaccinated or not otherwise immune. When we see cases they’ve been sporadic, but if you return to a community where immunization rates are low, you have the potential for more sustained spread,” Dr. Feemster said during her presentation.

Why are so many travelers unvaccinated? A key reason is that vaccine hesitance is growing. Most affected individuals involved in outbreaks are unvaccinated, usually by choice rather than for medical reasons. Concerns continue over the measles vaccine and autism, growing out of the debunked studies of Andrew Wakefield. In one example, a Somali community in Minnesota experienced a higher than usual number of autism cases and parents sought reasons to explain it. They discovered the supposed connection between vaccination and autism, and Wakefield himself met with a group of them. The result was a drop in vaccination and, in 2011 and 2017, sizable measles outbreaks.

2020 has of course brought a fresh challenge to measles vaccine with the COVID-19 pandemic, which has reduced access to health care and shifted scientific and health care interest away from measles and other vaccine-preventable diseases. On the positive side, social distancing, mask wearing, and restricted movement are likely reducing exposure to measles, but reduced vaccination rates are likely to result in future outbreaks. “There’s been a significant decrease in rates for routine immunizations globally, so there’s a potential for yet another resurgence of measles and other vaccine-preventable diseases,” said Dr. Feemster.

Dr. Feemster is an employee of Merck. Dr. Anlar and Dr. Hegde did not disclose any relevant financial relationships.

After almost 2 decades of progress, the global state of measles vaccination and measles mortality is deteriorating. Vaccine hesitancy, natural disasters, geopolitical disruptions, and most recently the COVID-19 pandemic have combined to undermine efforts, which had aimed to eradicate measles by this year.

One of the most serious concerns of measles infection is its long-term neurological complications, including the fatal subacute sclerosing panencephalitis (SSPE) and measles inclusion-body encephalitis (MIBE), which is usually seen in immune deficient children. Although some efforts are being made to determine which patients might be most vulnerable to these outcomes, and to treat them, the best approach is still prevention and vaccination, according to Banu Anlar, MD, of Hacettepe University, Ankara, Turkey, who spoke during a session at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

Worldwide vaccination strategies have slipped in recent years, leading to upticks in measles cases and vaccination rates. As a result, in 2018 the World Health Organization postponed its goal of eliminating measles by 2020. Future eradication goals will likely need to be modified, according to Anaita Udwadia Hegde MD, a pediatric neurologist in Mumbai, India, who also presented at the session.

After measles deaths dropped 74% between 2000 and 2010, coinciding with widespread increases in vaccination, the WHO felt emboldened to deal the disease a knockout blow. In 2010, it held a Global Technical Consultation to determine the feasibility of an eradication campaign, which concluded it should be possible by 2020. Several characteristics of measles made that a reasonable goal: It is passed only among humans, with no known animal reservoir; natural infection grants lifelong immunity; there is only one serotype; the virus is genetically stable; the vaccine is safe and leads to 95%-97% seroconversion after two doses, which provides long-term protection against known genotypes; the disease is easily recognized and tested for; and it had been successfully eliminated already in some regions of the world.

As of 2017, analyses showed that the vaccination program saved the lives of about 1.5 million children. That was a cause for celebration, but the goal of eradication has remained elusive. Vaccination rates have trailed targets. In 2018, UNICEF and WHO estimated that 86% of children globally received the first measles vaccine, unchanged from 2010 and below the goal of 95%. Only 69% of children received the second dose, below the goal of 80%. Four countries in Europe lost their measles elimination status in 2018.

Other attempts to eradicate diseases have met with mixed results. The only full success was smallpox, eliminated in 1977. Similar efforts with polio, malaria, guinea worm, and now measles have all come up short. Those failures could complicate future efforts because global agencies and donors may be leery of past failures because of potential harm to their reputations, according to Dr. Hegde.

Such programs require sustained financial commitment and political support as well as local trust. Nevertheless, they must continue for ethical reasons, said Dr. Hegde, but also for economic ones: Every $1 spent on vaccination programs saves $58 in future costs in low- and middle-income countries. Missed childhood vaccination also results in future vulnerable teenagers and young adults, and these populations are much harder to reach and can drive large outbreaks.

Several factors are contributing to the global regression in vaccine coverage, according to Kristen Feemster, MD, MPH, a pediatric infectious disease physician and the global director of medical affairs at Merck. Globalization has enabled the spread of the disease. Most cases in the United States are imported by travelers to countries where the disease is endemic. “Measles can happen anywhere in the world, and when it does it can travel and spread. If you have an unvaccinated traveler who is exposed to measles abroad, they can return home and spread it to anyone else who is unvaccinated or not otherwise immune. When we see cases they’ve been sporadic, but if you return to a community where immunization rates are low, you have the potential for more sustained spread,” Dr. Feemster said during her presentation.

Why are so many travelers unvaccinated? A key reason is that vaccine hesitance is growing. Most affected individuals involved in outbreaks are unvaccinated, usually by choice rather than for medical reasons. Concerns continue over the measles vaccine and autism, growing out of the debunked studies of Andrew Wakefield. In one example, a Somali community in Minnesota experienced a higher than usual number of autism cases and parents sought reasons to explain it. They discovered the supposed connection between vaccination and autism, and Wakefield himself met with a group of them. The result was a drop in vaccination and, in 2011 and 2017, sizable measles outbreaks.

2020 has of course brought a fresh challenge to measles vaccine with the COVID-19 pandemic, which has reduced access to health care and shifted scientific and health care interest away from measles and other vaccine-preventable diseases. On the positive side, social distancing, mask wearing, and restricted movement are likely reducing exposure to measles, but reduced vaccination rates are likely to result in future outbreaks. “There’s been a significant decrease in rates for routine immunizations globally, so there’s a potential for yet another resurgence of measles and other vaccine-preventable diseases,” said Dr. Feemster.

Dr. Feemster is an employee of Merck. Dr. Anlar and Dr. Hegde did not disclose any relevant financial relationships.

In pediatric Crohn’s disease, a Clostridioides difficile infection detected within the first year after diagnosis is associated with a shorter time to first bowel resection surgery, according to a study that included both a retrospective and prospective analysis. The researchers also found evidence that changes in methionine biosynthesis and depletion of beneficial bacteria may contribute to risk of surgery.

C. difficile infection (CDI) disproportionately affects individuals with inflammatory bowel disease (IBD). Pediatric IBD patients have a 34% risk of recurrent CDI infection, compared with 7.5% in the general population. Previous research found that adults with ulcerative colitis and CDI are at more risk of colectomy, but the finding has not been replicated in children.

In a study published in Inflammatory Bowel Diseases, researchers led by Jennifer Hellmann and Lee Denson of the University of Cincinnati conducted a single-center retrospective analysis of 75 pediatric Crohn’s disease patients. They also conducted a prospective study of 70 pediatric Crohn’s disease patients, using shotgun metagenome sequencing to examine the relationship between microbiota composition and C. difficile carriage or surgery history.

Nineteen percent of patients tested positive for C. difficile. Use of antibiotics was associated with C. difficile (odds ratio, 7.9; P = .02). Of patients who underwent C. difficile testing in the first year, 23 went on to have surgery: 21% who were C. difficile negative required surgery, compared with 67% of those who were positive (hazard ratio, 4.4; P = .0003). The mean time to surgery was 527 days for C. difficile–positive patients and 1,268 days for those who were negative.

A multivariate regression analysis on 54 patients with complete data sets showed that the presence of C. difficile was associated with increased risk of surgery (OR, 16.2; P = .0006). When the analysis was run on all 73 patients, using null value for missing data, the results were similar (OR, 9.17; P = .008).

Shotgun sequencing found that 47 of 114 bacterial species that were associated with the presence of C. difficile were also associated with prior surgery for Crohn’s disease. Species included some that may play a role in mucosal homeostasis, such as Bifidobacterium breve and several Alistipes and Ruminococcus species. That suggests that a reduction in the numbers of these taxa may be associated with C. difficile presence and surgical risk.

The researchers also found that methionine synthesis pathways were depressed in C. difficile–positive and surgery patients. Methionine may bolster antioxidant capacity and improve villus morphology. IBD patients with dysbiosis and those experiencing Crohn’s disease exacerbations have been shown to have decreased methionine pathway activity, suggesting methionine biosynthesis changes have clinical relevance.

The study was funded by the National Institutes of Health.

SOURCE: Hellmann J et al. Inflamm Bowel Dis. 2020. doi: 10.1093/ibd/izz263.

In pediatric Crohn’s disease, a Clostridioides difficile infection detected within the first year after diagnosis is associated with a shorter time to first bowel resection surgery, according to a study that included both a retrospective and prospective analysis. The researchers also found evidence that changes in methionine biosynthesis and depletion of beneficial bacteria may contribute to risk of surgery.

C. difficile infection (CDI) disproportionately affects individuals with inflammatory bowel disease (IBD). Pediatric IBD patients have a 34% risk of recurrent CDI infection, compared with 7.5% in the general population. Previous research found that adults with ulcerative colitis and CDI are at more risk of colectomy, but the finding has not been replicated in children.

In a study published in Inflammatory Bowel Diseases, researchers led by Jennifer Hellmann and Lee Denson of the University of Cincinnati conducted a single-center retrospective analysis of 75 pediatric Crohn’s disease patients. They also conducted a prospective study of 70 pediatric Crohn’s disease patients, using shotgun metagenome sequencing to examine the relationship between microbiota composition and C. difficile carriage or surgery history.

Nineteen percent of patients tested positive for C. difficile. Use of antibiotics was associated with C. difficile (odds ratio, 7.9; P = .02). Of patients who underwent C. difficile testing in the first year, 23 went on to have surgery: 21% who were C. difficile negative required surgery, compared with 67% of those who were positive (hazard ratio, 4.4; P = .0003). The mean time to surgery was 527 days for C. difficile–positive patients and 1,268 days for those who were negative.

A multivariate regression analysis on 54 patients with complete data sets showed that the presence of C. difficile was associated with increased risk of surgery (OR, 16.2; P = .0006). When the analysis was run on all 73 patients, using null value for missing data, the results were similar (OR, 9.17; P = .008).

Shotgun sequencing found that 47 of 114 bacterial species that were associated with the presence of C. difficile were also associated with prior surgery for Crohn’s disease. Species included some that may play a role in mucosal homeostasis, such as Bifidobacterium breve and several Alistipes and Ruminococcus species. That suggests that a reduction in the numbers of these taxa may be associated with C. difficile presence and surgical risk.

The researchers also found that methionine synthesis pathways were depressed in C. difficile–positive and surgery patients. Methionine may bolster antioxidant capacity and improve villus morphology. IBD patients with dysbiosis and those experiencing Crohn’s disease exacerbations have been shown to have decreased methionine pathway activity, suggesting methionine biosynthesis changes have clinical relevance.

The study was funded by the National Institutes of Health.

SOURCE: Hellmann J et al. Inflamm Bowel Dis. 2020. doi: 10.1093/ibd/izz263.

In pediatric Crohn’s disease, a Clostridioides difficile infection detected within the first year after diagnosis is associated with a shorter time to first bowel resection surgery, according to a study that included both a retrospective and prospective analysis. The researchers also found evidence that changes in methionine biosynthesis and depletion of beneficial bacteria may contribute to risk of surgery.

C. difficile infection (CDI) disproportionately affects individuals with inflammatory bowel disease (IBD). Pediatric IBD patients have a 34% risk of recurrent CDI infection, compared with 7.5% in the general population. Previous research found that adults with ulcerative colitis and CDI are at more risk of colectomy, but the finding has not been replicated in children.

In a study published in Inflammatory Bowel Diseases, researchers led by Jennifer Hellmann and Lee Denson of the University of Cincinnati conducted a single-center retrospective analysis of 75 pediatric Crohn’s disease patients. They also conducted a prospective study of 70 pediatric Crohn’s disease patients, using shotgun metagenome sequencing to examine the relationship between microbiota composition and C. difficile carriage or surgery history.

Nineteen percent of patients tested positive for C. difficile. Use of antibiotics was associated with C. difficile (odds ratio, 7.9; P = .02). Of patients who underwent C. difficile testing in the first year, 23 went on to have surgery: 21% who were C. difficile negative required surgery, compared with 67% of those who were positive (hazard ratio, 4.4; P = .0003). The mean time to surgery was 527 days for C. difficile–positive patients and 1,268 days for those who were negative.

A multivariate regression analysis on 54 patients with complete data sets showed that the presence of C. difficile was associated with increased risk of surgery (OR, 16.2; P = .0006). When the analysis was run on all 73 patients, using null value for missing data, the results were similar (OR, 9.17; P = .008).

Shotgun sequencing found that 47 of 114 bacterial species that were associated with the presence of C. difficile were also associated with prior surgery for Crohn’s disease. Species included some that may play a role in mucosal homeostasis, such as Bifidobacterium breve and several Alistipes and Ruminococcus species. That suggests that a reduction in the numbers of these taxa may be associated with C. difficile presence and surgical risk.

The researchers also found that methionine synthesis pathways were depressed in C. difficile–positive and surgery patients. Methionine may bolster antioxidant capacity and improve villus morphology. IBD patients with dysbiosis and those experiencing Crohn’s disease exacerbations have been shown to have decreased methionine pathway activity, suggesting methionine biosynthesis changes have clinical relevance.

The study was funded by the National Institutes of Health.

SOURCE: Hellmann J et al. Inflamm Bowel Dis. 2020. doi: 10.1093/ibd/izz263.

Vancomycin followed by fecal microbiota transplant (FMT) was associated with reduced Clostridioides difficile (C. diff)-related mortality in patients hospitalized with refractory severe or fulminant C. diff infection (CDI) at a single center. The improvements came after Indiana University implemented an FMT option in 2013.

About 8% of C. diff patients develop severe or fulminant CDI (SFCDI), which can lead to toxic colon and multiorgan failure. Surgery is the current recommended treatment for these patients if they are refractory to vancomycin, but 30-day mortality is above 40%. FMT is recommended for recurrent CDI, and it achieves cure rates greater than 80%, along with fewer relapses compared with anti-CDI antibiotic therapy.

FMT has been shown to be effective for SFCDI, with a 91% cure rate for serious CDI and 66% for fulminant CDI.

In the study published in the September issue of Clinical Gastroenterology and Hepatology, researchers led by Yao-Wen Cheng, MD, and Monika Fischer, MD, of Indiana University, assessed the effect of FMT on SFCDI after their institution adopted it as a treatment protocol for SFCDI. Patients could receive FMT if there was evidence that their SFCDI was refractory, or if they had two or more CDI recurrences. The treatment includes oral vancomycin and pseudomembrane-driven sequential FMT.

Two hundred five patients were admitted before FMT implementation, 225 after. Fifty patients received FMT because of refractory SFCDI. A median of two FMTs was conducted per patient. 21 other patients received FMT for nonrefractory SFCDI or other conditions, including 18 patients with multiple recurrent CDI.

Thirty-day CDI-related mortality dropped after FMT implementation (4.4% versus 10.2%; P =.02). This was true in both the fulminant subset (9.1% versus 21.3%; P =.015) and the refractory group (12.1% versus 43.2%; P < .001).

The researchers used segmented logistic regression to determine if the improved outcomes could be due to nontreatment factors that varied over time, and found that the difference in CDI-related mortality was eliminated except for refractory SFCDI patients (odds of mortality after FMT implementation, 0.09; P =.023). There was no significant difference between those receiving non-CDI antibiotics (4.8%) and those who did not (6.9%; P =.75).

FMT was associated with lower frequency of CDI-related colectomy overall (2.7% versus 6.8%; P =.041), as well as in the fulminant (5.5% versus 15.7%; P =.017) and refractory subgroups (7.6% versus 31.8%; P =.001).

The findings follow another study that showed improved 3-month mortality for FMT among patients hospitalized with severe CDI (12.1% versus 42.2%; P < .003).

The results underscore the utility of FMT for SFCDI, and suggest it might have the most benefit in refractory SFCDI. The authors believe that FMT should be an alternative to colectomy when first-line anti-CDI antibiotics are partially or completely ineffective. In the absence of FMT, patients who go on to fail vancomycin or fidaxomicin will likely continue to be managed medically, with up to 80% mortality, or through salvage colectomy, with postsurgical morality rates of 30-40%.

Although a randomized trial could answer the question of FMT efficacy more definitively, it is unlikely to be conducted for ethical reasons.

“Further investigation is required to clearly define FMT’s role and timing in the clinical course of severe and fulminant CDI. However, our study suggests that FMT should be offered to patients with severe and fulminant CDI who do not respond to a 5-day course of anti-CDI antibiotics and may be considered in lieu of or before colectomy,” the researchers wrote.

No source of funding was disclosed.

SOURCE: Cheng YW et al. Clin Gastroenterol Hepatol. 2020;18:2234-43. doi: 10.1016/j.cgh.2019.12.029.

Vancomycin followed by fecal microbiota transplant (FMT) was associated with reduced Clostridioides difficile (C. diff)-related mortality in patients hospitalized with refractory severe or fulminant C. diff infection (CDI) at a single center. The improvements came after Indiana University implemented an FMT option in 2013.

About 8% of C. diff patients develop severe or fulminant CDI (SFCDI), which can lead to toxic colon and multiorgan failure. Surgery is the current recommended treatment for these patients if they are refractory to vancomycin, but 30-day mortality is above 40%. FMT is recommended for recurrent CDI, and it achieves cure rates greater than 80%, along with fewer relapses compared with anti-CDI antibiotic therapy.

FMT has been shown to be effective for SFCDI, with a 91% cure rate for serious CDI and 66% for fulminant CDI.

In the study published in the September issue of Clinical Gastroenterology and Hepatology, researchers led by Yao-Wen Cheng, MD, and Monika Fischer, MD, of Indiana University, assessed the effect of FMT on SFCDI after their institution adopted it as a treatment protocol for SFCDI. Patients could receive FMT if there was evidence that their SFCDI was refractory, or if they had two or more CDI recurrences. The treatment includes oral vancomycin and pseudomembrane-driven sequential FMT.

Two hundred five patients were admitted before FMT implementation, 225 after. Fifty patients received FMT because of refractory SFCDI. A median of two FMTs was conducted per patient. 21 other patients received FMT for nonrefractory SFCDI or other conditions, including 18 patients with multiple recurrent CDI.

Thirty-day CDI-related mortality dropped after FMT implementation (4.4% versus 10.2%; P =.02). This was true in both the fulminant subset (9.1% versus 21.3%; P =.015) and the refractory group (12.1% versus 43.2%; P < .001).

The researchers used segmented logistic regression to determine if the improved outcomes could be due to nontreatment factors that varied over time, and found that the difference in CDI-related mortality was eliminated except for refractory SFCDI patients (odds of mortality after FMT implementation, 0.09; P =.023). There was no significant difference between those receiving non-CDI antibiotics (4.8%) and those who did not (6.9%; P =.75).

FMT was associated with lower frequency of CDI-related colectomy overall (2.7% versus 6.8%; P =.041), as well as in the fulminant (5.5% versus 15.7%; P =.017) and refractory subgroups (7.6% versus 31.8%; P =.001).

The findings follow another study that showed improved 3-month mortality for FMT among patients hospitalized with severe CDI (12.1% versus 42.2%; P < .003).

The results underscore the utility of FMT for SFCDI, and suggest it might have the most benefit in refractory SFCDI. The authors believe that FMT should be an alternative to colectomy when first-line anti-CDI antibiotics are partially or completely ineffective. In the absence of FMT, patients who go on to fail vancomycin or fidaxomicin will likely continue to be managed medically, with up to 80% mortality, or through salvage colectomy, with postsurgical morality rates of 30-40%.

Although a randomized trial could answer the question of FMT efficacy more definitively, it is unlikely to be conducted for ethical reasons.

“Further investigation is required to clearly define FMT’s role and timing in the clinical course of severe and fulminant CDI. However, our study suggests that FMT should be offered to patients with severe and fulminant CDI who do not respond to a 5-day course of anti-CDI antibiotics and may be considered in lieu of or before colectomy,” the researchers wrote.

No source of funding was disclosed.

SOURCE: Cheng YW et al. Clin Gastroenterol Hepatol. 2020;18:2234-43. doi: 10.1016/j.cgh.2019.12.029.

Vancomycin followed by fecal microbiota transplant (FMT) was associated with reduced Clostridioides difficile (C. diff)-related mortality in patients hospitalized with refractory severe or fulminant C. diff infection (CDI) at a single center. The improvements came after Indiana University implemented an FMT option in 2013.

About 8% of C. diff patients develop severe or fulminant CDI (SFCDI), which can lead to toxic colon and multiorgan failure. Surgery is the current recommended treatment for these patients if they are refractory to vancomycin, but 30-day mortality is above 40%. FMT is recommended for recurrent CDI, and it achieves cure rates greater than 80%, along with fewer relapses compared with anti-CDI antibiotic therapy.

FMT has been shown to be effective for SFCDI, with a 91% cure rate for serious CDI and 66% for fulminant CDI.

In the study published in the September issue of Clinical Gastroenterology and Hepatology, researchers led by Yao-Wen Cheng, MD, and Monika Fischer, MD, of Indiana University, assessed the effect of FMT on SFCDI after their institution adopted it as a treatment protocol for SFCDI. Patients could receive FMT if there was evidence that their SFCDI was refractory, or if they had two or more CDI recurrences. The treatment includes oral vancomycin and pseudomembrane-driven sequential FMT.

Two hundred five patients were admitted before FMT implementation, 225 after. Fifty patients received FMT because of refractory SFCDI. A median of two FMTs was conducted per patient. 21 other patients received FMT for nonrefractory SFCDI or other conditions, including 18 patients with multiple recurrent CDI.

Thirty-day CDI-related mortality dropped after FMT implementation (4.4% versus 10.2%; P =.02). This was true in both the fulminant subset (9.1% versus 21.3%; P =.015) and the refractory group (12.1% versus 43.2%; P < .001).

The researchers used segmented logistic regression to determine if the improved outcomes could be due to nontreatment factors that varied over time, and found that the difference in CDI-related mortality was eliminated except for refractory SFCDI patients (odds of mortality after FMT implementation, 0.09; P =.023). There was no significant difference between those receiving non-CDI antibiotics (4.8%) and those who did not (6.9%; P =.75).

FMT was associated with lower frequency of CDI-related colectomy overall (2.7% versus 6.8%; P =.041), as well as in the fulminant (5.5% versus 15.7%; P =.017) and refractory subgroups (7.6% versus 31.8%; P =.001).

The findings follow another study that showed improved 3-month mortality for FMT among patients hospitalized with severe CDI (12.1% versus 42.2%; P < .003).

The results underscore the utility of FMT for SFCDI, and suggest it might have the most benefit in refractory SFCDI. The authors believe that FMT should be an alternative to colectomy when first-line anti-CDI antibiotics are partially or completely ineffective. In the absence of FMT, patients who go on to fail vancomycin or fidaxomicin will likely continue to be managed medically, with up to 80% mortality, or through salvage colectomy, with postsurgical morality rates of 30-40%.

Although a randomized trial could answer the question of FMT efficacy more definitively, it is unlikely to be conducted for ethical reasons.

“Further investigation is required to clearly define FMT’s role and timing in the clinical course of severe and fulminant CDI. However, our study suggests that FMT should be offered to patients with severe and fulminant CDI who do not respond to a 5-day course of anti-CDI antibiotics and may be considered in lieu of or before colectomy,” the researchers wrote.

No source of funding was disclosed.

SOURCE: Cheng YW et al. Clin Gastroenterol Hepatol. 2020;18:2234-43. doi: 10.1016/j.cgh.2019.12.029.

The year 2020 has brought the COVID-19 pandemic and civil unrest and protests, which have resulted in unprecedented health care challenges to hospitals and clinics. The daunting prospect of a fall influenza season has hospital staff and administrators looking ahead to still greater challenges.

This year of crisis has put even greater emphasis on leadership in hospitals, as patients, clinicians, and staff look for direction in the face of uncertainty and stress. But hospital leaders often arrive at their positions unprepared for their roles, according to Leonard Marcus, PhD, director of the Program for Health Care Negotiation and Conflict Resolution at Harvard T.H. Chan School of Public Health, Boston.

“Many times what happens in medicine is that someone with the greatest technical skills or greatest clinical skills emerges to be leader of a department, or a group, or a hospital, without having really paid attention to how they can build their leadership skills,” Dr. Marcus said during the 2020 Society of Hospital Medicine Leadership Virtual Seminar, held online Sept. 16-17.

Over 2 days, Dr. Marcus discussed the complex environments faced by hospital leaders, and some of the tools and strategies that can be used to maintain calm, problem-solve, and chart a course ahead.

He emphasized that hospitals and medical systems are complex, nonlinear organizations, which could be swept up by change in the form of mergers, financial policies, patient surges due to local emergencies, or pandemics.

“Complexity has to be central to how you think about leadership. If you think you can control everything, that doesn’t work that well,” said Dr. Marcus.

Most think of leadership as hierarchical, with a boss on top and underlings below, though this is starting to change. Dr. Marcus suggested a different view. Instead of just “leading down” to those who report to them, leaders should consider “leading up” to their own bosses or oversight committees, and across to other departments or even beyond to interlinked organizations such as nursing homes.

“Being able to build that connectivity not only within your hospital, but beyond your hospital, lets you see the chain that goes through the experience of any patient. You are looking at the problem from a much wider lens. We call this meta-leadership,” Dr. Marcus said.

A key focus of meta-leadership is to create a culture where individuals are working together to help one another succeed. Leadership in hospitals is often dominated by egos, with individual leaders battling one another in a win-lose effort, and this gets in the way of incorporating different perspectives into problem-solving.

Dr. Marcus used an example from previous seminars in which he instructed participants to arm wrestle the person sitting next to them. The goal was to attain as many pins as possible in 30 seconds. About half would fight as hard as they could, and achieve a few victories. The other half worked cooperatively, letting one person win, then the other, so that they could have 30 or 40 wins each. Dr. Marcus told the story of a young nurse who was paired up with a much stronger surgeon. She let him win twice, and when he asked her why she wasn’t resisting, she took his arm and placed it in a winning position, then a losing position, and then a winning position again, and he instantly understood that the cooperative approach could be more effective. Why didn’t she just tell him? She told Dr. Marcus that she knew he wouldn’t take instruction, so she let him win and then demonstrated an alternative. “We nurses learned how to do that a long time ago,” she told Dr. Marcus.

The idea is collaborative problem-solving. “How do you orient people looking to you for leadership so that we’re in this together and we can accomplish a whole lot more in 30 seconds if we’re working together instead of always battling one another? If we’re always battling one another, we’re putting all of our effort into the contest,” said Dr. Marcus. This sort of approach is all the more important when facing the complexity experienced by hospital systems, especially during crises such as COVID-19.

A critical element of meta-leadership is emotional intelligence, which includes elements such as self-awareness, self-regulation, empathy, determining motivation of yourself and others, and the social skills to portray yourself as caring, open, and interested.

Emotional intelligence also can help recognize when you’ve entered survival mode in reaction to a crisis or incident, or something as simple as losing your car keys – what Dr. Marcus terms “going to the basement.” Responses revolve around freeze, fight, or flight. It’s helpful in the wake of a car accident, but not when trying to make managerial decisions or respond to a complex situation. It’s vital for leaders to quickly get themselves out of the basement, said Dr. Marcus, and that they help other members of the team get out as well.

He recommended protocols designed in advance, both to recognize when you’re in the basement, and to lift yourself out. Dr. Marcus uses a trigger script, telling himself “I can do this,” and then when he’s working with other people, “we can do this.” He also speaks slowly, measuring every word. Whatever you do, “it has to be a pivot you do to get yourself out of the basement,” he said. It can be helpful to predict the kinds of situations that send you “to the basement” to help recognize it when it has happened.

It’s very important not to lead, negotiate, or make important decisions while in the basement, according to Dr. Marcus. If one thinks about some of the things they’ve said to others while under duress, they are often some of the statements they regret most.
 

Practical leadership skills

On the second day of the Leadership Seminar, Dr. Marcus moved his focus to using leadership skills and techniques. One important technique is to incorporate multiple perspectives. He gave the example of an opaque cube with a cone inside it, with a window on the side and one on top. Viewers from the side see the cone in profile, and see it as a triangle. Viewers from the top see an aerial perspective that looks like the circular base of the cone. The two groups could argue about what’s inside the cube, but they can only identify the object if they work together.

“When dealing with complex reality, you oftentimes find there are different people with different perspectives on a problem. They may have different experiences of what the problem is, and what often happens is that people get into an adversarial fight. Looking at the problem from different perspectives actually allows a much richer and more comprehensive view,” said Dr. Marcus.

The metaphor comes from a study of the tragic events at the Twin Towers in Manhattan on Sept. 11, 2001. The New York Fire Department had a command center at the base of the building, while the police had a helicopter flying around the buildings. The helicopter could see the steel girders beginning to melt and predicted a collapse, and therefore ordered their personnel out of the buildings. But they were unable to convey that information to the firefighters, who continued to send personnel into the buildings. In all, 343 firefighters lost their lives. The police force lost 32.

To best understand a problem, a key element is the “unknown knowns.” That is, information that is available, that someone has, but is unknown to you. It takes some imagination to conceive of what “unknown knowns” might be out there, but it’s worth the effort to identify possible knowledge sources. It’s vital to seek out this information, because a common leadership mistake is to assume you know something when you really don’t.

“In many ways what you’re doing is looking for obstacles. It could be you don’t have access to the information, that it’s beyond some sort of curtain you need to overcome, or it could be people in your own department who have the information and they’re not sharing it with you,” Dr. Marcus said.

He outlined a tool called the POP-DOC loop, which is a 6-step exercise designed to analyze problems and implement solutions. Step 1 is Perceiving the situation, determining knowns and unknowns, and incorporating multiple perspectives, emotions, and politics. Step 2 is to Orient oneself: examine patterns and how they may replicate themselves as long as conditions don’t change. For example, during COVID-19, physicians have begun to learn how the virus transmits and how it affects the immune system. Step 3, based on those patterns is to make Predictions. With COVID-19, it’s predictable that people who assemble without wearing masks are vulnerable to transmission. Step 4 is to use the predictions to begin to make Decisions. Step 5 is to begin Operationalizing those decisions, and step 6 is to Communicate those decisions effectively.

Dr. Marcus emphasized that POP-DOC is not a one-time exercise. Once decisions have been made and implemented, if they aren’t having the planned effect, it’s important to incorporate the results of those actions and start right back at the beginning of the POP-DOC loop.

“The POP side of the loop is perceiving, analysis. You get out of the basement and understand the situation that surrounds you. On the DOC side, you lead down, lead up, lead across and lead beyond. You’re bringing people into the action to get things done,” Dr. Marcus said.

Another tool Dr. Marcus described, aimed at problem-solving and negotiation, is the “Walk in the Woods.” The idea is to bring two parties together to help each other succeed. The first step is Self-Interest, where both parties articulate their objectives, perspectives, and fears. The second step, Enlarged Interests, requires each party to list their points of agreement, and only then should they focus on and list their points of disagreement. During conflict, people tend to focus on their disagreements. The parties often find that they agree on more than they realize, and this can frame the disagreements as more manageable. The third step, Enlightened Interest, is a free thinking period where both parties come up with potential solutions that had not been previously considered. In step 4, Aligned Interests, the parties discuss some of those ideas that can be explored further.

The Walk in the Woods is applicable to a wide range of situations, and negotiation is central to being a leader. “Being a clinician is all about negotiating – with patients, family members, with other clinicians, with the institution,” Dr. Marcus said. “We all want the patient to have the best possible care, and in the course of those conversations if we can better understand people, have empathy, and if there are new ideas or ways we can individualize our care, let’s do it, and then at the end of the day combine our motivations so that we’re providing the best possible care.”

In the end, meta-leadership is about creating a culture where individuals strive to help each other succeed, said Dr. Marcus. “That’s the essence: involving people, making them part of the solution, and if it’s a solution they’ve created together, everyone wants to make that solution a success.”

For more information, see the book “You’re It,” coauthored by Dr. Marcus, and available on Amazon for $16.99 in hardback, or $3.99 in Kindle format.

The year 2020 has brought the COVID-19 pandemic and civil unrest and protests, which have resulted in unprecedented health care challenges to hospitals and clinics. The daunting prospect of a fall influenza season has hospital staff and administrators looking ahead to still greater challenges.

This year of crisis has put even greater emphasis on leadership in hospitals, as patients, clinicians, and staff look for direction in the face of uncertainty and stress. But hospital leaders often arrive at their positions unprepared for their roles, according to Leonard Marcus, PhD, director of the Program for Health Care Negotiation and Conflict Resolution at Harvard T.H. Chan School of Public Health, Boston.

“Many times what happens in medicine is that someone with the greatest technical skills or greatest clinical skills emerges to be leader of a department, or a group, or a hospital, without having really paid attention to how they can build their leadership skills,” Dr. Marcus said during the 2020 Society of Hospital Medicine Leadership Virtual Seminar, held online Sept. 16-17.

Over 2 days, Dr. Marcus discussed the complex environments faced by hospital leaders, and some of the tools and strategies that can be used to maintain calm, problem-solve, and chart a course ahead.

He emphasized that hospitals and medical systems are complex, nonlinear organizations, which could be swept up by change in the form of mergers, financial policies, patient surges due to local emergencies, or pandemics.

“Complexity has to be central to how you think about leadership. If you think you can control everything, that doesn’t work that well,” said Dr. Marcus.

Most think of leadership as hierarchical, with a boss on top and underlings below, though this is starting to change. Dr. Marcus suggested a different view. Instead of just “leading down” to those who report to them, leaders should consider “leading up” to their own bosses or oversight committees, and across to other departments or even beyond to interlinked organizations such as nursing homes.

“Being able to build that connectivity not only within your hospital, but beyond your hospital, lets you see the chain that goes through the experience of any patient. You are looking at the problem from a much wider lens. We call this meta-leadership,” Dr. Marcus said.

A key focus of meta-leadership is to create a culture where individuals are working together to help one another succeed. Leadership in hospitals is often dominated by egos, with individual leaders battling one another in a win-lose effort, and this gets in the way of incorporating different perspectives into problem-solving.

Dr. Marcus used an example from previous seminars in which he instructed participants to arm wrestle the person sitting next to them. The goal was to attain as many pins as possible in 30 seconds. About half would fight as hard as they could, and achieve a few victories. The other half worked cooperatively, letting one person win, then the other, so that they could have 30 or 40 wins each. Dr. Marcus told the story of a young nurse who was paired up with a much stronger surgeon. She let him win twice, and when he asked her why she wasn’t resisting, she took his arm and placed it in a winning position, then a losing position, and then a winning position again, and he instantly understood that the cooperative approach could be more effective. Why didn’t she just tell him? She told Dr. Marcus that she knew he wouldn’t take instruction, so she let him win and then demonstrated an alternative. “We nurses learned how to do that a long time ago,” she told Dr. Marcus.

The idea is collaborative problem-solving. “How do you orient people looking to you for leadership so that we’re in this together and we can accomplish a whole lot more in 30 seconds if we’re working together instead of always battling one another? If we’re always battling one another, we’re putting all of our effort into the contest,” said Dr. Marcus. This sort of approach is all the more important when facing the complexity experienced by hospital systems, especially during crises such as COVID-19.

A critical element of meta-leadership is emotional intelligence, which includes elements such as self-awareness, self-regulation, empathy, determining motivation of yourself and others, and the social skills to portray yourself as caring, open, and interested.

Emotional intelligence also can help recognize when you’ve entered survival mode in reaction to a crisis or incident, or something as simple as losing your car keys – what Dr. Marcus terms “going to the basement.” Responses revolve around freeze, fight, or flight. It’s helpful in the wake of a car accident, but not when trying to make managerial decisions or respond to a complex situation. It’s vital for leaders to quickly get themselves out of the basement, said Dr. Marcus, and that they help other members of the team get out as well.

He recommended protocols designed in advance, both to recognize when you’re in the basement, and to lift yourself out. Dr. Marcus uses a trigger script, telling himself “I can do this,” and then when he’s working with other people, “we can do this.” He also speaks slowly, measuring every word. Whatever you do, “it has to be a pivot you do to get yourself out of the basement,” he said. It can be helpful to predict the kinds of situations that send you “to the basement” to help recognize it when it has happened.

It’s very important not to lead, negotiate, or make important decisions while in the basement, according to Dr. Marcus. If one thinks about some of the things they’ve said to others while under duress, they are often some of the statements they regret most.
 

Practical leadership skills

On the second day of the Leadership Seminar, Dr. Marcus moved his focus to using leadership skills and techniques. One important technique is to incorporate multiple perspectives. He gave the example of an opaque cube with a cone inside it, with a window on the side and one on top. Viewers from the side see the cone in profile, and see it as a triangle. Viewers from the top see an aerial perspective that looks like the circular base of the cone. The two groups could argue about what’s inside the cube, but they can only identify the object if they work together.

“When dealing with complex reality, you oftentimes find there are different people with different perspectives on a problem. They may have different experiences of what the problem is, and what often happens is that people get into an adversarial fight. Looking at the problem from different perspectives actually allows a much richer and more comprehensive view,” said Dr. Marcus.

The metaphor comes from a study of the tragic events at the Twin Towers in Manhattan on Sept. 11, 2001. The New York Fire Department had a command center at the base of the building, while the police had a helicopter flying around the buildings. The helicopter could see the steel girders beginning to melt and predicted a collapse, and therefore ordered their personnel out of the buildings. But they were unable to convey that information to the firefighters, who continued to send personnel into the buildings. In all, 343 firefighters lost their lives. The police force lost 32.

To best understand a problem, a key element is the “unknown knowns.” That is, information that is available, that someone has, but is unknown to you. It takes some imagination to conceive of what “unknown knowns” might be out there, but it’s worth the effort to identify possible knowledge sources. It’s vital to seek out this information, because a common leadership mistake is to assume you know something when you really don’t.

“In many ways what you’re doing is looking for obstacles. It could be you don’t have access to the information, that it’s beyond some sort of curtain you need to overcome, or it could be people in your own department who have the information and they’re not sharing it with you,” Dr. Marcus said.

He outlined a tool called the POP-DOC loop, which is a 6-step exercise designed to analyze problems and implement solutions. Step 1 is Perceiving the situation, determining knowns and unknowns, and incorporating multiple perspectives, emotions, and politics. Step 2 is to Orient oneself: examine patterns and how they may replicate themselves as long as conditions don’t change. For example, during COVID-19, physicians have begun to learn how the virus transmits and how it affects the immune system. Step 3, based on those patterns is to make Predictions. With COVID-19, it’s predictable that people who assemble without wearing masks are vulnerable to transmission. Step 4 is to use the predictions to begin to make Decisions. Step 5 is to begin Operationalizing those decisions, and step 6 is to Communicate those decisions effectively.

Dr. Marcus emphasized that POP-DOC is not a one-time exercise. Once decisions have been made and implemented, if they aren’t having the planned effect, it’s important to incorporate the results of those actions and start right back at the beginning of the POP-DOC loop.

“The POP side of the loop is perceiving, analysis. You get out of the basement and understand the situation that surrounds you. On the DOC side, you lead down, lead up, lead across and lead beyond. You’re bringing people into the action to get things done,” Dr. Marcus said.

Another tool Dr. Marcus described, aimed at problem-solving and negotiation, is the “Walk in the Woods.” The idea is to bring two parties together to help each other succeed. The first step is Self-Interest, where both parties articulate their objectives, perspectives, and fears. The second step, Enlarged Interests, requires each party to list their points of agreement, and only then should they focus on and list their points of disagreement. During conflict, people tend to focus on their disagreements. The parties often find that they agree on more than they realize, and this can frame the disagreements as more manageable. The third step, Enlightened Interest, is a free thinking period where both parties come up with potential solutions that had not been previously considered. In step 4, Aligned Interests, the parties discuss some of those ideas that can be explored further.

The Walk in the Woods is applicable to a wide range of situations, and negotiation is central to being a leader. “Being a clinician is all about negotiating – with patients, family members, with other clinicians, with the institution,” Dr. Marcus said. “We all want the patient to have the best possible care, and in the course of those conversations if we can better understand people, have empathy, and if there are new ideas or ways we can individualize our care, let’s do it, and then at the end of the day combine our motivations so that we’re providing the best possible care.”

In the end, meta-leadership is about creating a culture where individuals strive to help each other succeed, said Dr. Marcus. “That’s the essence: involving people, making them part of the solution, and if it’s a solution they’ve created together, everyone wants to make that solution a success.”

For more information, see the book “You’re It,” coauthored by Dr. Marcus, and available on Amazon for $16.99 in hardback, or $3.99 in Kindle format.

The year 2020 has brought the COVID-19 pandemic and civil unrest and protests, which have resulted in unprecedented health care challenges to hospitals and clinics. The daunting prospect of a fall influenza season has hospital staff and administrators looking ahead to still greater challenges.

This year of crisis has put even greater emphasis on leadership in hospitals, as patients, clinicians, and staff look for direction in the face of uncertainty and stress. But hospital leaders often arrive at their positions unprepared for their roles, according to Leonard Marcus, PhD, director of the Program for Health Care Negotiation and Conflict Resolution at Harvard T.H. Chan School of Public Health, Boston.

“Many times what happens in medicine is that someone with the greatest technical skills or greatest clinical skills emerges to be leader of a department, or a group, or a hospital, without having really paid attention to how they can build their leadership skills,” Dr. Marcus said during the 2020 Society of Hospital Medicine Leadership Virtual Seminar, held online Sept. 16-17.

Over 2 days, Dr. Marcus discussed the complex environments faced by hospital leaders, and some of the tools and strategies that can be used to maintain calm, problem-solve, and chart a course ahead.

He emphasized that hospitals and medical systems are complex, nonlinear organizations, which could be swept up by change in the form of mergers, financial policies, patient surges due to local emergencies, or pandemics.

“Complexity has to be central to how you think about leadership. If you think you can control everything, that doesn’t work that well,” said Dr. Marcus.

Most think of leadership as hierarchical, with a boss on top and underlings below, though this is starting to change. Dr. Marcus suggested a different view. Instead of just “leading down” to those who report to them, leaders should consider “leading up” to their own bosses or oversight committees, and across to other departments or even beyond to interlinked organizations such as nursing homes.

“Being able to build that connectivity not only within your hospital, but beyond your hospital, lets you see the chain that goes through the experience of any patient. You are looking at the problem from a much wider lens. We call this meta-leadership,” Dr. Marcus said.

A key focus of meta-leadership is to create a culture where individuals are working together to help one another succeed. Leadership in hospitals is often dominated by egos, with individual leaders battling one another in a win-lose effort, and this gets in the way of incorporating different perspectives into problem-solving.

Dr. Marcus used an example from previous seminars in which he instructed participants to arm wrestle the person sitting next to them. The goal was to attain as many pins as possible in 30 seconds. About half would fight as hard as they could, and achieve a few victories. The other half worked cooperatively, letting one person win, then the other, so that they could have 30 or 40 wins each. Dr. Marcus told the story of a young nurse who was paired up with a much stronger surgeon. She let him win twice, and when he asked her why she wasn’t resisting, she took his arm and placed it in a winning position, then a losing position, and then a winning position again, and he instantly understood that the cooperative approach could be more effective. Why didn’t she just tell him? She told Dr. Marcus that she knew he wouldn’t take instruction, so she let him win and then demonstrated an alternative. “We nurses learned how to do that a long time ago,” she told Dr. Marcus.

The idea is collaborative problem-solving. “How do you orient people looking to you for leadership so that we’re in this together and we can accomplish a whole lot more in 30 seconds if we’re working together instead of always battling one another? If we’re always battling one another, we’re putting all of our effort into the contest,” said Dr. Marcus. This sort of approach is all the more important when facing the complexity experienced by hospital systems, especially during crises such as COVID-19.

A critical element of meta-leadership is emotional intelligence, which includes elements such as self-awareness, self-regulation, empathy, determining motivation of yourself and others, and the social skills to portray yourself as caring, open, and interested.

Emotional intelligence also can help recognize when you’ve entered survival mode in reaction to a crisis or incident, or something as simple as losing your car keys – what Dr. Marcus terms “going to the basement.” Responses revolve around freeze, fight, or flight. It’s helpful in the wake of a car accident, but not when trying to make managerial decisions or respond to a complex situation. It’s vital for leaders to quickly get themselves out of the basement, said Dr. Marcus, and that they help other members of the team get out as well.

He recommended protocols designed in advance, both to recognize when you’re in the basement, and to lift yourself out. Dr. Marcus uses a trigger script, telling himself “I can do this,” and then when he’s working with other people, “we can do this.” He also speaks slowly, measuring every word. Whatever you do, “it has to be a pivot you do to get yourself out of the basement,” he said. It can be helpful to predict the kinds of situations that send you “to the basement” to help recognize it when it has happened.

It’s very important not to lead, negotiate, or make important decisions while in the basement, according to Dr. Marcus. If one thinks about some of the things they’ve said to others while under duress, they are often some of the statements they regret most.
 

Practical leadership skills

On the second day of the Leadership Seminar, Dr. Marcus moved his focus to using leadership skills and techniques. One important technique is to incorporate multiple perspectives. He gave the example of an opaque cube with a cone inside it, with a window on the side and one on top. Viewers from the side see the cone in profile, and see it as a triangle. Viewers from the top see an aerial perspective that looks like the circular base of the cone. The two groups could argue about what’s inside the cube, but they can only identify the object if they work together.

“When dealing with complex reality, you oftentimes find there are different people with different perspectives on a problem. They may have different experiences of what the problem is, and what often happens is that people get into an adversarial fight. Looking at the problem from different perspectives actually allows a much richer and more comprehensive view,” said Dr. Marcus.

The metaphor comes from a study of the tragic events at the Twin Towers in Manhattan on Sept. 11, 2001. The New York Fire Department had a command center at the base of the building, while the police had a helicopter flying around the buildings. The helicopter could see the steel girders beginning to melt and predicted a collapse, and therefore ordered their personnel out of the buildings. But they were unable to convey that information to the firefighters, who continued to send personnel into the buildings. In all, 343 firefighters lost their lives. The police force lost 32.

To best understand a problem, a key element is the “unknown knowns.” That is, information that is available, that someone has, but is unknown to you. It takes some imagination to conceive of what “unknown knowns” might be out there, but it’s worth the effort to identify possible knowledge sources. It’s vital to seek out this information, because a common leadership mistake is to assume you know something when you really don’t.

“In many ways what you’re doing is looking for obstacles. It could be you don’t have access to the information, that it’s beyond some sort of curtain you need to overcome, or it could be people in your own department who have the information and they’re not sharing it with you,” Dr. Marcus said.

He outlined a tool called the POP-DOC loop, which is a 6-step exercise designed to analyze problems and implement solutions. Step 1 is Perceiving the situation, determining knowns and unknowns, and incorporating multiple perspectives, emotions, and politics. Step 2 is to Orient oneself: examine patterns and how they may replicate themselves as long as conditions don’t change. For example, during COVID-19, physicians have begun to learn how the virus transmits and how it affects the immune system. Step 3, based on those patterns is to make Predictions. With COVID-19, it’s predictable that people who assemble without wearing masks are vulnerable to transmission. Step 4 is to use the predictions to begin to make Decisions. Step 5 is to begin Operationalizing those decisions, and step 6 is to Communicate those decisions effectively.

Dr. Marcus emphasized that POP-DOC is not a one-time exercise. Once decisions have been made and implemented, if they aren’t having the planned effect, it’s important to incorporate the results of those actions and start right back at the beginning of the POP-DOC loop.

“The POP side of the loop is perceiving, analysis. You get out of the basement and understand the situation that surrounds you. On the DOC side, you lead down, lead up, lead across and lead beyond. You’re bringing people into the action to get things done,” Dr. Marcus said.

Another tool Dr. Marcus described, aimed at problem-solving and negotiation, is the “Walk in the Woods.” The idea is to bring two parties together to help each other succeed. The first step is Self-Interest, where both parties articulate their objectives, perspectives, and fears. The second step, Enlarged Interests, requires each party to list their points of agreement, and only then should they focus on and list their points of disagreement. During conflict, people tend to focus on their disagreements. The parties often find that they agree on more than they realize, and this can frame the disagreements as more manageable. The third step, Enlightened Interest, is a free thinking period where both parties come up with potential solutions that had not been previously considered. In step 4, Aligned Interests, the parties discuss some of those ideas that can be explored further.

The Walk in the Woods is applicable to a wide range of situations, and negotiation is central to being a leader. “Being a clinician is all about negotiating – with patients, family members, with other clinicians, with the institution,” Dr. Marcus said. “We all want the patient to have the best possible care, and in the course of those conversations if we can better understand people, have empathy, and if there are new ideas or ways we can individualize our care, let’s do it, and then at the end of the day combine our motivations so that we’re providing the best possible care.”

In the end, meta-leadership is about creating a culture where individuals strive to help each other succeed, said Dr. Marcus. “That’s the essence: involving people, making them part of the solution, and if it’s a solution they’ve created together, everyone wants to make that solution a success.”

For more information, see the book “You’re It,” coauthored by Dr. Marcus, and available on Amazon for $16.99 in hardback, or $3.99 in Kindle format.

Regular use of proton pump inhibitors (PPIs) is associated with an increased risk of type 2 diabetes, according to a large prospective analysis of the Nurses’ Health Study. The results follow on other studies suggesting other potential adverse effects of PPIs such as dementia, kidney damage, and micronutrient deficiencies.

The authors, led by Jinqiu Yuan and Changhua Zhang of Sun Yat-sen University (Guangdong, China), call for regular blood glucose testing and diabetes screening for patients on long-term PPIs. But not all are convinced. “I think that’s a strong recommendation from the available data and it’s unclear how oe who would implement that in practice. I think instead practitioners should adhere to best practices, which emphasize using the lowest effective dose of PPIs for patients with appropriate indications,” David Leiman, MD, MSHP, assistant professor of medicine at Duke University, Durham, N.C. said in an interview.

“Overall, the data from the study can be classified as provocative results that I think may warrant further study,” he added. Consistent and strongly positive findings from more observationsal studies would be required to establish causality between PPI use and diabetes risk, and in any case the findings of the surrent study don't warrant a change in practice, Dr. Leiman said, noting that the study’s design makes it likely that much or all of the observed associations were due to unmeasured confounding.

The study appeared online Sept. 28 in Gut.

The researchers analyzed data from 80,500 women from the Nurses’ Health Study, 95,550 women from the Nurses’ Health Study II, and 28,639 men from the Health Professionals Follow-up Study (HPFS), with a median follow-up time of 12 years in NHS and NHS2 and 9.8 years in HPFS.

The absolute risk of diabetes was 7.44 per 1,000 person-years in PPI users versus 4.32 among nonusers. After adjustment for lagging PPI use for 2 years and stratification by age and study period, PPI use was associated with a 74% increased risk of diabetes (hazard ratio , 1.74; 95% confidence interval, 1.37-2.20). Multivariable adjustment for demographic factors, lifestyle habits, comorbidities, and use of other medications and clinical indications for PPI use attenuated the association but did not eliminate it (HR, 1.24; 95% CI, 1.17-1.31).

There was no statistically significant association in the HPFS group (HR, 1.12; 95% CI, 0.91-1.38), possibly because of the smaller sample size.

At 1 year, the number needed to harm with PPIs was 318.9 (95% CI, 285.2-385.0). At 2 years it was 170.8 (95% CI, 150.8-209.7) and at 3 years it was 77.3 (95% CI, 66.8-97.0).

At 0-2 years, PPI use was associated with a 5% increase in diabetes risk (HR, 1.05; 95% CI, 0.93-1.19). More than 2 years of use was associated with higher risk (HR, 1.26; 95% CI, 1.18-1.35).

There was also an association between stopping PPI use and a decreased risk of diabetes: Compared with current PPI users, those who had stopped within the past 2 years had a 17% reduction in risk (HR, 0.83; 95% CI, 0.70-0.98), and those who had stopped more than 2 years previously had a 19% reduction (HR, 0.81; 95% CI, 0.76-0.86).

The researchers also examined diabetes risk associated with use of H₂ receptor agonists (H₂RAs), since the drugs share clinical indications with PPIs. H₂RA use was also associated with a higher risk of diabetes (adjusted HR, 1.14; 95% CI, 1.07-1.23).

The researchers suggested that the fact that the less potent H₂RA inhibitors had a less pronounced association with diabetes risk supports the idea that acid suppression may be related to diabetes pathogenesis.

The authors also suggest that changes to the gut microbiota may underlie increased risk. PPI use has been shown to reduce gut microbiome diversity and alter its phenotype. Such changes could lead to weight gain, metabolic syndrome, and chronic liver disease, which could in turn heighten risk.

The study is limited by its observational nature, and lacked detailed information on dosage, frequency, and indications for PPI use.

SOURCE: Yuan J et al. Gut. 2020 Sep 28. doi: 10.1136/gutjnl-2020-322557.

This story was updated on 11/24/2020.

Help your patients understand the risks and benefits of long-term PPI use by sharing the AGA Clinical Practice Update patient companion at http://ow.ly/N1 

Regular use of proton pump inhibitors (PPIs) is associated with an increased risk of type 2 diabetes, according to a large prospective analysis of the Nurses’ Health Study. The results follow on other studies suggesting other potential adverse effects of PPIs such as dementia, kidney damage, and micronutrient deficiencies.

The authors, led by Jinqiu Yuan and Changhua Zhang of Sun Yat-sen University (Guangdong, China), call for regular blood glucose testing and diabetes screening for patients on long-term PPIs. But not all are convinced. “I think that’s a strong recommendation from the available data and it’s unclear how oe who would implement that in practice. I think instead practitioners should adhere to best practices, which emphasize using the lowest effective dose of PPIs for patients with appropriate indications,” David Leiman, MD, MSHP, assistant professor of medicine at Duke University, Durham, N.C. said in an interview.

“Overall, the data from the study can be classified as provocative results that I think may warrant further study,” he added. Consistent and strongly positive findings from more observationsal studies would be required to establish causality between PPI use and diabetes risk, and in any case the findings of the surrent study don't warrant a change in practice, Dr. Leiman said, noting that the study’s design makes it likely that much or all of the observed associations were due to unmeasured confounding.

The study appeared online Sept. 28 in Gut.

The researchers analyzed data from 80,500 women from the Nurses’ Health Study, 95,550 women from the Nurses’ Health Study II, and 28,639 men from the Health Professionals Follow-up Study (HPFS), with a median follow-up time of 12 years in NHS and NHS2 and 9.8 years in HPFS.

The absolute risk of diabetes was 7.44 per 1,000 person-years in PPI users versus 4.32 among nonusers. After adjustment for lagging PPI use for 2 years and stratification by age and study period, PPI use was associated with a 74% increased risk of diabetes (hazard ratio , 1.74; 95% confidence interval, 1.37-2.20). Multivariable adjustment for demographic factors, lifestyle habits, comorbidities, and use of other medications and clinical indications for PPI use attenuated the association but did not eliminate it (HR, 1.24; 95% CI, 1.17-1.31).

There was no statistically significant association in the HPFS group (HR, 1.12; 95% CI, 0.91-1.38), possibly because of the smaller sample size.

At 1 year, the number needed to harm with PPIs was 318.9 (95% CI, 285.2-385.0). At 2 years it was 170.8 (95% CI, 150.8-209.7) and at 3 years it was 77.3 (95% CI, 66.8-97.0).

At 0-2 years, PPI use was associated with a 5% increase in diabetes risk (HR, 1.05; 95% CI, 0.93-1.19). More than 2 years of use was associated with higher risk (HR, 1.26; 95% CI, 1.18-1.35).

There was also an association between stopping PPI use and a decreased risk of diabetes: Compared with current PPI users, those who had stopped within the past 2 years had a 17% reduction in risk (HR, 0.83; 95% CI, 0.70-0.98), and those who had stopped more than 2 years previously had a 19% reduction (HR, 0.81; 95% CI, 0.76-0.86).

The researchers also examined diabetes risk associated with use of H₂ receptor agonists (H₂RAs), since the drugs share clinical indications with PPIs. H₂RA use was also associated with a higher risk of diabetes (adjusted HR, 1.14; 95% CI, 1.07-1.23).

The researchers suggested that the fact that the less potent H₂RA inhibitors had a less pronounced association with diabetes risk supports the idea that acid suppression may be related to diabetes pathogenesis.

The authors also suggest that changes to the gut microbiota may underlie increased risk. PPI use has been shown to reduce gut microbiome diversity and alter its phenotype. Such changes could lead to weight gain, metabolic syndrome, and chronic liver disease, which could in turn heighten risk.

The study is limited by its observational nature, and lacked detailed information on dosage, frequency, and indications for PPI use.

SOURCE: Yuan J et al. Gut. 2020 Sep 28. doi: 10.1136/gutjnl-2020-322557.

This story was updated on 11/24/2020.

Help your patients understand the risks and benefits of long-term PPI use by sharing the AGA Clinical Practice Update patient companion at http://ow.ly/N1 

Regular use of proton pump inhibitors (PPIs) is associated with an increased risk of type 2 diabetes, according to a large prospective analysis of the Nurses’ Health Study. The results follow on other studies suggesting other potential adverse effects of PPIs such as dementia, kidney damage, and micronutrient deficiencies.

The authors, led by Jinqiu Yuan and Changhua Zhang of Sun Yat-sen University (Guangdong, China), call for regular blood glucose testing and diabetes screening for patients on long-term PPIs. But not all are convinced. “I think that’s a strong recommendation from the available data and it’s unclear how oe who would implement that in practice. I think instead practitioners should adhere to best practices, which emphasize using the lowest effective dose of PPIs for patients with appropriate indications,” David Leiman, MD, MSHP, assistant professor of medicine at Duke University, Durham, N.C. said in an interview.

“Overall, the data from the study can be classified as provocative results that I think may warrant further study,” he added. Consistent and strongly positive findings from more observationsal studies would be required to establish causality between PPI use and diabetes risk, and in any case the findings of the surrent study don't warrant a change in practice, Dr. Leiman said, noting that the study’s design makes it likely that much or all of the observed associations were due to unmeasured confounding.

The study appeared online Sept. 28 in Gut.

The researchers analyzed data from 80,500 women from the Nurses’ Health Study, 95,550 women from the Nurses’ Health Study II, and 28,639 men from the Health Professionals Follow-up Study (HPFS), with a median follow-up time of 12 years in NHS and NHS2 and 9.8 years in HPFS.

The absolute risk of diabetes was 7.44 per 1,000 person-years in PPI users versus 4.32 among nonusers. After adjustment for lagging PPI use for 2 years and stratification by age and study period, PPI use was associated with a 74% increased risk of diabetes (hazard ratio , 1.74; 95% confidence interval, 1.37-2.20). Multivariable adjustment for demographic factors, lifestyle habits, comorbidities, and use of other medications and clinical indications for PPI use attenuated the association but did not eliminate it (HR, 1.24; 95% CI, 1.17-1.31).

There was no statistically significant association in the HPFS group (HR, 1.12; 95% CI, 0.91-1.38), possibly because of the smaller sample size.

At 1 year, the number needed to harm with PPIs was 318.9 (95% CI, 285.2-385.0). At 2 years it was 170.8 (95% CI, 150.8-209.7) and at 3 years it was 77.3 (95% CI, 66.8-97.0).

At 0-2 years, PPI use was associated with a 5% increase in diabetes risk (HR, 1.05; 95% CI, 0.93-1.19). More than 2 years of use was associated with higher risk (HR, 1.26; 95% CI, 1.18-1.35).

There was also an association between stopping PPI use and a decreased risk of diabetes: Compared with current PPI users, those who had stopped within the past 2 years had a 17% reduction in risk (HR, 0.83; 95% CI, 0.70-0.98), and those who had stopped more than 2 years previously had a 19% reduction (HR, 0.81; 95% CI, 0.76-0.86).

The researchers also examined diabetes risk associated with use of H₂ receptor agonists (H₂RAs), since the drugs share clinical indications with PPIs. H₂RA use was also associated with a higher risk of diabetes (adjusted HR, 1.14; 95% CI, 1.07-1.23).

The researchers suggested that the fact that the less potent H₂RA inhibitors had a less pronounced association with diabetes risk supports the idea that acid suppression may be related to diabetes pathogenesis.

The authors also suggest that changes to the gut microbiota may underlie increased risk. PPI use has been shown to reduce gut microbiome diversity and alter its phenotype. Such changes could lead to weight gain, metabolic syndrome, and chronic liver disease, which could in turn heighten risk.

The study is limited by its observational nature, and lacked detailed information on dosage, frequency, and indications for PPI use.

SOURCE: Yuan J et al. Gut. 2020 Sep 28. doi: 10.1136/gutjnl-2020-322557.

This story was updated on 11/24/2020.

Help your patients understand the risks and benefits of long-term PPI use by sharing the AGA Clinical Practice Update patient companion at http://ow.ly/N1 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Regular use of proton pump inhibitors (PPIs) is associated with an increased risk of type 2 diabetes, according to a large prospective analysis of the Nurses’ Health Study. The results follow on other studies suggesting other potential adverse effects of PPIs such as dementia, kidney damage, and micronutrient deficiencies.

The authors, led by Jinqiu Yuan and Changhua Zhang of Sun Yat-sen University (Guangdong, China), call for regular blood glucose testing and diabetes screening for patients on long-term PPIs. But not all are convinced. “I think that’s a strong recommendation from the available data and it’s unclear how that would be put into practice. I think instead practitioners should adhere to best practices, which emphasize using the lowest effective dose of PPIs for patients with appropriate indications,” David Leiman, MD, MSHP, assistant professor of medicine at Duke University, Durham, N.C. said in an interview.

“Overall, the data from the study can be classified as provocative results that I think may warrant further study,” he added. Randomized, controlled trials or many more observational studies would be required to establish causality between PPI use and diabetes risk, and in any case the findings of the current study don’t warrant a change in practice, Dr. Leiman said, noting that the study’s design makes it likely that much or all of the observed associations were due to confounding.

The study appeared online Sept. 28 in Gut.

The researchers analyzed data from 80,500 women from the Nurses’ Health Study, 95,550 women from the Nurses’ Health Study II, and 28,639 men from the Health Professionals Follow-up Study (HPFS), with a median follow-up time of 12 years in NHS and NHS2 and 9.8 years in HPFS.

The absolute risk of diabetes was 7.44 per 1,000 person-years in PPI users versus 4.32 among nonusers. After adjustment for lagging PPI use for 2 years and stratification by age and study period, PPI use was associated with a 74% increased risk of diabetes (hazard ratio , 1.74; 95% confidence interval, 1.37-2.20). Multivariable adjustment for demographic factors, lifestyle habits, comorbidities, and use of other medications and clinical indications for PPI use attenuated the association but did not eliminate it (HR, 1.24; 95% CI, 1.17-1.31).

There was no statistically significant association in the HPFS group (HR, 1.12; 95% CI, 0.91-1.38), possibly because of the smaller sample size.

At 1 year, the number needed to harm with PPIs was 318.9 (95% CI, 285.2-385.0). At 2 years it was 170.8 (95% CI, 150.8-209.7) and at 3 years it was 77.3 (95% CI, 66.8-97.0).

At 0-2 years, PPI use was associated with a 5% increase in diabetes risk (HR, 1.05; 95% CI, 0.93-1.19). More than 2 years of use was associated with higher risk (HR, 1.26; 95% CI, 1.18-1.35).

There was also an association between stopping PPI use and a decreased risk of diabetes: Compared with current PPI users, those who had stopped within the past 2 years had a 17% reduction in risk (HR, 0.83; 95% CI, 0.70-0.98), and those who had stopped more than 2 years previously had a 19% reduction (HR, 0.81; 95% CI, 0.76-0.86).

The researchers also examined diabetes risk associated with use of H₂ receptor agonists (H₂RAs), since the drugs share clinical indications with PPIs. H₂RA use was also associated with a higher risk of diabetes (adjusted HR, 1.14; 95% CI, 1.07-1.23).

The researchers suggested that the fact that the less potent H₂RA inhibitors had a less pronounced association with diabetes risk supports the idea that acid suppression may be related to diabetes pathogenesis.

The authors also suggest that changes to the gut microbiota may underlie increased risk. PPI use has been shown to reduce gut microbiome diversity and alter its phenotype. Such changes could lead to weight gain, metabolic syndrome, and chronic liver disease, which could in turn heighten risk.

The study is limited by its observational nature, and lacked detailed information on dosage, frequency, and indications for PPI use.

SOURCE: Yuan J et al. Gut. 2020 Sep 28. doi: 10.1136/gutjnl-2020-322557.

Regular use of proton pump inhibitors (PPIs) is associated with an increased risk of type 2 diabetes, according to a large prospective analysis of the Nurses’ Health Study. The results follow on other studies suggesting other potential adverse effects of PPIs such as dementia, kidney damage, and micronutrient deficiencies.

The authors, led by Jinqiu Yuan and Changhua Zhang of Sun Yat-sen University (Guangdong, China), call for regular blood glucose testing and diabetes screening for patients on long-term PPIs. But not all are convinced. “I think that’s a strong recommendation from the available data and it’s unclear how that would be put into practice. I think instead practitioners should adhere to best practices, which emphasize using the lowest effective dose of PPIs for patients with appropriate indications,” David Leiman, MD, MSHP, assistant professor of medicine at Duke University, Durham, N.C. said in an interview.

“Overall, the data from the study can be classified as provocative results that I think may warrant further study,” he added. Randomized, controlled trials or many more observational studies would be required to establish causality between PPI use and diabetes risk, and in any case the findings of the current study don’t warrant a change in practice, Dr. Leiman said, noting that the study’s design makes it likely that much or all of the observed associations were due to confounding.

The study appeared online Sept. 28 in Gut.

The researchers analyzed data from 80,500 women from the Nurses’ Health Study, 95,550 women from the Nurses’ Health Study II, and 28,639 men from the Health Professionals Follow-up Study (HPFS), with a median follow-up time of 12 years in NHS and NHS2 and 9.8 years in HPFS.

The absolute risk of diabetes was 7.44 per 1,000 person-years in PPI users versus 4.32 among nonusers. After adjustment for lagging PPI use for 2 years and stratification by age and study period, PPI use was associated with a 74% increased risk of diabetes (hazard ratio , 1.74; 95% confidence interval, 1.37-2.20). Multivariable adjustment for demographic factors, lifestyle habits, comorbidities, and use of other medications and clinical indications for PPI use attenuated the association but did not eliminate it (HR, 1.24; 95% CI, 1.17-1.31).

There was no statistically significant association in the HPFS group (HR, 1.12; 95% CI, 0.91-1.38), possibly because of the smaller sample size.

At 1 year, the number needed to harm with PPIs was 318.9 (95% CI, 285.2-385.0). At 2 years it was 170.8 (95% CI, 150.8-209.7) and at 3 years it was 77.3 (95% CI, 66.8-97.0).

At 0-2 years, PPI use was associated with a 5% increase in diabetes risk (HR, 1.05; 95% CI, 0.93-1.19). More than 2 years of use was associated with higher risk (HR, 1.26; 95% CI, 1.18-1.35).

There was also an association between stopping PPI use and a decreased risk of diabetes: Compared with current PPI users, those who had stopped within the past 2 years had a 17% reduction in risk (HR, 0.83; 95% CI, 0.70-0.98), and those who had stopped more than 2 years previously had a 19% reduction (HR, 0.81; 95% CI, 0.76-0.86).

The researchers also examined diabetes risk associated with use of H₂ receptor agonists (H₂RAs), since the drugs share clinical indications with PPIs. H₂RA use was also associated with a higher risk of diabetes (adjusted HR, 1.14; 95% CI, 1.07-1.23).

The researchers suggested that the fact that the less potent H₂RA inhibitors had a less pronounced association with diabetes risk supports the idea that acid suppression may be related to diabetes pathogenesis.

The authors also suggest that changes to the gut microbiota may underlie increased risk. PPI use has been shown to reduce gut microbiome diversity and alter its phenotype. Such changes could lead to weight gain, metabolic syndrome, and chronic liver disease, which could in turn heighten risk.

The study is limited by its observational nature, and lacked detailed information on dosage, frequency, and indications for PPI use.

SOURCE: Yuan J et al. Gut. 2020 Sep 28. doi: 10.1136/gutjnl-2020-322557.

Regular use of proton pump inhibitors (PPIs) is associated with an increased risk of type 2 diabetes, according to a large prospective analysis of the Nurses’ Health Study. The results follow on other studies suggesting other potential adverse effects of PPIs such as dementia, kidney damage, and micronutrient deficiencies.

The authors, led by Jinqiu Yuan and Changhua Zhang of Sun Yat-sen University (Guangdong, China), call for regular blood glucose testing and diabetes screening for patients on long-term PPIs. But not all are convinced. “I think that’s a strong recommendation from the available data and it’s unclear how that would be put into practice. I think instead practitioners should adhere to best practices, which emphasize using the lowest effective dose of PPIs for patients with appropriate indications,” David Leiman, MD, MSHP, assistant professor of medicine at Duke University, Durham, N.C. said in an interview.

“Overall, the data from the study can be classified as provocative results that I think may warrant further study,” he added. Randomized, controlled trials or many more observational studies would be required to establish causality between PPI use and diabetes risk, and in any case the findings of the current study don’t warrant a change in practice, Dr. Leiman said, noting that the study’s design makes it likely that much or all of the observed associations were due to confounding.

The study appeared online Sept. 28 in Gut.

The researchers analyzed data from 80,500 women from the Nurses’ Health Study, 95,550 women from the Nurses’ Health Study II, and 28,639 men from the Health Professionals Follow-up Study (HPFS), with a median follow-up time of 12 years in NHS and NHS2 and 9.8 years in HPFS.

The absolute risk of diabetes was 7.44 per 1,000 person-years in PPI users versus 4.32 among nonusers. After adjustment for lagging PPI use for 2 years and stratification by age and study period, PPI use was associated with a 74% increased risk of diabetes (hazard ratio , 1.74; 95% confidence interval, 1.37-2.20). Multivariable adjustment for demographic factors, lifestyle habits, comorbidities, and use of other medications and clinical indications for PPI use attenuated the association but did not eliminate it (HR, 1.24; 95% CI, 1.17-1.31).

There was no statistically significant association in the HPFS group (HR, 1.12; 95% CI, 0.91-1.38), possibly because of the smaller sample size.

At 1 year, the number needed to harm with PPIs was 318.9 (95% CI, 285.2-385.0). At 2 years it was 170.8 (95% CI, 150.8-209.7) and at 3 years it was 77.3 (95% CI, 66.8-97.0).

At 0-2 years, PPI use was associated with a 5% increase in diabetes risk (HR, 1.05; 95% CI, 0.93-1.19). More than 2 years of use was associated with higher risk (HR, 1.26; 95% CI, 1.18-1.35).

There was also an association between stopping PPI use and a decreased risk of diabetes: Compared with current PPI users, those who had stopped within the past 2 years had a 17% reduction in risk (HR, 0.83; 95% CI, 0.70-0.98), and those who had stopped more than 2 years previously had a 19% reduction (HR, 0.81; 95% CI, 0.76-0.86).

The researchers also examined diabetes risk associated with use of H₂ receptor agonists (H₂RAs), since the drugs share clinical indications with PPIs. H₂RA use was also associated with a higher risk of diabetes (adjusted HR, 1.14; 95% CI, 1.07-1.23).

The researchers suggested that the fact that the less potent H₂RA inhibitors had a less pronounced association with diabetes risk supports the idea that acid suppression may be related to diabetes pathogenesis.

The authors also suggest that changes to the gut microbiota may underlie increased risk. PPI use has been shown to reduce gut microbiome diversity and alter its phenotype. Such changes could lead to weight gain, metabolic syndrome, and chronic liver disease, which could in turn heighten risk.

The study is limited by its observational nature, and lacked detailed information on dosage, frequency, and indications for PPI use.

SOURCE: Yuan J et al. Gut. 2020 Sep 28. doi: 10.1136/gutjnl-2020-322557.