Nathalie Raffier

In several countries, including China, Mexico, and the United States, the incidence of type 2 diabetes now exceeds that of type 1 diabetes among patients younger than 20 years.

“This is an emerging epidemic,” said Orit Pinhas-Hamiel, MD, director of the Pediatric Endocrinology and Diabetes Unit at Sheba Medical Center in Ramat Gan, Israel, at the annual meeting of the European Association for the Study of Diabetes, noting that these young patients, most with obesity, exhibit a significantly higher incidence of complications than adults with type 2 diabetes or young people with type 1 diabetes.

In 2017-2018, the incidence of type 2 diabetes among patients aged 15-19 years (19.7 per 100,000) surpassed that of type 1 diabetes (14.6 per 100,000), according to data from the United States.

“This is the first time that the incidence of type 2 diabetes has exceeded that of type 1 among youth,” said Pinhas-Hamiel. A review of 2021 published a few months ago highlighted this surge, with countries like China, India, the United States, Brazil, and Mexico leading the way.
 

SEARCH and TODAY

The SEARCH for Diabetes in Youth study, which was launched in 2000, is a multicenter observational study in the United States aimed at estimating the prevalence, incidence, and complications of types 1 and 2 diabetes among young patients. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is an interventional study focusing on adolescents with type 2 diabetes to evaluate the effectiveness of various treatment options.

“Diabesity” — the dual global epidemic of obesity and type 2 diabetes — has visible consequences from the moment of diagnosis, including hypertension. In the TODAY study, 11.6% adolescents had hypertension at diagnosis. A study conducted in Hong Kong involving 391 children younger than 18 years revealed that 22.5% had hypertension. In SEARCH, 27% young patients diagnosed with type 2 diabetes for 1.5 years had hypertension.

In addition, the SEARCH study found that 27% young individuals had low levels of high-density lipoprotein cholesterol, while 25% had high triglyceride levels, at 1.5 years after diagnosis.

Overall, the cumulative incidence of long-term diabetic complications was assessed in 500 adolescents participating in TODAY (mean age, 26.4 ± 2.8 years; mean time since diagnosis, 13.3 ± 1.8 years). The initial prevalence was 19.2%, while the cumulative incidence rose to 67.5% after 15 years of follow-up.

For dyslipidemia, the initial prevalence was 20.8%, with a cumulative incidence of 51.6%. The incidence of diabetic nephropathy was 54.8% and neuropathies was 32.4%. The prevalence of retinopathy was 13.7% for the period 2010-2011 and 51% for 2017-2018.

At least one complication was observed in 60.1% participants and at least two in 28.4%. As expected, risk factors for developing complications included belonging to a racial or ethnic minority, hyperglycemia, hypertension, and dyslipidemia.

“Among those who developed type 2 diabetes in adolescence, the risk for complications, including microvascular complications, has continuously increased and affected most participants in young adulthood,” said Pinhas-Hamiel.

At the same time, the rate of treatment with lipid-lowering and antihypertensive medications remains low among young people with type 2 diabetes. The management of dyslipidemia is suboptimal, with only 5% young patients with diabetes and dyslipidemia receiving appropriate medications. Furthermore, treatment adherence is lacking. In the TODAY cohort, for example, only one third of participants with high levels of low-density lipoprotein cholesterol were on lipid-lowering medications, and only half of the young patients with hypertension were taking antihypertensives.
 

Focus on Diabetic Nephropathy

Diabetic kidney disease is the leading microvascular complication of type 2 diabetes in adolescents. It is associated with rapid progression and poor prognosis. The natural history begins with hyperfiltration: A consequence of obesity and impaired glucose tolerance. Structural renal changes can be detected as early as 1.5 years after diagnosis.

The second stage is characterized by a reduction in the glomerular filtration rate. At this stage, “the structural changes in the kidney are typical but often present,” said Pinhas-Hamiel, making this period critical for reducing risk factors.

In TODAY, the cumulative incidence of diabetic nephropathy was 54.8%. The prevalence at inclusion was 8%. In SEARCH, after 8 years, the prevalence of diabetic kidney disease was 19.9% among adolescents with type 2 diabetes vs 5.8% among those with type 1 diabetes. A pre-analysis revealed that the overall prevalence of macroalbuminuria among 730 children and adolescents with type 2 diabetes was 3.8%. The ages at diagnosis of type 2 diabetes ranged from 6.5 to 21 years, and the duration of the disease varied from diagnosis to 15 years after.

Diabetic retinopathy was present in 50% participants in the TODAY study at age 25 years (ie, after 12 years of disease). In SEARCH, 56% young patients had diabetic retinopathy after 12.5 years of diabetes. In addition, in the same study, the prevalence of peripheral neuropathy, assessed after 8 years, was 22% among adolescents with type 2 diabetes vs 7% among those with type 1 diabetes.
 

Cardiovascular Autonomic Neuropathy

A decrease in heart rate variability was observed in 47% young patients with type 2 diabetes after an average disease duration of only 1.7 years. In SEARCH, the prevalence of cardiovascular autonomic neuropathy, assessed after 8 years of disease, was 17% in adolescents with type 2 diabetes versus 12% in those with type 1 diabetes.

Overall, 7.1% participants had three complications: nephropathy, retinopathy, and neuropathy. The cumulative incidence of microvascular complications was 80%.

Moreover, A1c levels deteriorated progressively throughout the follow-up period. Approximately 45% participants had an A1c of at least 10%, and 20% were between 8% and 10%. Body mass index consistently remained between 35 and 37.5.

Young patients with type 2 diabetes exhibit endothelial dysfunction, increased carotid intima-media thickness, elevated arterial stiffness, left ventricular hypertrophy, diastolic dysfunction, and reduced maximal exercise capacity. All these factors predict cardiovascular morbidity and mortality.

In TODAY, 17 serious cardiovascular events were recorded, including four myocardial infarctions, six cases of congestive heart failure, three coronary events, and four strokes.

In an analysis of the TODAY and SEARCH studies, although the average duration of diabetes was similar, complications were more frequent among young patients with type 2 diabetes than among those with type 1 diabetes. Microvascular complications were 2.5 times more frequent, and macrovascular complications were four times more frequent.

In SEARCH, excessive mortality was observed among young adults for each type of diabetes. Differences in risk were associated with diabetes type, age, race/ethnicity, and sex. Mortality ratios were 1.5 and 2.3 for types 1 and 2 diabetes, respectively.

Women had higher mortality rates than men. Diabetes was the underlying cause of death in 9.1% cases, which was comparable to cardiovascular diseases or cancer (10.9%). According to a life expectancy model, young patients with type 2 diabetes lose about 15 years of life.
 

Eating Disorders and Depression

Beyond these complications, other issues are often present among adolescents with type 2 diabetes. Approximately 50% have eating disorders (compared with 21% among those with type 1 diabetes), 19.3% report depressive symptoms, and 18.9% have expressed thoughts of self-harm. In addition, 19.6% have polycystic ovary syndrome. Z-scores for bone mineral density at the femoral neck and lumbar spine were significantly lower in adolescents with type 2 diabetes than in healthy peers. The presence of metabolic dysfunction–associated fatty liver disease is also more pronounced.

“The recent approvals of new pharmacological interventions for weight loss and improved glycemic control in adolescents offer hope. We hope that, over the next decade, the prevalence of complications among these young patients with type 2 diabetes will decline. In the meantime, a proactive approach is essential to prevent complications related to type 2 diabetes in these youth,” Pinhas-Hamiel concluded.

For more information, see ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 Diabetes in Children and Adolescents.

Pinhas-Hamiel reported no relevant financial relationships.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In several countries, including China, Mexico, and the United States, the incidence of type 2 diabetes now exceeds that of type 1 diabetes among patients younger than 20 years.

“This is an emerging epidemic,” said Orit Pinhas-Hamiel, MD, director of the Pediatric Endocrinology and Diabetes Unit at Sheba Medical Center in Ramat Gan, Israel, at the annual meeting of the European Association for the Study of Diabetes, noting that these young patients, most with obesity, exhibit a significantly higher incidence of complications than adults with type 2 diabetes or young people with type 1 diabetes.

In 2017-2018, the incidence of type 2 diabetes among patients aged 15-19 years (19.7 per 100,000) surpassed that of type 1 diabetes (14.6 per 100,000), according to data from the United States.

“This is the first time that the incidence of type 2 diabetes has exceeded that of type 1 among youth,” said Pinhas-Hamiel. A review of 2021 published a few months ago highlighted this surge, with countries like China, India, the United States, Brazil, and Mexico leading the way.
 

SEARCH and TODAY

The SEARCH for Diabetes in Youth study, which was launched in 2000, is a multicenter observational study in the United States aimed at estimating the prevalence, incidence, and complications of types 1 and 2 diabetes among young patients. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is an interventional study focusing on adolescents with type 2 diabetes to evaluate the effectiveness of various treatment options.

“Diabesity” — the dual global epidemic of obesity and type 2 diabetes — has visible consequences from the moment of diagnosis, including hypertension. In the TODAY study, 11.6% adolescents had hypertension at diagnosis. A study conducted in Hong Kong involving 391 children younger than 18 years revealed that 22.5% had hypertension. In SEARCH, 27% young patients diagnosed with type 2 diabetes for 1.5 years had hypertension.

In addition, the SEARCH study found that 27% young individuals had low levels of high-density lipoprotein cholesterol, while 25% had high triglyceride levels, at 1.5 years after diagnosis.

Overall, the cumulative incidence of long-term diabetic complications was assessed in 500 adolescents participating in TODAY (mean age, 26.4 ± 2.8 years; mean time since diagnosis, 13.3 ± 1.8 years). The initial prevalence was 19.2%, while the cumulative incidence rose to 67.5% after 15 years of follow-up.

For dyslipidemia, the initial prevalence was 20.8%, with a cumulative incidence of 51.6%. The incidence of diabetic nephropathy was 54.8% and neuropathies was 32.4%. The prevalence of retinopathy was 13.7% for the period 2010-2011 and 51% for 2017-2018.

At least one complication was observed in 60.1% participants and at least two in 28.4%. As expected, risk factors for developing complications included belonging to a racial or ethnic minority, hyperglycemia, hypertension, and dyslipidemia.

“Among those who developed type 2 diabetes in adolescence, the risk for complications, including microvascular complications, has continuously increased and affected most participants in young adulthood,” said Pinhas-Hamiel.

At the same time, the rate of treatment with lipid-lowering and antihypertensive medications remains low among young people with type 2 diabetes. The management of dyslipidemia is suboptimal, with only 5% young patients with diabetes and dyslipidemia receiving appropriate medications. Furthermore, treatment adherence is lacking. In the TODAY cohort, for example, only one third of participants with high levels of low-density lipoprotein cholesterol were on lipid-lowering medications, and only half of the young patients with hypertension were taking antihypertensives.
 

Focus on Diabetic Nephropathy

Diabetic kidney disease is the leading microvascular complication of type 2 diabetes in adolescents. It is associated with rapid progression and poor prognosis. The natural history begins with hyperfiltration: A consequence of obesity and impaired glucose tolerance. Structural renal changes can be detected as early as 1.5 years after diagnosis.

The second stage is characterized by a reduction in the glomerular filtration rate. At this stage, “the structural changes in the kidney are typical but often present,” said Pinhas-Hamiel, making this period critical for reducing risk factors.

In TODAY, the cumulative incidence of diabetic nephropathy was 54.8%. The prevalence at inclusion was 8%. In SEARCH, after 8 years, the prevalence of diabetic kidney disease was 19.9% among adolescents with type 2 diabetes vs 5.8% among those with type 1 diabetes. A pre-analysis revealed that the overall prevalence of macroalbuminuria among 730 children and adolescents with type 2 diabetes was 3.8%. The ages at diagnosis of type 2 diabetes ranged from 6.5 to 21 years, and the duration of the disease varied from diagnosis to 15 years after.

Diabetic retinopathy was present in 50% participants in the TODAY study at age 25 years (ie, after 12 years of disease). In SEARCH, 56% young patients had diabetic retinopathy after 12.5 years of diabetes. In addition, in the same study, the prevalence of peripheral neuropathy, assessed after 8 years, was 22% among adolescents with type 2 diabetes vs 7% among those with type 1 diabetes.
 

Cardiovascular Autonomic Neuropathy

A decrease in heart rate variability was observed in 47% young patients with type 2 diabetes after an average disease duration of only 1.7 years. In SEARCH, the prevalence of cardiovascular autonomic neuropathy, assessed after 8 years of disease, was 17% in adolescents with type 2 diabetes versus 12% in those with type 1 diabetes.

Overall, 7.1% participants had three complications: nephropathy, retinopathy, and neuropathy. The cumulative incidence of microvascular complications was 80%.

Moreover, A1c levels deteriorated progressively throughout the follow-up period. Approximately 45% participants had an A1c of at least 10%, and 20% were between 8% and 10%. Body mass index consistently remained between 35 and 37.5.

Young patients with type 2 diabetes exhibit endothelial dysfunction, increased carotid intima-media thickness, elevated arterial stiffness, left ventricular hypertrophy, diastolic dysfunction, and reduced maximal exercise capacity. All these factors predict cardiovascular morbidity and mortality.

In TODAY, 17 serious cardiovascular events were recorded, including four myocardial infarctions, six cases of congestive heart failure, three coronary events, and four strokes.

In an analysis of the TODAY and SEARCH studies, although the average duration of diabetes was similar, complications were more frequent among young patients with type 2 diabetes than among those with type 1 diabetes. Microvascular complications were 2.5 times more frequent, and macrovascular complications were four times more frequent.

In SEARCH, excessive mortality was observed among young adults for each type of diabetes. Differences in risk were associated with diabetes type, age, race/ethnicity, and sex. Mortality ratios were 1.5 and 2.3 for types 1 and 2 diabetes, respectively.

Women had higher mortality rates than men. Diabetes was the underlying cause of death in 9.1% cases, which was comparable to cardiovascular diseases or cancer (10.9%). According to a life expectancy model, young patients with type 2 diabetes lose about 15 years of life.
 

Eating Disorders and Depression

Beyond these complications, other issues are often present among adolescents with type 2 diabetes. Approximately 50% have eating disorders (compared with 21% among those with type 1 diabetes), 19.3% report depressive symptoms, and 18.9% have expressed thoughts of self-harm. In addition, 19.6% have polycystic ovary syndrome. Z-scores for bone mineral density at the femoral neck and lumbar spine were significantly lower in adolescents with type 2 diabetes than in healthy peers. The presence of metabolic dysfunction–associated fatty liver disease is also more pronounced.

“The recent approvals of new pharmacological interventions for weight loss and improved glycemic control in adolescents offer hope. We hope that, over the next decade, the prevalence of complications among these young patients with type 2 diabetes will decline. In the meantime, a proactive approach is essential to prevent complications related to type 2 diabetes in these youth,” Pinhas-Hamiel concluded.

For more information, see ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 Diabetes in Children and Adolescents.

Pinhas-Hamiel reported no relevant financial relationships.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In several countries, including China, Mexico, and the United States, the incidence of type 2 diabetes now exceeds that of type 1 diabetes among patients younger than 20 years.

“This is an emerging epidemic,” said Orit Pinhas-Hamiel, MD, director of the Pediatric Endocrinology and Diabetes Unit at Sheba Medical Center in Ramat Gan, Israel, at the annual meeting of the European Association for the Study of Diabetes, noting that these young patients, most with obesity, exhibit a significantly higher incidence of complications than adults with type 2 diabetes or young people with type 1 diabetes.

In 2017-2018, the incidence of type 2 diabetes among patients aged 15-19 years (19.7 per 100,000) surpassed that of type 1 diabetes (14.6 per 100,000), according to data from the United States.

“This is the first time that the incidence of type 2 diabetes has exceeded that of type 1 among youth,” said Pinhas-Hamiel. A review of 2021 published a few months ago highlighted this surge, with countries like China, India, the United States, Brazil, and Mexico leading the way.
 

SEARCH and TODAY

The SEARCH for Diabetes in Youth study, which was launched in 2000, is a multicenter observational study in the United States aimed at estimating the prevalence, incidence, and complications of types 1 and 2 diabetes among young patients. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is an interventional study focusing on adolescents with type 2 diabetes to evaluate the effectiveness of various treatment options.

“Diabesity” — the dual global epidemic of obesity and type 2 diabetes — has visible consequences from the moment of diagnosis, including hypertension. In the TODAY study, 11.6% adolescents had hypertension at diagnosis. A study conducted in Hong Kong involving 391 children younger than 18 years revealed that 22.5% had hypertension. In SEARCH, 27% young patients diagnosed with type 2 diabetes for 1.5 years had hypertension.

In addition, the SEARCH study found that 27% young individuals had low levels of high-density lipoprotein cholesterol, while 25% had high triglyceride levels, at 1.5 years after diagnosis.

Overall, the cumulative incidence of long-term diabetic complications was assessed in 500 adolescents participating in TODAY (mean age, 26.4 ± 2.8 years; mean time since diagnosis, 13.3 ± 1.8 years). The initial prevalence was 19.2%, while the cumulative incidence rose to 67.5% after 15 years of follow-up.

For dyslipidemia, the initial prevalence was 20.8%, with a cumulative incidence of 51.6%. The incidence of diabetic nephropathy was 54.8% and neuropathies was 32.4%. The prevalence of retinopathy was 13.7% for the period 2010-2011 and 51% for 2017-2018.

At least one complication was observed in 60.1% participants and at least two in 28.4%. As expected, risk factors for developing complications included belonging to a racial or ethnic minority, hyperglycemia, hypertension, and dyslipidemia.

“Among those who developed type 2 diabetes in adolescence, the risk for complications, including microvascular complications, has continuously increased and affected most participants in young adulthood,” said Pinhas-Hamiel.

At the same time, the rate of treatment with lipid-lowering and antihypertensive medications remains low among young people with type 2 diabetes. The management of dyslipidemia is suboptimal, with only 5% young patients with diabetes and dyslipidemia receiving appropriate medications. Furthermore, treatment adherence is lacking. In the TODAY cohort, for example, only one third of participants with high levels of low-density lipoprotein cholesterol were on lipid-lowering medications, and only half of the young patients with hypertension were taking antihypertensives.
 

Focus on Diabetic Nephropathy

Diabetic kidney disease is the leading microvascular complication of type 2 diabetes in adolescents. It is associated with rapid progression and poor prognosis. The natural history begins with hyperfiltration: A consequence of obesity and impaired glucose tolerance. Structural renal changes can be detected as early as 1.5 years after diagnosis.

The second stage is characterized by a reduction in the glomerular filtration rate. At this stage, “the structural changes in the kidney are typical but often present,” said Pinhas-Hamiel, making this period critical for reducing risk factors.

In TODAY, the cumulative incidence of diabetic nephropathy was 54.8%. The prevalence at inclusion was 8%. In SEARCH, after 8 years, the prevalence of diabetic kidney disease was 19.9% among adolescents with type 2 diabetes vs 5.8% among those with type 1 diabetes. A pre-analysis revealed that the overall prevalence of macroalbuminuria among 730 children and adolescents with type 2 diabetes was 3.8%. The ages at diagnosis of type 2 diabetes ranged from 6.5 to 21 years, and the duration of the disease varied from diagnosis to 15 years after.

Diabetic retinopathy was present in 50% participants in the TODAY study at age 25 years (ie, after 12 years of disease). In SEARCH, 56% young patients had diabetic retinopathy after 12.5 years of diabetes. In addition, in the same study, the prevalence of peripheral neuropathy, assessed after 8 years, was 22% among adolescents with type 2 diabetes vs 7% among those with type 1 diabetes.
 

Cardiovascular Autonomic Neuropathy

A decrease in heart rate variability was observed in 47% young patients with type 2 diabetes after an average disease duration of only 1.7 years. In SEARCH, the prevalence of cardiovascular autonomic neuropathy, assessed after 8 years of disease, was 17% in adolescents with type 2 diabetes versus 12% in those with type 1 diabetes.

Overall, 7.1% participants had three complications: nephropathy, retinopathy, and neuropathy. The cumulative incidence of microvascular complications was 80%.

Moreover, A1c levels deteriorated progressively throughout the follow-up period. Approximately 45% participants had an A1c of at least 10%, and 20% were between 8% and 10%. Body mass index consistently remained between 35 and 37.5.

Young patients with type 2 diabetes exhibit endothelial dysfunction, increased carotid intima-media thickness, elevated arterial stiffness, left ventricular hypertrophy, diastolic dysfunction, and reduced maximal exercise capacity. All these factors predict cardiovascular morbidity and mortality.

In TODAY, 17 serious cardiovascular events were recorded, including four myocardial infarctions, six cases of congestive heart failure, three coronary events, and four strokes.

In an analysis of the TODAY and SEARCH studies, although the average duration of diabetes was similar, complications were more frequent among young patients with type 2 diabetes than among those with type 1 diabetes. Microvascular complications were 2.5 times more frequent, and macrovascular complications were four times more frequent.

In SEARCH, excessive mortality was observed among young adults for each type of diabetes. Differences in risk were associated with diabetes type, age, race/ethnicity, and sex. Mortality ratios were 1.5 and 2.3 for types 1 and 2 diabetes, respectively.

Women had higher mortality rates than men. Diabetes was the underlying cause of death in 9.1% cases, which was comparable to cardiovascular diseases or cancer (10.9%). According to a life expectancy model, young patients with type 2 diabetes lose about 15 years of life.
 

Eating Disorders and Depression

Beyond these complications, other issues are often present among adolescents with type 2 diabetes. Approximately 50% have eating disorders (compared with 21% among those with type 1 diabetes), 19.3% report depressive symptoms, and 18.9% have expressed thoughts of self-harm. In addition, 19.6% have polycystic ovary syndrome. Z-scores for bone mineral density at the femoral neck and lumbar spine were significantly lower in adolescents with type 2 diabetes than in healthy peers. The presence of metabolic dysfunction–associated fatty liver disease is also more pronounced.

“The recent approvals of new pharmacological interventions for weight loss and improved glycemic control in adolescents offer hope. We hope that, over the next decade, the prevalence of complications among these young patients with type 2 diabetes will decline. In the meantime, a proactive approach is essential to prevent complications related to type 2 diabetes in these youth,” Pinhas-Hamiel concluded.

For more information, see ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 Diabetes in Children and Adolescents.

Pinhas-Hamiel reported no relevant financial relationships.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

PARIS — Pregnancy is a period of asthma instability; it entails an increased risk for exacerbations. While therapeutic de-escalation, if not the outright cessation of maintenance treatment, is common, experts used the 19th Francophone Congress of Allergology to emphasize the importance of well-controlled asthma for the mother, the fetus, and the pregnancy.

About 12% of women of childbearing age have asthma. It is the most common chronic condition in pregnant women. Pregnancy affects asthma, and vice versa. Due to mechanical, hormonal, and immunological changes, allergic conditions, including asthma, can worsen.

First, pregnancy exerts mechanical pressure on respiratory function because of the progressive increase in uterine volume, diaphragm elevation, and various anatomical changes leading to chest expansion. The latter changes include increased subcostal angle, anteroposterior and transverse diameters, and thoracic circumference. 

Respiratory function is affected, with a decrease in functional residual capacity and expiratory reserve volume but an increase in inspiratory capacity, maximal ventilation, and tidal volume. The resulting hyperventilation manifests clinically as dyspnea, which affects up to 70% of pregnant women and can be mistaken for exacerbation symptoms.

Besides mechanical impact, hormonal changes occur during pregnancy, including elevated estrogen and progesterone levels. Placental hormones increase during the third trimester. These steroid hormones weaken the respiratory mucosa through structural changes in the bronchial wall and the activity of inflammatory cells involved in asthma, while influencing bronchial muscle tone. Estrogens have a dual effect. They are immunostimulatory at low doses and immunosuppressive at high doses (as in late pregnancy). This phenomenon suggests a role in immune tolerance toward the fetus.
 

The Rule of Thirds

Asthma progression during pregnancy is unpredictable. According to older studies, about one third of cases remain stable, one third worsen, and one third improve. In 60% of cases, the course remains similar from one pregnancy to another. Pregnancy is considered a period of asthma instability, with a doubled risk for exacerbation compared with nonpregnant women. Several pregnancy-specific factors contribute, including gastroesophageal reflux, excessive weight gain, active or passive smoking, and usual risk factors like infections. However, the main risk factor for exacerbation and loss of asthma control is insufficient maintenance treatment.

“The control of asthma during pregnancy is influenced by pregnancy itself, but especially by the severity of the disease before pregnancy and the underuse of inhaled corticosteroids,” said Mohammed Tawfik el Fassy Fihry, MD, pulmonologist at Ibn Sina Souissi Hospital in Rabat, Morocco. “This treatment insufficiency is the main cause of poor asthma control and sometimes of severe exacerbations.”
 

Inhaled Corticosteroid Often Insufficient

A 2017 study conducted in France found that one third of women had their asthma treatment reduced in the first trimester of pregnancy. Another observation was the frequent replacement of fixed combinations (such as long- and short-acting bronchodilators and inhaled corticosteroids) with simple inhaled corticosteroid therapy.

“A significant proportion of pregnant women on maintenance therapy decide to stop it as soon as they discover their pregnancy,” said Chantal Raherison-Semjen, PhD, coordinator of the Women and Lung group of the French Society of Pulmonology (SPLF) and of the pulmonology department at the University Hospital of Pointe-à-Pitre in Guadeloupe, France. “Treating physicians also often opt for therapeutic de-escalation, which involves stopping long-acting bronchodilators in favor of only inhaled corticosteroid therapy, which is usually insufficient for optimal asthma control.”

In severe exacerbations, especially during the first trimester of pregnancy, poorly controlled asthma can lead to complications in fetal development, such as low birth weight, intrauterine growth retardation, prematurity, and congenital malformations.

It can also affect maternal health by increasing the risk for gestational diabetes and affecting the course of pregnancy itself, favoring the occurrence of preeclampsia, placenta previa, placental abruption, premature rupture of membranes, spontaneous miscarriage, cesarean section, and hemorrhagic complications before and after delivery.

“When a pregnant woman presents to the emergency room due to an asthma exacerbation, physicians are often reluctant to administer optimal treatment for fear of the effects of bronchodilators and systemic corticosteroids,” said Dr. Raherison-Semjen. “As a result, these women generally receive less effective treatment in such situations, compared with nonpregnant women. This is despite the risk that severe asthma exacerbations pose to the mother and her child.”
 

‘Pregnant Woman’ Pictogram

In France, manufacturers of teratogenic or fetotoxic drugs are required to display a pictogram on the label indicating the danger for pregnant women or the fetus. The guidelines for this labeling are left to the discretion of the laboratories, however, which sometimes leads to unjustified warnings on the packaging of inhaled corticosteroids or emergency treatments. French medical societies were not consulted on this matter, which complicates prescriptions for pregnant asthmatic women, said Dr. Raherison-Semjen. The SPLF condemns the harmful effects of this decision.

Corticosteroids and Omalizumab

“Given the low, if any, risks associated with the main asthma treatments for the mother and fetus, continuing treatments started before conception is highly recommended,” said Dr. Raherison-Semjen. Inhaled corticosteroids, the cornerstone of asthma treatment, are the primary therapy, and the dosage can be adjusted as strictly necessary. “When properly managed, treatment generally allows for asthma control and reduces the risk for complications during pregnancy to the same level observed in the general population.”

Depending on asthma control levels, long-acting beta-2 agonists (eg, formoterol, salmeterol, and indacaterol) can be added, and possibly leukotriene antagonists. Before pregnancy, prescribed medications should be continued, including biologics prescribed for severe asthma. The exception is omalizumab, which can be started during pregnancy without risk.

For its part, allergen immunotherapy should also be maintained but without dose increases. Oral corticosteroids are reserved for severe exacerbations.

As specified by the GINA report of 2023, the benefits of active asthma treatment during pregnancy far outweigh the risks of usual asthma medications (Level A). This view is supported by reassuring data from the Reference Center for Teratogenic Agents. “There is no scientific-medical evidence justifying that pregnant women with asthma should not be treated the same way as when they are not pregnant,” said Dr. Raherison-Semjen.
 

Useful Links

The Asthma Control Test is a quick questionnaire that allows practitioners to ensure their patient›s asthma control. A score below 20 of 25 indicates poor asthma control. It has been specifically validated for pregnancy.

Dr. Tawfik el Fassy Fihry reported having no relevant financial relationships. Dr. Raherison-Semjen reported receiving compensation from AstraZeneca, B. Ingelheim, ALK, Novartis, Banook, GSK, and Mundi Pharma.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

PARIS — Pregnancy is a period of asthma instability; it entails an increased risk for exacerbations. While therapeutic de-escalation, if not the outright cessation of maintenance treatment, is common, experts used the 19th Francophone Congress of Allergology to emphasize the importance of well-controlled asthma for the mother, the fetus, and the pregnancy.

About 12% of women of childbearing age have asthma. It is the most common chronic condition in pregnant women. Pregnancy affects asthma, and vice versa. Due to mechanical, hormonal, and immunological changes, allergic conditions, including asthma, can worsen.

First, pregnancy exerts mechanical pressure on respiratory function because of the progressive increase in uterine volume, diaphragm elevation, and various anatomical changes leading to chest expansion. The latter changes include increased subcostal angle, anteroposterior and transverse diameters, and thoracic circumference. 

Respiratory function is affected, with a decrease in functional residual capacity and expiratory reserve volume but an increase in inspiratory capacity, maximal ventilation, and tidal volume. The resulting hyperventilation manifests clinically as dyspnea, which affects up to 70% of pregnant women and can be mistaken for exacerbation symptoms.

Besides mechanical impact, hormonal changes occur during pregnancy, including elevated estrogen and progesterone levels. Placental hormones increase during the third trimester. These steroid hormones weaken the respiratory mucosa through structural changes in the bronchial wall and the activity of inflammatory cells involved in asthma, while influencing bronchial muscle tone. Estrogens have a dual effect. They are immunostimulatory at low doses and immunosuppressive at high doses (as in late pregnancy). This phenomenon suggests a role in immune tolerance toward the fetus.
 

The Rule of Thirds

Asthma progression during pregnancy is unpredictable. According to older studies, about one third of cases remain stable, one third worsen, and one third improve. In 60% of cases, the course remains similar from one pregnancy to another. Pregnancy is considered a period of asthma instability, with a doubled risk for exacerbation compared with nonpregnant women. Several pregnancy-specific factors contribute, including gastroesophageal reflux, excessive weight gain, active or passive smoking, and usual risk factors like infections. However, the main risk factor for exacerbation and loss of asthma control is insufficient maintenance treatment.

“The control of asthma during pregnancy is influenced by pregnancy itself, but especially by the severity of the disease before pregnancy and the underuse of inhaled corticosteroids,” said Mohammed Tawfik el Fassy Fihry, MD, pulmonologist at Ibn Sina Souissi Hospital in Rabat, Morocco. “This treatment insufficiency is the main cause of poor asthma control and sometimes of severe exacerbations.”
 

Inhaled Corticosteroid Often Insufficient

A 2017 study conducted in France found that one third of women had their asthma treatment reduced in the first trimester of pregnancy. Another observation was the frequent replacement of fixed combinations (such as long- and short-acting bronchodilators and inhaled corticosteroids) with simple inhaled corticosteroid therapy.

“A significant proportion of pregnant women on maintenance therapy decide to stop it as soon as they discover their pregnancy,” said Chantal Raherison-Semjen, PhD, coordinator of the Women and Lung group of the French Society of Pulmonology (SPLF) and of the pulmonology department at the University Hospital of Pointe-à-Pitre in Guadeloupe, France. “Treating physicians also often opt for therapeutic de-escalation, which involves stopping long-acting bronchodilators in favor of only inhaled corticosteroid therapy, which is usually insufficient for optimal asthma control.”

In severe exacerbations, especially during the first trimester of pregnancy, poorly controlled asthma can lead to complications in fetal development, such as low birth weight, intrauterine growth retardation, prematurity, and congenital malformations.

It can also affect maternal health by increasing the risk for gestational diabetes and affecting the course of pregnancy itself, favoring the occurrence of preeclampsia, placenta previa, placental abruption, premature rupture of membranes, spontaneous miscarriage, cesarean section, and hemorrhagic complications before and after delivery.

“When a pregnant woman presents to the emergency room due to an asthma exacerbation, physicians are often reluctant to administer optimal treatment for fear of the effects of bronchodilators and systemic corticosteroids,” said Dr. Raherison-Semjen. “As a result, these women generally receive less effective treatment in such situations, compared with nonpregnant women. This is despite the risk that severe asthma exacerbations pose to the mother and her child.”
 

‘Pregnant Woman’ Pictogram

In France, manufacturers of teratogenic or fetotoxic drugs are required to display a pictogram on the label indicating the danger for pregnant women or the fetus. The guidelines for this labeling are left to the discretion of the laboratories, however, which sometimes leads to unjustified warnings on the packaging of inhaled corticosteroids or emergency treatments. French medical societies were not consulted on this matter, which complicates prescriptions for pregnant asthmatic women, said Dr. Raherison-Semjen. The SPLF condemns the harmful effects of this decision.

Corticosteroids and Omalizumab

“Given the low, if any, risks associated with the main asthma treatments for the mother and fetus, continuing treatments started before conception is highly recommended,” said Dr. Raherison-Semjen. Inhaled corticosteroids, the cornerstone of asthma treatment, are the primary therapy, and the dosage can be adjusted as strictly necessary. “When properly managed, treatment generally allows for asthma control and reduces the risk for complications during pregnancy to the same level observed in the general population.”

Depending on asthma control levels, long-acting beta-2 agonists (eg, formoterol, salmeterol, and indacaterol) can be added, and possibly leukotriene antagonists. Before pregnancy, prescribed medications should be continued, including biologics prescribed for severe asthma. The exception is omalizumab, which can be started during pregnancy without risk.

For its part, allergen immunotherapy should also be maintained but without dose increases. Oral corticosteroids are reserved for severe exacerbations.

As specified by the GINA report of 2023, the benefits of active asthma treatment during pregnancy far outweigh the risks of usual asthma medications (Level A). This view is supported by reassuring data from the Reference Center for Teratogenic Agents. “There is no scientific-medical evidence justifying that pregnant women with asthma should not be treated the same way as when they are not pregnant,” said Dr. Raherison-Semjen.
 

Useful Links

The Asthma Control Test is a quick questionnaire that allows practitioners to ensure their patient›s asthma control. A score below 20 of 25 indicates poor asthma control. It has been specifically validated for pregnancy.

Dr. Tawfik el Fassy Fihry reported having no relevant financial relationships. Dr. Raherison-Semjen reported receiving compensation from AstraZeneca, B. Ingelheim, ALK, Novartis, Banook, GSK, and Mundi Pharma.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

PARIS — Pregnancy is a period of asthma instability; it entails an increased risk for exacerbations. While therapeutic de-escalation, if not the outright cessation of maintenance treatment, is common, experts used the 19th Francophone Congress of Allergology to emphasize the importance of well-controlled asthma for the mother, the fetus, and the pregnancy.

About 12% of women of childbearing age have asthma. It is the most common chronic condition in pregnant women. Pregnancy affects asthma, and vice versa. Due to mechanical, hormonal, and immunological changes, allergic conditions, including asthma, can worsen.

First, pregnancy exerts mechanical pressure on respiratory function because of the progressive increase in uterine volume, diaphragm elevation, and various anatomical changes leading to chest expansion. The latter changes include increased subcostal angle, anteroposterior and transverse diameters, and thoracic circumference. 

Respiratory function is affected, with a decrease in functional residual capacity and expiratory reserve volume but an increase in inspiratory capacity, maximal ventilation, and tidal volume. The resulting hyperventilation manifests clinically as dyspnea, which affects up to 70% of pregnant women and can be mistaken for exacerbation symptoms.

Besides mechanical impact, hormonal changes occur during pregnancy, including elevated estrogen and progesterone levels. Placental hormones increase during the third trimester. These steroid hormones weaken the respiratory mucosa through structural changes in the bronchial wall and the activity of inflammatory cells involved in asthma, while influencing bronchial muscle tone. Estrogens have a dual effect. They are immunostimulatory at low doses and immunosuppressive at high doses (as in late pregnancy). This phenomenon suggests a role in immune tolerance toward the fetus.
 

The Rule of Thirds

Asthma progression during pregnancy is unpredictable. According to older studies, about one third of cases remain stable, one third worsen, and one third improve. In 60% of cases, the course remains similar from one pregnancy to another. Pregnancy is considered a period of asthma instability, with a doubled risk for exacerbation compared with nonpregnant women. Several pregnancy-specific factors contribute, including gastroesophageal reflux, excessive weight gain, active or passive smoking, and usual risk factors like infections. However, the main risk factor for exacerbation and loss of asthma control is insufficient maintenance treatment.

“The control of asthma during pregnancy is influenced by pregnancy itself, but especially by the severity of the disease before pregnancy and the underuse of inhaled corticosteroids,” said Mohammed Tawfik el Fassy Fihry, MD, pulmonologist at Ibn Sina Souissi Hospital in Rabat, Morocco. “This treatment insufficiency is the main cause of poor asthma control and sometimes of severe exacerbations.”
 

Inhaled Corticosteroid Often Insufficient

A 2017 study conducted in France found that one third of women had their asthma treatment reduced in the first trimester of pregnancy. Another observation was the frequent replacement of fixed combinations (such as long- and short-acting bronchodilators and inhaled corticosteroids) with simple inhaled corticosteroid therapy.

“A significant proportion of pregnant women on maintenance therapy decide to stop it as soon as they discover their pregnancy,” said Chantal Raherison-Semjen, PhD, coordinator of the Women and Lung group of the French Society of Pulmonology (SPLF) and of the pulmonology department at the University Hospital of Pointe-à-Pitre in Guadeloupe, France. “Treating physicians also often opt for therapeutic de-escalation, which involves stopping long-acting bronchodilators in favor of only inhaled corticosteroid therapy, which is usually insufficient for optimal asthma control.”

In severe exacerbations, especially during the first trimester of pregnancy, poorly controlled asthma can lead to complications in fetal development, such as low birth weight, intrauterine growth retardation, prematurity, and congenital malformations.

It can also affect maternal health by increasing the risk for gestational diabetes and affecting the course of pregnancy itself, favoring the occurrence of preeclampsia, placenta previa, placental abruption, premature rupture of membranes, spontaneous miscarriage, cesarean section, and hemorrhagic complications before and after delivery.

“When a pregnant woman presents to the emergency room due to an asthma exacerbation, physicians are often reluctant to administer optimal treatment for fear of the effects of bronchodilators and systemic corticosteroids,” said Dr. Raherison-Semjen. “As a result, these women generally receive less effective treatment in such situations, compared with nonpregnant women. This is despite the risk that severe asthma exacerbations pose to the mother and her child.”
 

‘Pregnant Woman’ Pictogram

In France, manufacturers of teratogenic or fetotoxic drugs are required to display a pictogram on the label indicating the danger for pregnant women or the fetus. The guidelines for this labeling are left to the discretion of the laboratories, however, which sometimes leads to unjustified warnings on the packaging of inhaled corticosteroids or emergency treatments. French medical societies were not consulted on this matter, which complicates prescriptions for pregnant asthmatic women, said Dr. Raherison-Semjen. The SPLF condemns the harmful effects of this decision.

Corticosteroids and Omalizumab

“Given the low, if any, risks associated with the main asthma treatments for the mother and fetus, continuing treatments started before conception is highly recommended,” said Dr. Raherison-Semjen. Inhaled corticosteroids, the cornerstone of asthma treatment, are the primary therapy, and the dosage can be adjusted as strictly necessary. “When properly managed, treatment generally allows for asthma control and reduces the risk for complications during pregnancy to the same level observed in the general population.”

Depending on asthma control levels, long-acting beta-2 agonists (eg, formoterol, salmeterol, and indacaterol) can be added, and possibly leukotriene antagonists. Before pregnancy, prescribed medications should be continued, including biologics prescribed for severe asthma. The exception is omalizumab, which can be started during pregnancy without risk.

For its part, allergen immunotherapy should also be maintained but without dose increases. Oral corticosteroids are reserved for severe exacerbations.

As specified by the GINA report of 2023, the benefits of active asthma treatment during pregnancy far outweigh the risks of usual asthma medications (Level A). This view is supported by reassuring data from the Reference Center for Teratogenic Agents. “There is no scientific-medical evidence justifying that pregnant women with asthma should not be treated the same way as when they are not pregnant,” said Dr. Raherison-Semjen.
 

Useful Links

The Asthma Control Test is a quick questionnaire that allows practitioners to ensure their patient›s asthma control. A score below 20 of 25 indicates poor asthma control. It has been specifically validated for pregnancy.

Dr. Tawfik el Fassy Fihry reported having no relevant financial relationships. Dr. Raherison-Semjen reported receiving compensation from AstraZeneca, B. Ingelheim, ALK, Novartis, Banook, GSK, and Mundi Pharma.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

PARIS — While anaphylaxis requires immediate adrenaline administration through autoinjection, the use of this treatment is not optimal. Therefore, the development of new adrenaline formulations (such as for intranasal, sublingual, and transcutaneous routes) aims to facilitate the drug’s use and reduce persistent delays in administration by patients and caregivers. An overview of the research was presented at the 19th French-speaking Congress of Allergology.

Anaphylaxis is a severe and potentially fatal immediate hypersensitivity reaction with highly variable and dynamic clinical presentations. It requires prompt recognition for immediate treatment with intramuscular (IM) adrenaline (at the anterolateral aspect of the mid-thigh).

One might think that this reflex is acquired, but in France, while the number of prescribed adrenaline autoinjection (AAI) devices has been increasing for a decade, reaching 965,944 units in 2022, this first-line treatment is underused. Anapen (150, 300, and 500 µg), EpiPen (150 and 300 µg), Jext (150 µg and 300 µg), and Emerade (150, 300, and 500 µg) are the four products marketed in France in 2024.

“Only 17.3% of individuals presenting to the emergency department in the Lorraine region used it in 2015,” said Catherine Neukirch, MD, a pneumologist at Hôpital Bichat–Claude Bernard in Paris, France, with rates of 11.3% for children and 20.3% for adults.
 

Anaphylaxis Incidence Increasing

Approximately 0.3% (95% CI, 0.1-0.5) of the population will experience an anaphylaxis episode in their lifetime. Incidence in Europe, across all causes, is estimated between 1.5 and 7.9 cases per 100,000 inhabitants per year. Although anaphylaxis is on the rise, its associated mortality remains low, ranging between 0.05 and 0.51 per million per year for drugs, between 0.03 and 0.32 per million per year for foods, and between 0.09 and 0.13 per million per year for hymenopteran venoms.

Data from the European Anaphylaxis Registry indicate that anaphylaxis manifests rapidly after allergen exposure: 55% of cases occur within 10 minutes and 80% within 30 minutes. In addition, a biphasic reaction, which can occur up to 72 hours after exposure, is observed in < 5% of cases.

While a delay in adrenaline use is associated with risk for increased morbidity and mortality, AAI significantly reduces error rates compared with manual treatments involving ampoules, needles, and syringes. It also reduces the associated panic risks. However, there are multiple barriers to adrenaline use. The clinical symptoms of anaphylaxis may be misleading, especially if it occurs without cutaneous and urticarial manifestations but with only acute bronchospasm. It may present as isolated laryngeal edema without digestive involvement, hypotension, or other respiratory problems.

Other limitations to adrenaline use include technical difficulties and the possibility of incorrect administration, the need for appropriate needle sizes for patients with obesity, needle phobia, potential adverse effects of adrenaline injections, failure to carry two autoinjectors, constraints related to storage and bulky transport, as well as the need for training and practice.

“These factors contribute to underuse of adrenaline by patients and caregivers,” said Dr. Neukirch, which results in delays in necessary administration.
 

Adrenaline Treatment Criteria?

An analysis published in 2023 based on pharmacovigilance data from 30 regional French centers from 1984 to 2022 included 42 reported cases (average age, 33 years; 26% children) of reactions to AAI, which probably is an underestimate. About 40% of AAI uses occurred during anaphylaxis. The remaining 60% were triggered outside of reactions. The main reasons were accidental injections, mainly in the fingers, and cases of not triggering the autoinjector, underlining the importance of patient education.

In 2015, the European Medicines Agency required pharmacological studies for injectable adrenaline on healthy volunteers. These studies include ultrasound measurements of bolus injection, pharmacokinetics (ie, absorption, distribution, metabolism, and excretion), and pharmacodynamics (ie, the effect of the drug and the mechanism of action in the body), with precise evaluation of cardiovascular effects (eg, systolic and diastolic blood pressures and heart rate).

Among the information collected with the different products, ultrasound studies have shown a different localization of the adrenaline bolus (ie, in muscle in patients with normal BMI and mostly in adipose tissue in patients with BMI indicating overweight and obesity). The consequences of this finding are still unknown.

In a study with 500 µg Anapen, women with overweight or obesity showed different pharmacokinetic or pharmacodynamic profiles from those in men with normal weight, with an increase in the area under the curve (0-240 min) and marked changes in the heart rate time curve.

IM administration of 0.5 mg produces rapid pharmacokinetic effects in patients with normal weight, overweight, or obesity, with a delay for the second peak in the latter case. This delay perhaps results from initial local vasoconstriction due to adrenaline.

The early peak plasma concentration occurs at 5-10 minutes for AAI, with a faster speed for Anapen and EpiPen.

Moreover, needle size is not the most important factor. Rather, it is the strength and speed of injection, which can vary depending on the AAI.

Also, the optimal plasma concentration of adrenaline to treat anaphylaxis is not known; studies cannot be conducted during anaphylaxis. In terms of pharmacokinetics, a small series discovered that increased skin or muscle thickness delays the absorption of EpiPen AAI.
 

Intranasal Adrenaline

To facilitate rapid adrenaline use and convince reluctant patients to carry and use adrenaline, intranasal, sublingual, or transcutaneous forms are under development.

Three intranasal forms of adrenaline are already well advanced, including Neffy from ARS Pharma, epinephrine sprays from Bryn Pharma and Hikma, and Oxero from Oragoo, which contains dry powder.

A comparison of intranasal adrenaline Neffy and AAI shows that the former has satisfactory pharmacokinetic and pharmacodynamic effects.

In a phase 1 randomized crossover study of 42 healthy adults comparing the pharmacokinetic effects of Neffy adrenaline (2 mg) and EpiPen (0.3 mg), as well as IM epinephrine 0.3 mg, several observations were made. For a single dose, the maximum concentration (Cmax) of Neffy was lower than that of EpiPen.

However, with repeated doses administered 10 minutes apart, the Cmax of Neffy was higher than that of EpiPen. At this stage, pharmacodynamic responses to intranasal products are at least comparable with those of approved injectable products.

A comparison of the pharmacodynamic effects, such as systolic and diastolic blood pressures and heart rate, of Neffy adrenaline and AAI concluded that the profile of Neffy is comparable with that of EpiPen and superior to that of IM epinephrine.

In patients with a history of allergic rhinitis, adrenaline Cmax appears to be increased, while time to peak plasma concentration (Tmax) is reduced. Low blood pressure does not prevent Neffy absorption. Neffy is currently under review by the American and European health authorities.

Intranasal absorption of dry powder adrenaline appears to be faster than that of EpiPen, thus offering a clinical advantage in the short therapeutic window for anaphylaxis treatment.

In an open-label trial conducted on 12 adults with seasonal allergic rhinitis without asthma, the pharmacokinetics, pharmacodynamics, and safety of adrenaline were compared between FMXIN002 (1.6 and 3.2 mg), which was administered intranasally with or without nasal allergen challenge, and IM EpiPen 0.3 mg. Pharmacokinetics varied by patient. Nevertheless, nasal FMXIN002 had a shorter Tmax, a doubled Cmax after the allergen challenge peak, and a higher area under the curve in the 8 hours following administration compared with EpiPen. Pharmacodynamic effects comparable with those of EpiPen were noted at 15 minutes to 4 hours after administration. The tolerance was good, with mild and local side effects. The powder seems to deposit slightly better in the nasal cavity. It remains stable for 6 months at a temperature of 40 °C and relative humidity of 75% and for 2 years at a temperature of 25 °C and relative humidity of 60%.
 

Sublingual Adrenaline Film

AQST-109 is a sublingual film that is intended to allow rapid administration of epinephrine 1, which is a prodrug of adrenaline. The product is the size of a postage stamp, weighs < 30 g, and dissolves on contact with the tongue.

The EPIPHAST II study was a phase 1, multiperiod, crossover study conducted on 24 healthy adults (age, 24-49 years) who were randomly assigned to receive either 12 or 0.3 mg of AQST-109  of manual IM adrenaline in the first two periods. All participants received 0.3 mg of EpiPen in the last period.

EpiPen 0.3 mg resulted in a higher Cmax than AQST-109 12 mg. AQST-109 12 mg had the fastest median Tmax of 12 minutes. The areas under the curve of AQST-109 12 mg fell between those of EpiPen 0.3 mg and manual IM adrenaline 0.3 mg.

Early increases in systolic blood pressure, diastolic blood pressure, and heart rate were observed with AQST-109 12 mg. Changes were more pronounced with AQST-109 12 mg despite a higher Cmax with EpiPen 0.3 mg.

Part 3 of the EPIPHAST study evaluated the impact of food exposure (ie, a peanut butter sandwich) on the pharmacokinetics of AQST-109 12 mg in 24 healthy adults. Oral food residues did not significantly affect pharmacodynamic parameters, and no treatment-related adverse events were reported.

Researchers concluded that AQST-109 12 mg absorption would not be altered by “real” situations if used during meals. “These results suggest that the sublingual adrenaline film could be promising in real situations,” said Dr. Neukirch, especially in cases of food allergy with recent ingestion of the allergenic food.
 

Transcutaneous Adrenaline

A transcutaneous form of adrenaline that uses the Zeneo device developed by Crossject, a company based in Dijon, France, comes in the form of an AAI that requires no needle. This project, funded by the European Union, uses a gas generator to propel the drug at very high speed through the skin in 50 milliseconds. This method allows for extended drug storage.

Dr. Neukirch reported financial relationships with Viatris, Stallergènes, ALK, Astrazeneca, Sanofi, GSK, and Novartis.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

PARIS — While anaphylaxis requires immediate adrenaline administration through autoinjection, the use of this treatment is not optimal. Therefore, the development of new adrenaline formulations (such as for intranasal, sublingual, and transcutaneous routes) aims to facilitate the drug’s use and reduce persistent delays in administration by patients and caregivers. An overview of the research was presented at the 19th French-speaking Congress of Allergology.

Anaphylaxis is a severe and potentially fatal immediate hypersensitivity reaction with highly variable and dynamic clinical presentations. It requires prompt recognition for immediate treatment with intramuscular (IM) adrenaline (at the anterolateral aspect of the mid-thigh).

One might think that this reflex is acquired, but in France, while the number of prescribed adrenaline autoinjection (AAI) devices has been increasing for a decade, reaching 965,944 units in 2022, this first-line treatment is underused. Anapen (150, 300, and 500 µg), EpiPen (150 and 300 µg), Jext (150 µg and 300 µg), and Emerade (150, 300, and 500 µg) are the four products marketed in France in 2024.

“Only 17.3% of individuals presenting to the emergency department in the Lorraine region used it in 2015,” said Catherine Neukirch, MD, a pneumologist at Hôpital Bichat–Claude Bernard in Paris, France, with rates of 11.3% for children and 20.3% for adults.
 

Anaphylaxis Incidence Increasing

Approximately 0.3% (95% CI, 0.1-0.5) of the population will experience an anaphylaxis episode in their lifetime. Incidence in Europe, across all causes, is estimated between 1.5 and 7.9 cases per 100,000 inhabitants per year. Although anaphylaxis is on the rise, its associated mortality remains low, ranging between 0.05 and 0.51 per million per year for drugs, between 0.03 and 0.32 per million per year for foods, and between 0.09 and 0.13 per million per year for hymenopteran venoms.

Data from the European Anaphylaxis Registry indicate that anaphylaxis manifests rapidly after allergen exposure: 55% of cases occur within 10 minutes and 80% within 30 minutes. In addition, a biphasic reaction, which can occur up to 72 hours after exposure, is observed in < 5% of cases.

While a delay in adrenaline use is associated with risk for increased morbidity and mortality, AAI significantly reduces error rates compared with manual treatments involving ampoules, needles, and syringes. It also reduces the associated panic risks. However, there are multiple barriers to adrenaline use. The clinical symptoms of anaphylaxis may be misleading, especially if it occurs without cutaneous and urticarial manifestations but with only acute bronchospasm. It may present as isolated laryngeal edema without digestive involvement, hypotension, or other respiratory problems.

Other limitations to adrenaline use include technical difficulties and the possibility of incorrect administration, the need for appropriate needle sizes for patients with obesity, needle phobia, potential adverse effects of adrenaline injections, failure to carry two autoinjectors, constraints related to storage and bulky transport, as well as the need for training and practice.

“These factors contribute to underuse of adrenaline by patients and caregivers,” said Dr. Neukirch, which results in delays in necessary administration.
 

Adrenaline Treatment Criteria?

An analysis published in 2023 based on pharmacovigilance data from 30 regional French centers from 1984 to 2022 included 42 reported cases (average age, 33 years; 26% children) of reactions to AAI, which probably is an underestimate. About 40% of AAI uses occurred during anaphylaxis. The remaining 60% were triggered outside of reactions. The main reasons were accidental injections, mainly in the fingers, and cases of not triggering the autoinjector, underlining the importance of patient education.

In 2015, the European Medicines Agency required pharmacological studies for injectable adrenaline on healthy volunteers. These studies include ultrasound measurements of bolus injection, pharmacokinetics (ie, absorption, distribution, metabolism, and excretion), and pharmacodynamics (ie, the effect of the drug and the mechanism of action in the body), with precise evaluation of cardiovascular effects (eg, systolic and diastolic blood pressures and heart rate).

Among the information collected with the different products, ultrasound studies have shown a different localization of the adrenaline bolus (ie, in muscle in patients with normal BMI and mostly in adipose tissue in patients with BMI indicating overweight and obesity). The consequences of this finding are still unknown.

In a study with 500 µg Anapen, women with overweight or obesity showed different pharmacokinetic or pharmacodynamic profiles from those in men with normal weight, with an increase in the area under the curve (0-240 min) and marked changes in the heart rate time curve.

IM administration of 0.5 mg produces rapid pharmacokinetic effects in patients with normal weight, overweight, or obesity, with a delay for the second peak in the latter case. This delay perhaps results from initial local vasoconstriction due to adrenaline.

The early peak plasma concentration occurs at 5-10 minutes for AAI, with a faster speed for Anapen and EpiPen.

Moreover, needle size is not the most important factor. Rather, it is the strength and speed of injection, which can vary depending on the AAI.

Also, the optimal plasma concentration of adrenaline to treat anaphylaxis is not known; studies cannot be conducted during anaphylaxis. In terms of pharmacokinetics, a small series discovered that increased skin or muscle thickness delays the absorption of EpiPen AAI.
 

Intranasal Adrenaline

To facilitate rapid adrenaline use and convince reluctant patients to carry and use adrenaline, intranasal, sublingual, or transcutaneous forms are under development.

Three intranasal forms of adrenaline are already well advanced, including Neffy from ARS Pharma, epinephrine sprays from Bryn Pharma and Hikma, and Oxero from Oragoo, which contains dry powder.

A comparison of intranasal adrenaline Neffy and AAI shows that the former has satisfactory pharmacokinetic and pharmacodynamic effects.

In a phase 1 randomized crossover study of 42 healthy adults comparing the pharmacokinetic effects of Neffy adrenaline (2 mg) and EpiPen (0.3 mg), as well as IM epinephrine 0.3 mg, several observations were made. For a single dose, the maximum concentration (Cmax) of Neffy was lower than that of EpiPen.

However, with repeated doses administered 10 minutes apart, the Cmax of Neffy was higher than that of EpiPen. At this stage, pharmacodynamic responses to intranasal products are at least comparable with those of approved injectable products.

A comparison of the pharmacodynamic effects, such as systolic and diastolic blood pressures and heart rate, of Neffy adrenaline and AAI concluded that the profile of Neffy is comparable with that of EpiPen and superior to that of IM epinephrine.

In patients with a history of allergic rhinitis, adrenaline Cmax appears to be increased, while time to peak plasma concentration (Tmax) is reduced. Low blood pressure does not prevent Neffy absorption. Neffy is currently under review by the American and European health authorities.

Intranasal absorption of dry powder adrenaline appears to be faster than that of EpiPen, thus offering a clinical advantage in the short therapeutic window for anaphylaxis treatment.

In an open-label trial conducted on 12 adults with seasonal allergic rhinitis without asthma, the pharmacokinetics, pharmacodynamics, and safety of adrenaline were compared between FMXIN002 (1.6 and 3.2 mg), which was administered intranasally with or without nasal allergen challenge, and IM EpiPen 0.3 mg. Pharmacokinetics varied by patient. Nevertheless, nasal FMXIN002 had a shorter Tmax, a doubled Cmax after the allergen challenge peak, and a higher area under the curve in the 8 hours following administration compared with EpiPen. Pharmacodynamic effects comparable with those of EpiPen were noted at 15 minutes to 4 hours after administration. The tolerance was good, with mild and local side effects. The powder seems to deposit slightly better in the nasal cavity. It remains stable for 6 months at a temperature of 40 °C and relative humidity of 75% and for 2 years at a temperature of 25 °C and relative humidity of 60%.
 

Sublingual Adrenaline Film

AQST-109 is a sublingual film that is intended to allow rapid administration of epinephrine 1, which is a prodrug of adrenaline. The product is the size of a postage stamp, weighs < 30 g, and dissolves on contact with the tongue.

The EPIPHAST II study was a phase 1, multiperiod, crossover study conducted on 24 healthy adults (age, 24-49 years) who were randomly assigned to receive either 12 or 0.3 mg of AQST-109  of manual IM adrenaline in the first two periods. All participants received 0.3 mg of EpiPen in the last period.

EpiPen 0.3 mg resulted in a higher Cmax than AQST-109 12 mg. AQST-109 12 mg had the fastest median Tmax of 12 minutes. The areas under the curve of AQST-109 12 mg fell between those of EpiPen 0.3 mg and manual IM adrenaline 0.3 mg.

Early increases in systolic blood pressure, diastolic blood pressure, and heart rate were observed with AQST-109 12 mg. Changes were more pronounced with AQST-109 12 mg despite a higher Cmax with EpiPen 0.3 mg.

Part 3 of the EPIPHAST study evaluated the impact of food exposure (ie, a peanut butter sandwich) on the pharmacokinetics of AQST-109 12 mg in 24 healthy adults. Oral food residues did not significantly affect pharmacodynamic parameters, and no treatment-related adverse events were reported.

Researchers concluded that AQST-109 12 mg absorption would not be altered by “real” situations if used during meals. “These results suggest that the sublingual adrenaline film could be promising in real situations,” said Dr. Neukirch, especially in cases of food allergy with recent ingestion of the allergenic food.
 

Transcutaneous Adrenaline

A transcutaneous form of adrenaline that uses the Zeneo device developed by Crossject, a company based in Dijon, France, comes in the form of an AAI that requires no needle. This project, funded by the European Union, uses a gas generator to propel the drug at very high speed through the skin in 50 milliseconds. This method allows for extended drug storage.

Dr. Neukirch reported financial relationships with Viatris, Stallergènes, ALK, Astrazeneca, Sanofi, GSK, and Novartis.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

PARIS — While anaphylaxis requires immediate adrenaline administration through autoinjection, the use of this treatment is not optimal. Therefore, the development of new adrenaline formulations (such as for intranasal, sublingual, and transcutaneous routes) aims to facilitate the drug’s use and reduce persistent delays in administration by patients and caregivers. An overview of the research was presented at the 19th French-speaking Congress of Allergology.

Anaphylaxis is a severe and potentially fatal immediate hypersensitivity reaction with highly variable and dynamic clinical presentations. It requires prompt recognition for immediate treatment with intramuscular (IM) adrenaline (at the anterolateral aspect of the mid-thigh).

One might think that this reflex is acquired, but in France, while the number of prescribed adrenaline autoinjection (AAI) devices has been increasing for a decade, reaching 965,944 units in 2022, this first-line treatment is underused. Anapen (150, 300, and 500 µg), EpiPen (150 and 300 µg), Jext (150 µg and 300 µg), and Emerade (150, 300, and 500 µg) are the four products marketed in France in 2024.

“Only 17.3% of individuals presenting to the emergency department in the Lorraine region used it in 2015,” said Catherine Neukirch, MD, a pneumologist at Hôpital Bichat–Claude Bernard in Paris, France, with rates of 11.3% for children and 20.3% for adults.
 

Anaphylaxis Incidence Increasing

Approximately 0.3% (95% CI, 0.1-0.5) of the population will experience an anaphylaxis episode in their lifetime. Incidence in Europe, across all causes, is estimated between 1.5 and 7.9 cases per 100,000 inhabitants per year. Although anaphylaxis is on the rise, its associated mortality remains low, ranging between 0.05 and 0.51 per million per year for drugs, between 0.03 and 0.32 per million per year for foods, and between 0.09 and 0.13 per million per year for hymenopteran venoms.

Data from the European Anaphylaxis Registry indicate that anaphylaxis manifests rapidly after allergen exposure: 55% of cases occur within 10 minutes and 80% within 30 minutes. In addition, a biphasic reaction, which can occur up to 72 hours after exposure, is observed in < 5% of cases.

While a delay in adrenaline use is associated with risk for increased morbidity and mortality, AAI significantly reduces error rates compared with manual treatments involving ampoules, needles, and syringes. It also reduces the associated panic risks. However, there are multiple barriers to adrenaline use. The clinical symptoms of anaphylaxis may be misleading, especially if it occurs without cutaneous and urticarial manifestations but with only acute bronchospasm. It may present as isolated laryngeal edema without digestive involvement, hypotension, or other respiratory problems.

Other limitations to adrenaline use include technical difficulties and the possibility of incorrect administration, the need for appropriate needle sizes for patients with obesity, needle phobia, potential adverse effects of adrenaline injections, failure to carry two autoinjectors, constraints related to storage and bulky transport, as well as the need for training and practice.

“These factors contribute to underuse of adrenaline by patients and caregivers,” said Dr. Neukirch, which results in delays in necessary administration.
 

Adrenaline Treatment Criteria?

An analysis published in 2023 based on pharmacovigilance data from 30 regional French centers from 1984 to 2022 included 42 reported cases (average age, 33 years; 26% children) of reactions to AAI, which probably is an underestimate. About 40% of AAI uses occurred during anaphylaxis. The remaining 60% were triggered outside of reactions. The main reasons were accidental injections, mainly in the fingers, and cases of not triggering the autoinjector, underlining the importance of patient education.

In 2015, the European Medicines Agency required pharmacological studies for injectable adrenaline on healthy volunteers. These studies include ultrasound measurements of bolus injection, pharmacokinetics (ie, absorption, distribution, metabolism, and excretion), and pharmacodynamics (ie, the effect of the drug and the mechanism of action in the body), with precise evaluation of cardiovascular effects (eg, systolic and diastolic blood pressures and heart rate).

Among the information collected with the different products, ultrasound studies have shown a different localization of the adrenaline bolus (ie, in muscle in patients with normal BMI and mostly in adipose tissue in patients with BMI indicating overweight and obesity). The consequences of this finding are still unknown.

In a study with 500 µg Anapen, women with overweight or obesity showed different pharmacokinetic or pharmacodynamic profiles from those in men with normal weight, with an increase in the area under the curve (0-240 min) and marked changes in the heart rate time curve.

IM administration of 0.5 mg produces rapid pharmacokinetic effects in patients with normal weight, overweight, or obesity, with a delay for the second peak in the latter case. This delay perhaps results from initial local vasoconstriction due to adrenaline.

The early peak plasma concentration occurs at 5-10 minutes for AAI, with a faster speed for Anapen and EpiPen.

Moreover, needle size is not the most important factor. Rather, it is the strength and speed of injection, which can vary depending on the AAI.

Also, the optimal plasma concentration of adrenaline to treat anaphylaxis is not known; studies cannot be conducted during anaphylaxis. In terms of pharmacokinetics, a small series discovered that increased skin or muscle thickness delays the absorption of EpiPen AAI.
 

Intranasal Adrenaline

To facilitate rapid adrenaline use and convince reluctant patients to carry and use adrenaline, intranasal, sublingual, or transcutaneous forms are under development.

Three intranasal forms of adrenaline are already well advanced, including Neffy from ARS Pharma, epinephrine sprays from Bryn Pharma and Hikma, and Oxero from Oragoo, which contains dry powder.

A comparison of intranasal adrenaline Neffy and AAI shows that the former has satisfactory pharmacokinetic and pharmacodynamic effects.

In a phase 1 randomized crossover study of 42 healthy adults comparing the pharmacokinetic effects of Neffy adrenaline (2 mg) and EpiPen (0.3 mg), as well as IM epinephrine 0.3 mg, several observations were made. For a single dose, the maximum concentration (Cmax) of Neffy was lower than that of EpiPen.

However, with repeated doses administered 10 minutes apart, the Cmax of Neffy was higher than that of EpiPen. At this stage, pharmacodynamic responses to intranasal products are at least comparable with those of approved injectable products.

A comparison of the pharmacodynamic effects, such as systolic and diastolic blood pressures and heart rate, of Neffy adrenaline and AAI concluded that the profile of Neffy is comparable with that of EpiPen and superior to that of IM epinephrine.

In patients with a history of allergic rhinitis, adrenaline Cmax appears to be increased, while time to peak plasma concentration (Tmax) is reduced. Low blood pressure does not prevent Neffy absorption. Neffy is currently under review by the American and European health authorities.

Intranasal absorption of dry powder adrenaline appears to be faster than that of EpiPen, thus offering a clinical advantage in the short therapeutic window for anaphylaxis treatment.

In an open-label trial conducted on 12 adults with seasonal allergic rhinitis without asthma, the pharmacokinetics, pharmacodynamics, and safety of adrenaline were compared between FMXIN002 (1.6 and 3.2 mg), which was administered intranasally with or without nasal allergen challenge, and IM EpiPen 0.3 mg. Pharmacokinetics varied by patient. Nevertheless, nasal FMXIN002 had a shorter Tmax, a doubled Cmax after the allergen challenge peak, and a higher area under the curve in the 8 hours following administration compared with EpiPen. Pharmacodynamic effects comparable with those of EpiPen were noted at 15 minutes to 4 hours after administration. The tolerance was good, with mild and local side effects. The powder seems to deposit slightly better in the nasal cavity. It remains stable for 6 months at a temperature of 40 °C and relative humidity of 75% and for 2 years at a temperature of 25 °C and relative humidity of 60%.
 

Sublingual Adrenaline Film

AQST-109 is a sublingual film that is intended to allow rapid administration of epinephrine 1, which is a prodrug of adrenaline. The product is the size of a postage stamp, weighs < 30 g, and dissolves on contact with the tongue.

The EPIPHAST II study was a phase 1, multiperiod, crossover study conducted on 24 healthy adults (age, 24-49 years) who were randomly assigned to receive either 12 or 0.3 mg of AQST-109  of manual IM adrenaline in the first two periods. All participants received 0.3 mg of EpiPen in the last period.

EpiPen 0.3 mg resulted in a higher Cmax than AQST-109 12 mg. AQST-109 12 mg had the fastest median Tmax of 12 minutes. The areas under the curve of AQST-109 12 mg fell between those of EpiPen 0.3 mg and manual IM adrenaline 0.3 mg.

Early increases in systolic blood pressure, diastolic blood pressure, and heart rate were observed with AQST-109 12 mg. Changes were more pronounced with AQST-109 12 mg despite a higher Cmax with EpiPen 0.3 mg.

Part 3 of the EPIPHAST study evaluated the impact of food exposure (ie, a peanut butter sandwich) on the pharmacokinetics of AQST-109 12 mg in 24 healthy adults. Oral food residues did not significantly affect pharmacodynamic parameters, and no treatment-related adverse events were reported.

Researchers concluded that AQST-109 12 mg absorption would not be altered by “real” situations if used during meals. “These results suggest that the sublingual adrenaline film could be promising in real situations,” said Dr. Neukirch, especially in cases of food allergy with recent ingestion of the allergenic food.
 

Transcutaneous Adrenaline

A transcutaneous form of adrenaline that uses the Zeneo device developed by Crossject, a company based in Dijon, France, comes in the form of an AAI that requires no needle. This project, funded by the European Union, uses a gas generator to propel the drug at very high speed through the skin in 50 milliseconds. This method allows for extended drug storage.

Dr. Neukirch reported financial relationships with Viatris, Stallergènes, ALK, Astrazeneca, Sanofi, GSK, and Novartis.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

PARIS — Irritable bowel syndrome (IBS) is a common brain-gut axis disorder, and patients are often dissatisfied with conventional treatments.

The role of the microbiota in IBS is now well established, and patients frequently take probiotics on their own initiative or on the advice of a physician or pharmacist. However, not all probiotics have equal efficacy, so which ones should be recommended?

Jean-Marc Sabaté, MD, PhD, a gastroenterologist at Avicenne Hospital in Bobigny, France, shared insights about probiotics at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

IBS, according to the Rome IV symptom-based classification, is a “disorder of brain-gut axis interactions” with a prevalence of about 4% in the adult population. In France, during an average care pathway of about 8 years, patients try an average of five therapeutic strategies (and as many as 11), including antispasmodics (85%), diets (78%), and probiotics. In addition, 66.4% of patients had either taken or were taking probiotics at the time of a recent survey.

While the 2022 recommendations from the American College of Gastroenterology on the diagnosis and management of IBS do not support the use of probiotics for overall symptom relief — a recommendation for which they cite a low level of evidence — “there is nevertheless a rationale for prescribing probiotics in IBS due to the significant role of the microbiota (or dysbiosis) in this condition,” said Dr. Sabaté.
 

Microbiota in IBS 

Evidence indicating that antibiotics exacerbate IBS symptoms and revealing chronic bacterial overgrowth in the small intestine of patients with IBS supports the role of the microbiota. Studies using a molecular approach (16s rRNA) have settled the debate, confirming differences in the intestinal flora between patients with IBS and healthy subjects. Data also indicate differences in flora between patient subtypes, such as an increased Firmicutes to Bacteroidetes ratio. However, one subgroup, which can represent as much as a third of patients, seems to harbor a “normal” microbiota. 

Nonetheless, the microbiota plays a significant role in IBS. A Swedish study highlighted the influence of bacterial enterotypes on transit type associated with IBS and symptom severity, independent of diet composition or medication use. 

This dysbiosis could play a significant role as it interacts with other mechanisms involved in IBS, including changes in intestinal motility related to diet (related to fermentable carbohydrates, for example). Moreover, the microbiota seems to induce a low level of immune activation in patients with IBS, leading to microinflammation and increased intestinal permeability, especially after an infection.

Furthermore, alterations in the regulation of bile acid deconjugation by the microbiota partly explain the frequency and consistency of stools in diarrhea-predominant IBS patients.

In addition, colonic gas production is higher in these patients. Those complaining of flatulence have poor tolerance to intestinal gases after a flatulent meal, associated with microbiota instability.

Data regarding the interaction between the microbiota and central mechanisms mainly come from animal studies. In rodents, microbiota constituents seem to affect brain development, function, and morphology. Emotional and physical traumas during childhood appear to be risk factors. Moreover, even brief exposure to broad-spectrum antibiotics in neonates could cause subsequent visceral hypersensitivity.

Lastly, the role of the microbiota in changes in medullary pain control after visceral stimulation (eg, rectal distension) has still not been demonstrated in humans.
 

Recent Guideline 

In its February 2023 Global Guideline “Probiotics and Prebiotics” for IBS, the World Gastroenterology Organization looked at the level of evidence for probiotics.

Three strains, as well as a combination of several strains, were supported by level 2 evidence, meaning at least two randomized studies with converging results. These are Bifidobacterium bifidum MIMBb75, which improves overall symptoms and quality of life; Lactobacillus plantarum 299v (DSM 9843), which acts on the severity of abdominal pain and bloating; and B infantis 35624 (new name: B longum 35624), which improves the overall assessment of IBS symptoms, as does the multistrain product containing L rhamnosus GG, L rhamnosus LC705, Propionibacterium freudenreichii ssp shermanii JS DSM 7067, and B animalis ssp lactis B012 DSM 15954.
 

Efficacy and Availability 

Probiotics belonging to the category of dietary supplements or medical devices are not required to provide evidence for a mechanism of action or even efficacy to be marketed. Thus, for most probiotics sold, there are no human or even animal studies available.

Dr. Sabaté proposed a choice of probiotics based on the literature and the presence of at least one randomized placebo-controlled trial conducted in patients with IBS showing positive results.

“Probiotic efficacy largely depends on the bacterial species, strain, and clinical situation treated. Only probiotics with demonstrated clinical efficacy in randomized placebo-controlled trials should be recommended,” he emphasized. The parameters that can be improved include symptom severity, quality of life, abdominal pain, and bloating.
 

Effective Probiotics 

B longum 35624, which was developed with researchers from University College Cork in Ireland, is probably the most studied in animals and humans. Research has encompassed the mechanistic, clinical, and safety aspects of the probiotic. It has shown good results on the IBS-Symptom Severity Score (SSS), quality of life, abdominal pain, bowel disturbances, and bloating. The treatment duration in studies is 4-8 weeks.

L plantarum 299v (DSM 9843) affects the frequency of abdominal pain and pain score. The treatment duration in studies is 4 weeks.

The multistrain product that includes L plantarum CECT 7484/L plantarum CECT 7485/ Pediococcus acidilactici CECT 7483 allows for an improvement in quality of life and anxiety related to digestive symptoms. No positive effect has been described on digestive symptoms, especially diarrhea. The treatment duration is 6 weeks.

B bifidum MIMBb75 (both normal and heat-inactivated forms) is beneficial for pain, the composite IBS-SSS score, and quality of life. The treatment duration is 4-8 weeks.

“Except for the multistrain combination, which is more suited to patients with diarrhea-predominant IBS, the other three probiotics can be prescribed regardless of the IBS subtype,” said Dr. Sabaté. “Treatment durations are typically 4 weeks, but it is possible to continue up to 8 weeks, which is the maximum duration of these studies. In practice, there are no tolerance issues with probiotics prescribed for IBS based on the literature. These should be tested under the conditions and for the duration of the published studies and should only be continued if there is individual benefit on symptoms or quality of life.”

Note that microbiota analyses conducted for individual purposes are of no help in choosing probiotics.
 

Mechanisms of Action 

In a murine model, but not in humans, some strains, especially L acidophilus NCFM, have shown an antinociceptive effect by inducing opioid and cannabinoid receptors.

Only in animals to date, L farciminis and B lactis CNCM I-2494 have shown prevention of induced hypersensitivity (ie, inhibition of the cytoskeleton contraction of colon epithelial cells and subsequent opening of tight junctions).

B infantis 35624 has an anti-inflammatory action by modifying the IL-10 and IL-12 cytokine ratio in animals and humans. It has an immunomodulatory action by increasing dendritic cells in the mucosa and decreasing Th1 and Th7 helper T cells.

B infantis 35624 and L farciminis are two strains that decrease visceral sensitivity in mice.

Escherichia coli Nissle 1917 acts on lipopeptide production with an antinociceptive effect, as observed in mice, by decreasing visceral sensitivity through calcium nociceptor flux blockade (action on GABA type B receptor).

Acting on dysbiosis by modifying fecal microbiota during probiotic intake is possible but depends on the probiotics, like B infantis 35624. In humans, B longum NCC 3001 could modify brain activations.

Dr. Sabaté disclosed financial relationships with Mayoly Spindler, Kyowa Kirin, Tillotts, Servier, Norgine, Biocodex, Merck, Viatris, Abivax, and Inventiva.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

PARIS — Irritable bowel syndrome (IBS) is a common brain-gut axis disorder, and patients are often dissatisfied with conventional treatments.

The role of the microbiota in IBS is now well established, and patients frequently take probiotics on their own initiative or on the advice of a physician or pharmacist. However, not all probiotics have equal efficacy, so which ones should be recommended?

Jean-Marc Sabaté, MD, PhD, a gastroenterologist at Avicenne Hospital in Bobigny, France, shared insights about probiotics at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

IBS, according to the Rome IV symptom-based classification, is a “disorder of brain-gut axis interactions” with a prevalence of about 4% in the adult population. In France, during an average care pathway of about 8 years, patients try an average of five therapeutic strategies (and as many as 11), including antispasmodics (85%), diets (78%), and probiotics. In addition, 66.4% of patients had either taken or were taking probiotics at the time of a recent survey.

While the 2022 recommendations from the American College of Gastroenterology on the diagnosis and management of IBS do not support the use of probiotics for overall symptom relief — a recommendation for which they cite a low level of evidence — “there is nevertheless a rationale for prescribing probiotics in IBS due to the significant role of the microbiota (or dysbiosis) in this condition,” said Dr. Sabaté.
 

Microbiota in IBS 

Evidence indicating that antibiotics exacerbate IBS symptoms and revealing chronic bacterial overgrowth in the small intestine of patients with IBS supports the role of the microbiota. Studies using a molecular approach (16s rRNA) have settled the debate, confirming differences in the intestinal flora between patients with IBS and healthy subjects. Data also indicate differences in flora between patient subtypes, such as an increased Firmicutes to Bacteroidetes ratio. However, one subgroup, which can represent as much as a third of patients, seems to harbor a “normal” microbiota. 

Nonetheless, the microbiota plays a significant role in IBS. A Swedish study highlighted the influence of bacterial enterotypes on transit type associated with IBS and symptom severity, independent of diet composition or medication use. 

This dysbiosis could play a significant role as it interacts with other mechanisms involved in IBS, including changes in intestinal motility related to diet (related to fermentable carbohydrates, for example). Moreover, the microbiota seems to induce a low level of immune activation in patients with IBS, leading to microinflammation and increased intestinal permeability, especially after an infection.

Furthermore, alterations in the regulation of bile acid deconjugation by the microbiota partly explain the frequency and consistency of stools in diarrhea-predominant IBS patients.

In addition, colonic gas production is higher in these patients. Those complaining of flatulence have poor tolerance to intestinal gases after a flatulent meal, associated with microbiota instability.

Data regarding the interaction between the microbiota and central mechanisms mainly come from animal studies. In rodents, microbiota constituents seem to affect brain development, function, and morphology. Emotional and physical traumas during childhood appear to be risk factors. Moreover, even brief exposure to broad-spectrum antibiotics in neonates could cause subsequent visceral hypersensitivity.

Lastly, the role of the microbiota in changes in medullary pain control after visceral stimulation (eg, rectal distension) has still not been demonstrated in humans.
 

Recent Guideline 

In its February 2023 Global Guideline “Probiotics and Prebiotics” for IBS, the World Gastroenterology Organization looked at the level of evidence for probiotics.

Three strains, as well as a combination of several strains, were supported by level 2 evidence, meaning at least two randomized studies with converging results. These are Bifidobacterium bifidum MIMBb75, which improves overall symptoms and quality of life; Lactobacillus plantarum 299v (DSM 9843), which acts on the severity of abdominal pain and bloating; and B infantis 35624 (new name: B longum 35624), which improves the overall assessment of IBS symptoms, as does the multistrain product containing L rhamnosus GG, L rhamnosus LC705, Propionibacterium freudenreichii ssp shermanii JS DSM 7067, and B animalis ssp lactis B012 DSM 15954.
 

Efficacy and Availability 

Probiotics belonging to the category of dietary supplements or medical devices are not required to provide evidence for a mechanism of action or even efficacy to be marketed. Thus, for most probiotics sold, there are no human or even animal studies available.

Dr. Sabaté proposed a choice of probiotics based on the literature and the presence of at least one randomized placebo-controlled trial conducted in patients with IBS showing positive results.

“Probiotic efficacy largely depends on the bacterial species, strain, and clinical situation treated. Only probiotics with demonstrated clinical efficacy in randomized placebo-controlled trials should be recommended,” he emphasized. The parameters that can be improved include symptom severity, quality of life, abdominal pain, and bloating.
 

Effective Probiotics 

B longum 35624, which was developed with researchers from University College Cork in Ireland, is probably the most studied in animals and humans. Research has encompassed the mechanistic, clinical, and safety aspects of the probiotic. It has shown good results on the IBS-Symptom Severity Score (SSS), quality of life, abdominal pain, bowel disturbances, and bloating. The treatment duration in studies is 4-8 weeks.

L plantarum 299v (DSM 9843) affects the frequency of abdominal pain and pain score. The treatment duration in studies is 4 weeks.

The multistrain product that includes L plantarum CECT 7484/L plantarum CECT 7485/ Pediococcus acidilactici CECT 7483 allows for an improvement in quality of life and anxiety related to digestive symptoms. No positive effect has been described on digestive symptoms, especially diarrhea. The treatment duration is 6 weeks.

B bifidum MIMBb75 (both normal and heat-inactivated forms) is beneficial for pain, the composite IBS-SSS score, and quality of life. The treatment duration is 4-8 weeks.

“Except for the multistrain combination, which is more suited to patients with diarrhea-predominant IBS, the other three probiotics can be prescribed regardless of the IBS subtype,” said Dr. Sabaté. “Treatment durations are typically 4 weeks, but it is possible to continue up to 8 weeks, which is the maximum duration of these studies. In practice, there are no tolerance issues with probiotics prescribed for IBS based on the literature. These should be tested under the conditions and for the duration of the published studies and should only be continued if there is individual benefit on symptoms or quality of life.”

Note that microbiota analyses conducted for individual purposes are of no help in choosing probiotics.
 

Mechanisms of Action 

In a murine model, but not in humans, some strains, especially L acidophilus NCFM, have shown an antinociceptive effect by inducing opioid and cannabinoid receptors.

Only in animals to date, L farciminis and B lactis CNCM I-2494 have shown prevention of induced hypersensitivity (ie, inhibition of the cytoskeleton contraction of colon epithelial cells and subsequent opening of tight junctions).

B infantis 35624 has an anti-inflammatory action by modifying the IL-10 and IL-12 cytokine ratio in animals and humans. It has an immunomodulatory action by increasing dendritic cells in the mucosa and decreasing Th1 and Th7 helper T cells.

B infantis 35624 and L farciminis are two strains that decrease visceral sensitivity in mice.

Escherichia coli Nissle 1917 acts on lipopeptide production with an antinociceptive effect, as observed in mice, by decreasing visceral sensitivity through calcium nociceptor flux blockade (action on GABA type B receptor).

Acting on dysbiosis by modifying fecal microbiota during probiotic intake is possible but depends on the probiotics, like B infantis 35624. In humans, B longum NCC 3001 could modify brain activations.

Dr. Sabaté disclosed financial relationships with Mayoly Spindler, Kyowa Kirin, Tillotts, Servier, Norgine, Biocodex, Merck, Viatris, Abivax, and Inventiva.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

PARIS — Irritable bowel syndrome (IBS) is a common brain-gut axis disorder, and patients are often dissatisfied with conventional treatments.

The role of the microbiota in IBS is now well established, and patients frequently take probiotics on their own initiative or on the advice of a physician or pharmacist. However, not all probiotics have equal efficacy, so which ones should be recommended?

Jean-Marc Sabaté, MD, PhD, a gastroenterologist at Avicenne Hospital in Bobigny, France, shared insights about probiotics at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

IBS, according to the Rome IV symptom-based classification, is a “disorder of brain-gut axis interactions” with a prevalence of about 4% in the adult population. In France, during an average care pathway of about 8 years, patients try an average of five therapeutic strategies (and as many as 11), including antispasmodics (85%), diets (78%), and probiotics. In addition, 66.4% of patients had either taken or were taking probiotics at the time of a recent survey.

While the 2022 recommendations from the American College of Gastroenterology on the diagnosis and management of IBS do not support the use of probiotics for overall symptom relief — a recommendation for which they cite a low level of evidence — “there is nevertheless a rationale for prescribing probiotics in IBS due to the significant role of the microbiota (or dysbiosis) in this condition,” said Dr. Sabaté.
 

Microbiota in IBS 

Evidence indicating that antibiotics exacerbate IBS symptoms and revealing chronic bacterial overgrowth in the small intestine of patients with IBS supports the role of the microbiota. Studies using a molecular approach (16s rRNA) have settled the debate, confirming differences in the intestinal flora between patients with IBS and healthy subjects. Data also indicate differences in flora between patient subtypes, such as an increased Firmicutes to Bacteroidetes ratio. However, one subgroup, which can represent as much as a third of patients, seems to harbor a “normal” microbiota. 

Nonetheless, the microbiota plays a significant role in IBS. A Swedish study highlighted the influence of bacterial enterotypes on transit type associated with IBS and symptom severity, independent of diet composition or medication use. 

This dysbiosis could play a significant role as it interacts with other mechanisms involved in IBS, including changes in intestinal motility related to diet (related to fermentable carbohydrates, for example). Moreover, the microbiota seems to induce a low level of immune activation in patients with IBS, leading to microinflammation and increased intestinal permeability, especially after an infection.

Furthermore, alterations in the regulation of bile acid deconjugation by the microbiota partly explain the frequency and consistency of stools in diarrhea-predominant IBS patients.

In addition, colonic gas production is higher in these patients. Those complaining of flatulence have poor tolerance to intestinal gases after a flatulent meal, associated with microbiota instability.

Data regarding the interaction between the microbiota and central mechanisms mainly come from animal studies. In rodents, microbiota constituents seem to affect brain development, function, and morphology. Emotional and physical traumas during childhood appear to be risk factors. Moreover, even brief exposure to broad-spectrum antibiotics in neonates could cause subsequent visceral hypersensitivity.

Lastly, the role of the microbiota in changes in medullary pain control after visceral stimulation (eg, rectal distension) has still not been demonstrated in humans.
 

Recent Guideline 

In its February 2023 Global Guideline “Probiotics and Prebiotics” for IBS, the World Gastroenterology Organization looked at the level of evidence for probiotics.

Three strains, as well as a combination of several strains, were supported by level 2 evidence, meaning at least two randomized studies with converging results. These are Bifidobacterium bifidum MIMBb75, which improves overall symptoms and quality of life; Lactobacillus plantarum 299v (DSM 9843), which acts on the severity of abdominal pain and bloating; and B infantis 35624 (new name: B longum 35624), which improves the overall assessment of IBS symptoms, as does the multistrain product containing L rhamnosus GG, L rhamnosus LC705, Propionibacterium freudenreichii ssp shermanii JS DSM 7067, and B animalis ssp lactis B012 DSM 15954.
 

Efficacy and Availability 

Probiotics belonging to the category of dietary supplements or medical devices are not required to provide evidence for a mechanism of action or even efficacy to be marketed. Thus, for most probiotics sold, there are no human or even animal studies available.

Dr. Sabaté proposed a choice of probiotics based on the literature and the presence of at least one randomized placebo-controlled trial conducted in patients with IBS showing positive results.

“Probiotic efficacy largely depends on the bacterial species, strain, and clinical situation treated. Only probiotics with demonstrated clinical efficacy in randomized placebo-controlled trials should be recommended,” he emphasized. The parameters that can be improved include symptom severity, quality of life, abdominal pain, and bloating.
 

Effective Probiotics 

B longum 35624, which was developed with researchers from University College Cork in Ireland, is probably the most studied in animals and humans. Research has encompassed the mechanistic, clinical, and safety aspects of the probiotic. It has shown good results on the IBS-Symptom Severity Score (SSS), quality of life, abdominal pain, bowel disturbances, and bloating. The treatment duration in studies is 4-8 weeks.

L plantarum 299v (DSM 9843) affects the frequency of abdominal pain and pain score. The treatment duration in studies is 4 weeks.

The multistrain product that includes L plantarum CECT 7484/L plantarum CECT 7485/ Pediococcus acidilactici CECT 7483 allows for an improvement in quality of life and anxiety related to digestive symptoms. No positive effect has been described on digestive symptoms, especially diarrhea. The treatment duration is 6 weeks.

B bifidum MIMBb75 (both normal and heat-inactivated forms) is beneficial for pain, the composite IBS-SSS score, and quality of life. The treatment duration is 4-8 weeks.

“Except for the multistrain combination, which is more suited to patients with diarrhea-predominant IBS, the other three probiotics can be prescribed regardless of the IBS subtype,” said Dr. Sabaté. “Treatment durations are typically 4 weeks, but it is possible to continue up to 8 weeks, which is the maximum duration of these studies. In practice, there are no tolerance issues with probiotics prescribed for IBS based on the literature. These should be tested under the conditions and for the duration of the published studies and should only be continued if there is individual benefit on symptoms or quality of life.”

Note that microbiota analyses conducted for individual purposes are of no help in choosing probiotics.
 

Mechanisms of Action 

In a murine model, but not in humans, some strains, especially L acidophilus NCFM, have shown an antinociceptive effect by inducing opioid and cannabinoid receptors.

Only in animals to date, L farciminis and B lactis CNCM I-2494 have shown prevention of induced hypersensitivity (ie, inhibition of the cytoskeleton contraction of colon epithelial cells and subsequent opening of tight junctions).

B infantis 35624 has an anti-inflammatory action by modifying the IL-10 and IL-12 cytokine ratio in animals and humans. It has an immunomodulatory action by increasing dendritic cells in the mucosa and decreasing Th1 and Th7 helper T cells.

B infantis 35624 and L farciminis are two strains that decrease visceral sensitivity in mice.

Escherichia coli Nissle 1917 acts on lipopeptide production with an antinociceptive effect, as observed in mice, by decreasing visceral sensitivity through calcium nociceptor flux blockade (action on GABA type B receptor).

Acting on dysbiosis by modifying fecal microbiota during probiotic intake is possible but depends on the probiotics, like B infantis 35624. In humans, B longum NCC 3001 could modify brain activations.

Dr. Sabaté disclosed financial relationships with Mayoly Spindler, Kyowa Kirin, Tillotts, Servier, Norgine, Biocodex, Merck, Viatris, Abivax, and Inventiva.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

What dietary recommendations are appropriate for gastroesophageal reflux disease (GERD)? While 85% of patients identify at least one food associated with reflux symptoms, misconceptions about diet in GERD are widespread. The issue was discussed during a dedicated session at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

GERD occurs when the contents, especially acid, of the stomach back up into the esophagus, leading to symptoms or lesions of the esophageal mucosa.

In addition to proton pump inhibitors, several hygienic-dietary rules are integrated into the therapeutic management of GERD. Some, such as elevating the head of the bed and allowing a 2- to 3-hour gap between meals and bedtime, have proven effective.

Diet and obesity also play a role in the onset of GERD symptoms. Thus, hygienic-dietary rules are an integral part of current recommendations.

“Weight loss is effective in reducing reflux symptoms and should be recommended,” stated Frank Zerbib, MD, head of Hepatology, Gastroenterology, and Digestive Oncology at University Hospital of Bordeaux in France, during the presentation.

Furthermore, most patients with GERD identify foods that may trigger their symptoms, even if there is no evidence to support this in the literature. However, it has been shown that reducing the consumption of these foods is effective.
 

Caloric Intake and Lipid Content

Meal intake affects esophagogastric physiology in several ways: It reduces the tone of the lower esophageal sphincter (LES) and increases the number of transient LES relaxations (TLESRs), which are induced by distension and relaxation of the proximal stomach. These effects are mediated by vagal afferent stimulation and the stretching of the mechanoreceptors of the fundic wall. They are influenced by neuropeptide effects such as cholecystokinin (CCK), which is released in the presence of lipids in the duodenal lumen. Hence, the importance of caloric intake and lipid content, even though it is difficult to distinguish their respective effects.

A high-calorie meal slows gastric emptying, thus prolonging gastric distension, reducing LES tone, and promoting the onset of TLESRs. Several studies have emphasized that at equivalent caloric intake, lipid composition has no impact on LES tone and the number of TLESRs in healthy patients or those with GERD. However, with equivalent caloric intake, and thus equivalent acid exposure, the presence of lipids in the meal increases the perception of reflux. This “reflux hypersensitivity” effect induced by lipids is caused by the endogenous release of CCK and its action on vagal afferents. This effect also is observed in the perception of functional dyspepsia symptoms.

Several studies have established a correlation between saturated fat consumption and the presence of GERD symptoms.
 

The Role of Carbohydrates

While the protein component of a meal has little impact on esophagogastric physiology, carbohydrates produce effects on esophagogastric motility that are mediated by their fermentation products, especially short-chain fatty acids (SCFAs), which are synthesized in the colon. Colonic perfusion of these SCFAs leads to fundus relaxation, reduced LES tone, and increased TLESRs. Moreover, in patients with GERD, adding prebiotics (fructo-oligosaccharide) to the meal content increases the number of TLESRs, acid reflux, and symptoms by amplifying colonic fermentation and SCFA production.

Several studies have evaluated low-carbohydrate diets in GERD. A small study of eight patients with morbid obesity on a very low–carbohydrate diet observed benefits on symptoms and esophageal acid exposure in pH probe testing.

A randomized French study of 31 patients with refractory GERD found no significant difference between a low fermentable oligo-, di-, monosaccharides, and polyols diet and usual dietary advice.

A recent American study of 95 veterans found an improvement in pH in the group reducing simple sugars but symptomatic improvement in all groups reducing sugar consumption in general.

Therefore, based on all these data, according to Dr. Zerbib, “high-calorie meals, rich in fats or carbohydrates, promote the onset of reflux episodes and their perception. Diets low in fats and carbohydrates should be recommended.”
 

Questionable Studies

Certain foods can reduce LES pressure, such as coffee (excluding decaf), chocolate, and white wine. Moreover, white wine, beer, and chocolate have been associated with increased esophageal acid exposure. No significant effects on LES pressure or reflux have been observed with the consumption of citrus fruits or spicy foods. These conclusions, however, are based on older studies and subject to methodological criticisms.

Population studies on tea and coffee yield conflicting results. A recent study of 48,000 nurses without documented GERD found that consumption of tea, coffee, or sodas increased the risk for reflux symptoms by about 30% at least once per week, while water, milk, or fruit juice had no effect. Furthermore, the consumption of carbonated beverages also does not seem to increase the risk for GERD.

Regarding alcohol consumption as a risk factor for GERD, epidemiological data do not allow for a definitive conclusion. Most studies have not found a significant link, a finding confirmed by a recent meta-analysis of 24 publications.

Obesity contributes to GERD by promoting increased abdominal pressure and constraints on the esophagogastric junction. A high-resolution manometry study provided robust evidence for this mechanism. Generally, the relative risk for symptomatic GERD with obesity is 2-3 compared with normal body mass index (BMI), with a linear increase according to BMI.

Dr. Zerbib reported no relevant financial conflicts related to his presentation.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

What dietary recommendations are appropriate for gastroesophageal reflux disease (GERD)? While 85% of patients identify at least one food associated with reflux symptoms, misconceptions about diet in GERD are widespread. The issue was discussed during a dedicated session at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

GERD occurs when the contents, especially acid, of the stomach back up into the esophagus, leading to symptoms or lesions of the esophageal mucosa.

In addition to proton pump inhibitors, several hygienic-dietary rules are integrated into the therapeutic management of GERD. Some, such as elevating the head of the bed and allowing a 2- to 3-hour gap between meals and bedtime, have proven effective.

Diet and obesity also play a role in the onset of GERD symptoms. Thus, hygienic-dietary rules are an integral part of current recommendations.

“Weight loss is effective in reducing reflux symptoms and should be recommended,” stated Frank Zerbib, MD, head of Hepatology, Gastroenterology, and Digestive Oncology at University Hospital of Bordeaux in France, during the presentation.

Furthermore, most patients with GERD identify foods that may trigger their symptoms, even if there is no evidence to support this in the literature. However, it has been shown that reducing the consumption of these foods is effective.
 

Caloric Intake and Lipid Content

Meal intake affects esophagogastric physiology in several ways: It reduces the tone of the lower esophageal sphincter (LES) and increases the number of transient LES relaxations (TLESRs), which are induced by distension and relaxation of the proximal stomach. These effects are mediated by vagal afferent stimulation and the stretching of the mechanoreceptors of the fundic wall. They are influenced by neuropeptide effects such as cholecystokinin (CCK), which is released in the presence of lipids in the duodenal lumen. Hence, the importance of caloric intake and lipid content, even though it is difficult to distinguish their respective effects.

A high-calorie meal slows gastric emptying, thus prolonging gastric distension, reducing LES tone, and promoting the onset of TLESRs. Several studies have emphasized that at equivalent caloric intake, lipid composition has no impact on LES tone and the number of TLESRs in healthy patients or those with GERD. However, with equivalent caloric intake, and thus equivalent acid exposure, the presence of lipids in the meal increases the perception of reflux. This “reflux hypersensitivity” effect induced by lipids is caused by the endogenous release of CCK and its action on vagal afferents. This effect also is observed in the perception of functional dyspepsia symptoms.

Several studies have established a correlation between saturated fat consumption and the presence of GERD symptoms.
 

The Role of Carbohydrates

While the protein component of a meal has little impact on esophagogastric physiology, carbohydrates produce effects on esophagogastric motility that are mediated by their fermentation products, especially short-chain fatty acids (SCFAs), which are synthesized in the colon. Colonic perfusion of these SCFAs leads to fundus relaxation, reduced LES tone, and increased TLESRs. Moreover, in patients with GERD, adding prebiotics (fructo-oligosaccharide) to the meal content increases the number of TLESRs, acid reflux, and symptoms by amplifying colonic fermentation and SCFA production.

Several studies have evaluated low-carbohydrate diets in GERD. A small study of eight patients with morbid obesity on a very low–carbohydrate diet observed benefits on symptoms and esophageal acid exposure in pH probe testing.

A randomized French study of 31 patients with refractory GERD found no significant difference between a low fermentable oligo-, di-, monosaccharides, and polyols diet and usual dietary advice.

A recent American study of 95 veterans found an improvement in pH in the group reducing simple sugars but symptomatic improvement in all groups reducing sugar consumption in general.

Therefore, based on all these data, according to Dr. Zerbib, “high-calorie meals, rich in fats or carbohydrates, promote the onset of reflux episodes and their perception. Diets low in fats and carbohydrates should be recommended.”
 

Questionable Studies

Certain foods can reduce LES pressure, such as coffee (excluding decaf), chocolate, and white wine. Moreover, white wine, beer, and chocolate have been associated with increased esophageal acid exposure. No significant effects on LES pressure or reflux have been observed with the consumption of citrus fruits or spicy foods. These conclusions, however, are based on older studies and subject to methodological criticisms.

Population studies on tea and coffee yield conflicting results. A recent study of 48,000 nurses without documented GERD found that consumption of tea, coffee, or sodas increased the risk for reflux symptoms by about 30% at least once per week, while water, milk, or fruit juice had no effect. Furthermore, the consumption of carbonated beverages also does not seem to increase the risk for GERD.

Regarding alcohol consumption as a risk factor for GERD, epidemiological data do not allow for a definitive conclusion. Most studies have not found a significant link, a finding confirmed by a recent meta-analysis of 24 publications.

Obesity contributes to GERD by promoting increased abdominal pressure and constraints on the esophagogastric junction. A high-resolution manometry study provided robust evidence for this mechanism. Generally, the relative risk for symptomatic GERD with obesity is 2-3 compared with normal body mass index (BMI), with a linear increase according to BMI.

Dr. Zerbib reported no relevant financial conflicts related to his presentation.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

What dietary recommendations are appropriate for gastroesophageal reflux disease (GERD)? While 85% of patients identify at least one food associated with reflux symptoms, misconceptions about diet in GERD are widespread. The issue was discussed during a dedicated session at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

GERD occurs when the contents, especially acid, of the stomach back up into the esophagus, leading to symptoms or lesions of the esophageal mucosa.

In addition to proton pump inhibitors, several hygienic-dietary rules are integrated into the therapeutic management of GERD. Some, such as elevating the head of the bed and allowing a 2- to 3-hour gap between meals and bedtime, have proven effective.

Diet and obesity also play a role in the onset of GERD symptoms. Thus, hygienic-dietary rules are an integral part of current recommendations.

“Weight loss is effective in reducing reflux symptoms and should be recommended,” stated Frank Zerbib, MD, head of Hepatology, Gastroenterology, and Digestive Oncology at University Hospital of Bordeaux in France, during the presentation.

Furthermore, most patients with GERD identify foods that may trigger their symptoms, even if there is no evidence to support this in the literature. However, it has been shown that reducing the consumption of these foods is effective.
 

Caloric Intake and Lipid Content

Meal intake affects esophagogastric physiology in several ways: It reduces the tone of the lower esophageal sphincter (LES) and increases the number of transient LES relaxations (TLESRs), which are induced by distension and relaxation of the proximal stomach. These effects are mediated by vagal afferent stimulation and the stretching of the mechanoreceptors of the fundic wall. They are influenced by neuropeptide effects such as cholecystokinin (CCK), which is released in the presence of lipids in the duodenal lumen. Hence, the importance of caloric intake and lipid content, even though it is difficult to distinguish their respective effects.

A high-calorie meal slows gastric emptying, thus prolonging gastric distension, reducing LES tone, and promoting the onset of TLESRs. Several studies have emphasized that at equivalent caloric intake, lipid composition has no impact on LES tone and the number of TLESRs in healthy patients or those with GERD. However, with equivalent caloric intake, and thus equivalent acid exposure, the presence of lipids in the meal increases the perception of reflux. This “reflux hypersensitivity” effect induced by lipids is caused by the endogenous release of CCK and its action on vagal afferents. This effect also is observed in the perception of functional dyspepsia symptoms.

Several studies have established a correlation between saturated fat consumption and the presence of GERD symptoms.
 

The Role of Carbohydrates

While the protein component of a meal has little impact on esophagogastric physiology, carbohydrates produce effects on esophagogastric motility that are mediated by their fermentation products, especially short-chain fatty acids (SCFAs), which are synthesized in the colon. Colonic perfusion of these SCFAs leads to fundus relaxation, reduced LES tone, and increased TLESRs. Moreover, in patients with GERD, adding prebiotics (fructo-oligosaccharide) to the meal content increases the number of TLESRs, acid reflux, and symptoms by amplifying colonic fermentation and SCFA production.

Several studies have evaluated low-carbohydrate diets in GERD. A small study of eight patients with morbid obesity on a very low–carbohydrate diet observed benefits on symptoms and esophageal acid exposure in pH probe testing.

A randomized French study of 31 patients with refractory GERD found no significant difference between a low fermentable oligo-, di-, monosaccharides, and polyols diet and usual dietary advice.

A recent American study of 95 veterans found an improvement in pH in the group reducing simple sugars but symptomatic improvement in all groups reducing sugar consumption in general.

Therefore, based on all these data, according to Dr. Zerbib, “high-calorie meals, rich in fats or carbohydrates, promote the onset of reflux episodes and their perception. Diets low in fats and carbohydrates should be recommended.”
 

Questionable Studies

Certain foods can reduce LES pressure, such as coffee (excluding decaf), chocolate, and white wine. Moreover, white wine, beer, and chocolate have been associated with increased esophageal acid exposure. No significant effects on LES pressure or reflux have been observed with the consumption of citrus fruits or spicy foods. These conclusions, however, are based on older studies and subject to methodological criticisms.

Population studies on tea and coffee yield conflicting results. A recent study of 48,000 nurses without documented GERD found that consumption of tea, coffee, or sodas increased the risk for reflux symptoms by about 30% at least once per week, while water, milk, or fruit juice had no effect. Furthermore, the consumption of carbonated beverages also does not seem to increase the risk for GERD.

Regarding alcohol consumption as a risk factor for GERD, epidemiological data do not allow for a definitive conclusion. Most studies have not found a significant link, a finding confirmed by a recent meta-analysis of 24 publications.

Obesity contributes to GERD by promoting increased abdominal pressure and constraints on the esophagogastric junction. A high-resolution manometry study provided robust evidence for this mechanism. Generally, the relative risk for symptomatic GERD with obesity is 2-3 compared with normal body mass index (BMI), with a linear increase according to BMI.

Dr. Zerbib reported no relevant financial conflicts related to his presentation.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

The report from the 2023 annual conference of French Urology Association (AFU), which was dedicated to male fertility, focused heavily on the diagnosis and treatment of varicocele, the most common reversible cause of infertility in men. Long a controversial subject, it has now been determined that treating this condition improves sperm analysis results, spontaneous fertility, and outcomes from medically assisted reproduction techniques. The AFU’s conference was a chance to present an overall snapshot of the issue.

Between 1973 and 2018, male sperm concentration dropped by 51.6% around the world, whereas total sperm counts dropped by 62.3%, according to Charlotte Methorst, MD, urological surgeon in Saint Cloud, France, president of the French Language Andrology Society, and coordinator of the AFU 2023 Report on Male Fertility. What’s more, sperm plasma concentrations are going down year-on-year at a rate twice as fast since before 2000 compared with the post-1972 period (from 1.16% to 2.64%).
 

Declining Fertility

Nowadays, around 15% of couples experience infertility (60,000 new cases/year in France). About 20% of these are strictly attributed to male infertility and 40% are mixed, implying a male factor. Consequently, Dr. Methorst explained that “we must routinely assess male fertility within the context of a medically assisted reproduction (MAR) pathway, without limiting testing to semen analysis. Varicocele, one of the causes of infertility that men should be screened for and defined as an abnormal and/or tortuous enlargement of the pampiniform plexus veins, is present in 15%-20% of the overall male population, 35% of men with primary infertility, and more than 70% of those experiencing secondary infertility.”

In infertile men, varicocele is mostly unilateral, occurring on the left side (85%-90% of cases). A link has been established between varicocele and insufficiency at the saphenofemoral junction, as well as venous insufficiency of the lower limbs (odds ratio, 2.34; P < .0001), suggesting a predisposition towards a vascular network favoring the presence of varicoceles.
 

Varicocele Underdiagnosed

Analysis of a large multicenter database recently suggested the underdiagnosis of varicocele in men being assessed for infertility. Diagnosis is primarily based on physical examination, with physicians finding a soft, serpiginous swelling in the upper and posterior part of the affected side of the scrotum. Testicular Doppler ultrasonography provides confirmation of a varicocele, taking into account aspects such as size and reflux duration during the Valsalva maneuver. Generally, this is enough to make a differential diagnosis, but MRI may be considered, especially in cases where a millimeter-sized nodule is also found.
 

Reversal Improves Fertility

A Cochrane meta-analysis, despite containing significant bias, raised doubts about the efficacy of varicocele treatment. Nevertheless, over the past 10 years, a randomized trial and several meta-analyses have put an end to the controversy, confirming that treatment for varicocele significantly improves natural pregnancy rates.

Microscopic subinguinal varicocelectomy is the gold-standard option for cases of clinical varicocele and for those in which sperm analysis findings are abnormal. This approach is associated with superior efficacy outcomes, such as improvement in sperm analysis results and pregnancy rates while leading to lower rates of recurrence (< 4%) and a favorable outcome in terms of complications. It should be noted that treating subclinical varicocele is not recommended.

Specifically, microscopic subinguinal varicocelectomy improves live birth and pregnancy rates, both naturally and via in vitro fertilization. What’s more, it has a positive impact on sperm count, total and progressive motility, morphology, and DNA fragmentation levels. Overall, this surgery changes the MAR approach used in around one in two cases. The grade and unilateral or bilateral nature of varicocele are important predictive factors of improvement in sperm analysis findings and pregnancy rates associated with this interventional procedure. Treating clinical varicocele (grades 1-3) leads to improved sperm analysis results, observed in 60%-70% of cases. According to a meta-analysis, the mean increase is said to be a concentration of 12 million spermatozoids per milliliter, as well as a mean improvement of 11% in sperm motility.

Notably, embolization can be considered as an alternative to surgery. This minimally invasive X-ray-guided procedure performed by an interventional radiologist attempts to block the dilated testicular vein.

Guidelines for clinical practice in treating varicocele were recently published by the AFU’s Andrology committee.

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

The report from the 2023 annual conference of French Urology Association (AFU), which was dedicated to male fertility, focused heavily on the diagnosis and treatment of varicocele, the most common reversible cause of infertility in men. Long a controversial subject, it has now been determined that treating this condition improves sperm analysis results, spontaneous fertility, and outcomes from medically assisted reproduction techniques. The AFU’s conference was a chance to present an overall snapshot of the issue.

Between 1973 and 2018, male sperm concentration dropped by 51.6% around the world, whereas total sperm counts dropped by 62.3%, according to Charlotte Methorst, MD, urological surgeon in Saint Cloud, France, president of the French Language Andrology Society, and coordinator of the AFU 2023 Report on Male Fertility. What’s more, sperm plasma concentrations are going down year-on-year at a rate twice as fast since before 2000 compared with the post-1972 period (from 1.16% to 2.64%).
 

Declining Fertility

Nowadays, around 15% of couples experience infertility (60,000 new cases/year in France). About 20% of these are strictly attributed to male infertility and 40% are mixed, implying a male factor. Consequently, Dr. Methorst explained that “we must routinely assess male fertility within the context of a medically assisted reproduction (MAR) pathway, without limiting testing to semen analysis. Varicocele, one of the causes of infertility that men should be screened for and defined as an abnormal and/or tortuous enlargement of the pampiniform plexus veins, is present in 15%-20% of the overall male population, 35% of men with primary infertility, and more than 70% of those experiencing secondary infertility.”

In infertile men, varicocele is mostly unilateral, occurring on the left side (85%-90% of cases). A link has been established between varicocele and insufficiency at the saphenofemoral junction, as well as venous insufficiency of the lower limbs (odds ratio, 2.34; P < .0001), suggesting a predisposition towards a vascular network favoring the presence of varicoceles.
 

Varicocele Underdiagnosed

Analysis of a large multicenter database recently suggested the underdiagnosis of varicocele in men being assessed for infertility. Diagnosis is primarily based on physical examination, with physicians finding a soft, serpiginous swelling in the upper and posterior part of the affected side of the scrotum. Testicular Doppler ultrasonography provides confirmation of a varicocele, taking into account aspects such as size and reflux duration during the Valsalva maneuver. Generally, this is enough to make a differential diagnosis, but MRI may be considered, especially in cases where a millimeter-sized nodule is also found.
 

Reversal Improves Fertility

A Cochrane meta-analysis, despite containing significant bias, raised doubts about the efficacy of varicocele treatment. Nevertheless, over the past 10 years, a randomized trial and several meta-analyses have put an end to the controversy, confirming that treatment for varicocele significantly improves natural pregnancy rates.

Microscopic subinguinal varicocelectomy is the gold-standard option for cases of clinical varicocele and for those in which sperm analysis findings are abnormal. This approach is associated with superior efficacy outcomes, such as improvement in sperm analysis results and pregnancy rates while leading to lower rates of recurrence (< 4%) and a favorable outcome in terms of complications. It should be noted that treating subclinical varicocele is not recommended.

Specifically, microscopic subinguinal varicocelectomy improves live birth and pregnancy rates, both naturally and via in vitro fertilization. What’s more, it has a positive impact on sperm count, total and progressive motility, morphology, and DNA fragmentation levels. Overall, this surgery changes the MAR approach used in around one in two cases. The grade and unilateral or bilateral nature of varicocele are important predictive factors of improvement in sperm analysis findings and pregnancy rates associated with this interventional procedure. Treating clinical varicocele (grades 1-3) leads to improved sperm analysis results, observed in 60%-70% of cases. According to a meta-analysis, the mean increase is said to be a concentration of 12 million spermatozoids per milliliter, as well as a mean improvement of 11% in sperm motility.

Notably, embolization can be considered as an alternative to surgery. This minimally invasive X-ray-guided procedure performed by an interventional radiologist attempts to block the dilated testicular vein.

Guidelines for clinical practice in treating varicocele were recently published by the AFU’s Andrology committee.

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

The report from the 2023 annual conference of French Urology Association (AFU), which was dedicated to male fertility, focused heavily on the diagnosis and treatment of varicocele, the most common reversible cause of infertility in men. Long a controversial subject, it has now been determined that treating this condition improves sperm analysis results, spontaneous fertility, and outcomes from medically assisted reproduction techniques. The AFU’s conference was a chance to present an overall snapshot of the issue.

Between 1973 and 2018, male sperm concentration dropped by 51.6% around the world, whereas total sperm counts dropped by 62.3%, according to Charlotte Methorst, MD, urological surgeon in Saint Cloud, France, president of the French Language Andrology Society, and coordinator of the AFU 2023 Report on Male Fertility. What’s more, sperm plasma concentrations are going down year-on-year at a rate twice as fast since before 2000 compared with the post-1972 period (from 1.16% to 2.64%).
 

Declining Fertility

Nowadays, around 15% of couples experience infertility (60,000 new cases/year in France). About 20% of these are strictly attributed to male infertility and 40% are mixed, implying a male factor. Consequently, Dr. Methorst explained that “we must routinely assess male fertility within the context of a medically assisted reproduction (MAR) pathway, without limiting testing to semen analysis. Varicocele, one of the causes of infertility that men should be screened for and defined as an abnormal and/or tortuous enlargement of the pampiniform plexus veins, is present in 15%-20% of the overall male population, 35% of men with primary infertility, and more than 70% of those experiencing secondary infertility.”

In infertile men, varicocele is mostly unilateral, occurring on the left side (85%-90% of cases). A link has been established between varicocele and insufficiency at the saphenofemoral junction, as well as venous insufficiency of the lower limbs (odds ratio, 2.34; P < .0001), suggesting a predisposition towards a vascular network favoring the presence of varicoceles.
 

Varicocele Underdiagnosed

Analysis of a large multicenter database recently suggested the underdiagnosis of varicocele in men being assessed for infertility. Diagnosis is primarily based on physical examination, with physicians finding a soft, serpiginous swelling in the upper and posterior part of the affected side of the scrotum. Testicular Doppler ultrasonography provides confirmation of a varicocele, taking into account aspects such as size and reflux duration during the Valsalva maneuver. Generally, this is enough to make a differential diagnosis, but MRI may be considered, especially in cases where a millimeter-sized nodule is also found.
 

Reversal Improves Fertility

A Cochrane meta-analysis, despite containing significant bias, raised doubts about the efficacy of varicocele treatment. Nevertheless, over the past 10 years, a randomized trial and several meta-analyses have put an end to the controversy, confirming that treatment for varicocele significantly improves natural pregnancy rates.

Microscopic subinguinal varicocelectomy is the gold-standard option for cases of clinical varicocele and for those in which sperm analysis findings are abnormal. This approach is associated with superior efficacy outcomes, such as improvement in sperm analysis results and pregnancy rates while leading to lower rates of recurrence (< 4%) and a favorable outcome in terms of complications. It should be noted that treating subclinical varicocele is not recommended.

Specifically, microscopic subinguinal varicocelectomy improves live birth and pregnancy rates, both naturally and via in vitro fertilization. What’s more, it has a positive impact on sperm count, total and progressive motility, morphology, and DNA fragmentation levels. Overall, this surgery changes the MAR approach used in around one in two cases. The grade and unilateral or bilateral nature of varicocele are important predictive factors of improvement in sperm analysis findings and pregnancy rates associated with this interventional procedure. Treating clinical varicocele (grades 1-3) leads to improved sperm analysis results, observed in 60%-70% of cases. According to a meta-analysis, the mean increase is said to be a concentration of 12 million spermatozoids per milliliter, as well as a mean improvement of 11% in sperm motility.

Notably, embolization can be considered as an alternative to surgery. This minimally invasive X-ray-guided procedure performed by an interventional radiologist attempts to block the dilated testicular vein.

Guidelines for clinical practice in treating varicocele were recently published by the AFU’s Andrology committee.

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Sabine Roman, MD, PhD, associate professor of gastroenterology and physiology at Lyon University Hospital in France, took the floor at the United European Gastroenterology Week to discuss the link between a chronic cough and gastroesophageal reflux disease (GERD). During a session on extraesophageal symptoms, Dr. Roman relayed two key messages: In patients with a chronic cough, reflux absolutely must be documented, and proton pump inhibitors (PPIs) must only be prescribed when a diagnosis of GERD has been made.
 

Overestimated Cause

Chronic cough is a widespread problem with a prevalence of between 9% and 33%, according to clinical studies. The root causes of this cough are varied; they’re mainly related to the respiratory system (eg, asthma, chronic obstructive pulmonary disease, respiratory infections, or smoking) and the ear, nose, and throat field (eg, postnasal drip). What’s more, taking certain medicines, notably angiotensin-converting enzyme inhibitors, can also be at the root of this condition.

GERD is also a possible cause of a chronic cough but one that is likely overestimated. A 2023 Spanish study provides evidence of this; GERD was suspected to be linked to cough in 46% of patients (compared with 32% for asthma and 15% for postnasal drip).

The treatments most commonly prescribed include PPIs (79.6%) and respiratory medicines (87.8%). Note that antibiotics are administered empirically to 28.6% of patients. For Roman, “the blame for a chronic cough is too often assigned to GERD, especially considering that in this study, only 43% of patients had seen a gastroenterologist, 27% had an endoscopy, and 24% had undergone esophageal pH monitoring.”

Added to this observation is the difficulty of establishing a causal link between a cough and GERD when the latter is present, even when the patient has had a diagnosis of GERD. Of course, a link between the two does not necessarily imply a cause–effect relationship, especially given that studies have shown that a cough itself can induce GERD. Studies using automatic cough detection to count cough events have shown that GERD certainly preceded a cough in 48% of patients, but in 56% of cases, it was the cough that came before the GERD. What’s more, both mechanisms were present in one third of patients.
 

Prescribing PPIs Effectively

PPIs are commonly prescribed as a test treatment. However, their efficacy is in no way proof of the existence of underlying GERD. In reality, all placebo-controlled studies have shown that in cases where no prior diagnosis of GERD has been made, PPIs have no superior efficacy.

If reflux has been proven, then the improvement provided by PPIs, compared with placebo, is between 12% and 35%. Therefore, it is essential that the presence of GERD be demonstrated, particularly if the patient has no characteristic symptoms of GERD, such as heartburn and acid reflux.

Response factors to PPIs were evaluated in 178 Italian patients with a chronic cough who presented with suspected GERD. Of those, 45% responded to treatment. It has been shown that typical symptoms, severe esophagitis (grade C/D), abnormal acid exposure, and low levels of nocturnal baseline impedance were independent factors of response to treatment.

In conclusion, patients with a chronic cough must be comprehensively tested for GERD before a long-term prescription of PPIs can be considered.
 

Cough Reflex Threshold

Various studies have also revealed that patients with GERD and presenting with a chronic cough have an increased sensitivity to the cough reflex. This hypersensitivity to the cough reflex has inspired several trials involving gabapentin and baclofen. A randomized controlled trial found the two treatments to be equally effective, achieving improvement of around 50%.

Lesogaberan, a new GABA(B) receptor agonist acting on the peripheral nervous system which is better tolerated than baclofen, a drug belonging to the same therapeutic class, showed a 26% benefit over placebo, but it was not statistically significant; lesogaberan has not been developed further.

Anti-reflux surgery is an option. A 2021 meta-analysis revealed that 84% of patients enrolled in these studies saw an improvement in their symptoms. However, these results must be regarded with caution because none of these studies were controlled, most of them were retrospective with very heterogeneous patient populations, and the data obtained on postoperative reflux control were often found to be lacking.

A retrospective study showed that among the factors for nonresponse or recurrence of symptoms after anti-reflux surgery, lack of response to medical treatment and extraesophageal symptoms such as a cough were significant factors. Consequently, potential candidates for surgery must be rigorously screened before being considered for such a procedure.

The recent recommendations for good practice published by the American Gastroenterological Association also insist that lack of response to medical treatment is a major factor for failure of surgical treatment.

In sum, patients with a chronic cough can be prescribed PPIs as first-line treatment if they have typical symptoms of GERD. In the event of treatment failure or isolated cough without typical symptoms, tests to confirm or rule out GERD are essential (such as endoscopy, esophageal pH monitoring, or impedance-pH monitoring).
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Sabine Roman, MD, PhD, associate professor of gastroenterology and physiology at Lyon University Hospital in France, took the floor at the United European Gastroenterology Week to discuss the link between a chronic cough and gastroesophageal reflux disease (GERD). During a session on extraesophageal symptoms, Dr. Roman relayed two key messages: In patients with a chronic cough, reflux absolutely must be documented, and proton pump inhibitors (PPIs) must only be prescribed when a diagnosis of GERD has been made.
 

Overestimated Cause

Chronic cough is a widespread problem with a prevalence of between 9% and 33%, according to clinical studies. The root causes of this cough are varied; they’re mainly related to the respiratory system (eg, asthma, chronic obstructive pulmonary disease, respiratory infections, or smoking) and the ear, nose, and throat field (eg, postnasal drip). What’s more, taking certain medicines, notably angiotensin-converting enzyme inhibitors, can also be at the root of this condition.

GERD is also a possible cause of a chronic cough but one that is likely overestimated. A 2023 Spanish study provides evidence of this; GERD was suspected to be linked to cough in 46% of patients (compared with 32% for asthma and 15% for postnasal drip).

The treatments most commonly prescribed include PPIs (79.6%) and respiratory medicines (87.8%). Note that antibiotics are administered empirically to 28.6% of patients. For Roman, “the blame for a chronic cough is too often assigned to GERD, especially considering that in this study, only 43% of patients had seen a gastroenterologist, 27% had an endoscopy, and 24% had undergone esophageal pH monitoring.”

Added to this observation is the difficulty of establishing a causal link between a cough and GERD when the latter is present, even when the patient has had a diagnosis of GERD. Of course, a link between the two does not necessarily imply a cause–effect relationship, especially given that studies have shown that a cough itself can induce GERD. Studies using automatic cough detection to count cough events have shown that GERD certainly preceded a cough in 48% of patients, but in 56% of cases, it was the cough that came before the GERD. What’s more, both mechanisms were present in one third of patients.
 

Prescribing PPIs Effectively

PPIs are commonly prescribed as a test treatment. However, their efficacy is in no way proof of the existence of underlying GERD. In reality, all placebo-controlled studies have shown that in cases where no prior diagnosis of GERD has been made, PPIs have no superior efficacy.

If reflux has been proven, then the improvement provided by PPIs, compared with placebo, is between 12% and 35%. Therefore, it is essential that the presence of GERD be demonstrated, particularly if the patient has no characteristic symptoms of GERD, such as heartburn and acid reflux.

Response factors to PPIs were evaluated in 178 Italian patients with a chronic cough who presented with suspected GERD. Of those, 45% responded to treatment. It has been shown that typical symptoms, severe esophagitis (grade C/D), abnormal acid exposure, and low levels of nocturnal baseline impedance were independent factors of response to treatment.

In conclusion, patients with a chronic cough must be comprehensively tested for GERD before a long-term prescription of PPIs can be considered.
 

Cough Reflex Threshold

Various studies have also revealed that patients with GERD and presenting with a chronic cough have an increased sensitivity to the cough reflex. This hypersensitivity to the cough reflex has inspired several trials involving gabapentin and baclofen. A randomized controlled trial found the two treatments to be equally effective, achieving improvement of around 50%.

Lesogaberan, a new GABA(B) receptor agonist acting on the peripheral nervous system which is better tolerated than baclofen, a drug belonging to the same therapeutic class, showed a 26% benefit over placebo, but it was not statistically significant; lesogaberan has not been developed further.

Anti-reflux surgery is an option. A 2021 meta-analysis revealed that 84% of patients enrolled in these studies saw an improvement in their symptoms. However, these results must be regarded with caution because none of these studies were controlled, most of them were retrospective with very heterogeneous patient populations, and the data obtained on postoperative reflux control were often found to be lacking.

A retrospective study showed that among the factors for nonresponse or recurrence of symptoms after anti-reflux surgery, lack of response to medical treatment and extraesophageal symptoms such as a cough were significant factors. Consequently, potential candidates for surgery must be rigorously screened before being considered for such a procedure.

The recent recommendations for good practice published by the American Gastroenterological Association also insist that lack of response to medical treatment is a major factor for failure of surgical treatment.

In sum, patients with a chronic cough can be prescribed PPIs as first-line treatment if they have typical symptoms of GERD. In the event of treatment failure or isolated cough without typical symptoms, tests to confirm or rule out GERD are essential (such as endoscopy, esophageal pH monitoring, or impedance-pH monitoring).
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Sabine Roman, MD, PhD, associate professor of gastroenterology and physiology at Lyon University Hospital in France, took the floor at the United European Gastroenterology Week to discuss the link between a chronic cough and gastroesophageal reflux disease (GERD). During a session on extraesophageal symptoms, Dr. Roman relayed two key messages: In patients with a chronic cough, reflux absolutely must be documented, and proton pump inhibitors (PPIs) must only be prescribed when a diagnosis of GERD has been made.
 

Overestimated Cause

Chronic cough is a widespread problem with a prevalence of between 9% and 33%, according to clinical studies. The root causes of this cough are varied; they’re mainly related to the respiratory system (eg, asthma, chronic obstructive pulmonary disease, respiratory infections, or smoking) and the ear, nose, and throat field (eg, postnasal drip). What’s more, taking certain medicines, notably angiotensin-converting enzyme inhibitors, can also be at the root of this condition.

GERD is also a possible cause of a chronic cough but one that is likely overestimated. A 2023 Spanish study provides evidence of this; GERD was suspected to be linked to cough in 46% of patients (compared with 32% for asthma and 15% for postnasal drip).

The treatments most commonly prescribed include PPIs (79.6%) and respiratory medicines (87.8%). Note that antibiotics are administered empirically to 28.6% of patients. For Roman, “the blame for a chronic cough is too often assigned to GERD, especially considering that in this study, only 43% of patients had seen a gastroenterologist, 27% had an endoscopy, and 24% had undergone esophageal pH monitoring.”

Added to this observation is the difficulty of establishing a causal link between a cough and GERD when the latter is present, even when the patient has had a diagnosis of GERD. Of course, a link between the two does not necessarily imply a cause–effect relationship, especially given that studies have shown that a cough itself can induce GERD. Studies using automatic cough detection to count cough events have shown that GERD certainly preceded a cough in 48% of patients, but in 56% of cases, it was the cough that came before the GERD. What’s more, both mechanisms were present in one third of patients.
 

Prescribing PPIs Effectively

PPIs are commonly prescribed as a test treatment. However, their efficacy is in no way proof of the existence of underlying GERD. In reality, all placebo-controlled studies have shown that in cases where no prior diagnosis of GERD has been made, PPIs have no superior efficacy.

If reflux has been proven, then the improvement provided by PPIs, compared with placebo, is between 12% and 35%. Therefore, it is essential that the presence of GERD be demonstrated, particularly if the patient has no characteristic symptoms of GERD, such as heartburn and acid reflux.

Response factors to PPIs were evaluated in 178 Italian patients with a chronic cough who presented with suspected GERD. Of those, 45% responded to treatment. It has been shown that typical symptoms, severe esophagitis (grade C/D), abnormal acid exposure, and low levels of nocturnal baseline impedance were independent factors of response to treatment.

In conclusion, patients with a chronic cough must be comprehensively tested for GERD before a long-term prescription of PPIs can be considered.
 

Cough Reflex Threshold

Various studies have also revealed that patients with GERD and presenting with a chronic cough have an increased sensitivity to the cough reflex. This hypersensitivity to the cough reflex has inspired several trials involving gabapentin and baclofen. A randomized controlled trial found the two treatments to be equally effective, achieving improvement of around 50%.

Lesogaberan, a new GABA(B) receptor agonist acting on the peripheral nervous system which is better tolerated than baclofen, a drug belonging to the same therapeutic class, showed a 26% benefit over placebo, but it was not statistically significant; lesogaberan has not been developed further.

Anti-reflux surgery is an option. A 2021 meta-analysis revealed that 84% of patients enrolled in these studies saw an improvement in their symptoms. However, these results must be regarded with caution because none of these studies were controlled, most of them were retrospective with very heterogeneous patient populations, and the data obtained on postoperative reflux control were often found to be lacking.

A retrospective study showed that among the factors for nonresponse or recurrence of symptoms after anti-reflux surgery, lack of response to medical treatment and extraesophageal symptoms such as a cough were significant factors. Consequently, potential candidates for surgery must be rigorously screened before being considered for such a procedure.

The recent recommendations for good practice published by the American Gastroenterological Association also insist that lack of response to medical treatment is a major factor for failure of surgical treatment.

In sum, patients with a chronic cough can be prescribed PPIs as first-line treatment if they have typical symptoms of GERD. In the event of treatment failure or isolated cough without typical symptoms, tests to confirm or rule out GERD are essential (such as endoscopy, esophageal pH monitoring, or impedance-pH monitoring).
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Multicancer early-detection blood (MCED) tests are the focus of intensive development. What techniques do these tests use? What potential do they show? Suzette Delaloge, MD, MSc, oncologist, breast cancer specialist, and director of the individualized cancer prevention program (Interception) at the Gustave Roussy Institute in Villejuif, France, looks into these “liquid biopsies” and shares her reservations about their potential marketing, especially to the organized care plans.

Question: What are the general principles underpinning these MCED tests?

Suzette Delaloge, MD, MSc: Despite their specificities, the general idea is to detect certain cancer markers in various body fluids (blood, urine, saliva, etc.), for example, molecules released by cancer cells (cytokines, inflammatory proteins, leptin, etc.) or distinctive features of the DNA in tumor cells. In blood, these molecules can be found in plasma or in serum. In urine, it’s more about detecting kidney, bladder, and urinary tract cancers.

Q: What sort of time frame are we looking at for these MCED tests to be used in routine practice?

Dr. Delaloge: They first appeared around 10 years ago. Development of these tests has intensified in recent years. There are numerous research laboratories, both public and private, that are developing different early-detection tests for cancer.

Some of these development processes are about to come to an end and are expected to be in regular, concrete use within 5-10 years. For the most advanced developments, the main biologic material researched and analyzed is DNA from cancer cells. We all have fragments of DNA from dead cells in our plasma (apoptosis), but cancer cells release more of these than others, and most importantly, their DNA has distinctive characteristics. The idea is to develop tests capable of detecting these characteristics.

Liquid biopsies based on genomic biomarkers could make MCED a reality, especially for cancers for which there is no standard screening process. But at this stage of the research, there are limitations, including low sensitivity for detecting stage I cancers in validation studies and an increased risk for overdiagnosis.

Q: What specific set of characteristics are the most advanced approaches based on?

Dr. Delaloge: They’re based on the analysis of DNA methylation, a biological process by which CH3 methyl groups are added to the DNA molecule and that determines gene expression. This phenomenon differs depending on whether the cell is cancerous. Among the tests currently under development making use of this specific characteristic is the Galleri test, which is the most advanced of them all.

A previous British National Health Service study, SYMPLIFY, which was published in 2023 by researchers at the University of Oxford, was conducted in symptomatic patients attending a health center. It offers promising results in a diagnostic situation. It has nothing at all to do with screening here. A large, randomized English study, NHS-Galleri, is underway, this time involving the general population, with the aim of assessing the potential benefit of the same test as screening in 140,000 people between ages 50 and 77 years.

In the SYMPLIFY study, which was carried out in symptomatic patients attending a health center, the Galleri MCED test had a positive predictive value of 75.5%, a negative predictive value of 97.6%, a sensitivity of 66.3%, and a specificity of 98.4%. Sensitivity increased with age and cancer stage from 24.2% at stage I to 95.3% at stage IV. For cases for which a cancer signal was detected in patients with cancer, the prediction of the original site of the cancer by the MCED test was accurate in 85.2% of cases. This large-scale prospective evaluation of an MCED diagnostic test confirms its feasibility in a symptomatic population but is not yet sufficiently accurate to “confirm or rule out the presence of cancer.” According to the authors, “in cases in which the MCED test detects a cancer signal in this context, the probability of a diagnosis of cancer being made is considerably higher and may identify cancers at sites other than those suspected during the initial referral phase, thus reducing delays in diagnosis.” A negative test means a lower likelihood of cancer but not so low that proper investigation can be ruled out. Further tests will be needed to optimize use of a negative predictive value.

Q: Does MCED testing concern all types of cancer?

Dr. Delaloge: The Galleri test is based on full profiling of DNA methylation. This allows for early diagnosis of cancer even before it can be seen on imaging tests. The issue with these tests is that they aren’t that good at early diagnosis of the most common types of cancer (breast, colorectal, cervical, etc.) for which we already have more efficient means such as the fecal immunochemical test for colorectal cancer, mammography, HPV testing, and so on.

These blood tests would thus not be aimed at replacing routine screening but rather at screening asymptomatic individuals or those with nonspecific signs for cancers for which we have few or no screening measures and which are on the rise, such as deep tumors and cancer diagnosed at a late stage, namely pancreas, bile duct, ovarian, esophageal, lung, stomach, etc.

The results from the studies published are promising, but others are underway to confirm the benefit of these MCEDs. The challenge is to identify cancer at an early stage, at a stage where it will be easier to cure the patient and control its growth using treatments that are less onerous for the patient and that have fewer aftereffects but not at the expense of a massive increase in overdiagnosis, as seen with prostate-specific antigen levels in prostate cancer a few years ago!

Q: What would be the focus of these MCED tests?

Dr. Delaloge: We must be alert to the risk for the market development of MCED tests. For now, they are mostly, especially the Galleri test, developed in the general population to screen for types of cancer that could not be detected in any other way but also because it’s the most financially beneficial situation. The designers want to position themselves in the general population, regardless of whether this means they’ll have to test hundreds of people to find one for whom the test is beneficial. What’s more, developing tests in isolation, without considering their place in ad hoc treatment pathways, is not realistic. It’s likely that some of these tests will be marketed within the next 10 years, but the health care systems destined to receive them are not remotely ready to do so.

Q: An even more recent publication, from late July 2023, is even more exciting in relation to early detection of lung cancer using circulating DNA sequencing. What are your thoughts on it?

Dr. Delaloge: Initially overtaken by other technologies in favor of MCED approaches, DNA sequencing as a technique to detect somatic mutations seems to have reentered the competition with this new-generation research. The authors published some very interesting results, especially for stage I lung cancer with a very high sensitivity of 75%. [Editor’s note: A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected more than 90% of patients with lung cancer, including those with stage I and II disease.]

This research illustrates the difficulty of providing high performance while covering a broad range of cancers. Here, the good results mainly concern lung cancer. Researchers and health care authorities must be alert to ensuring that MCED tests prove themselves in terms of sensitivity and specificity in responding to a medical need and in their impact on specific mortality. This craze for MCED tests must not hinder the development of “single-cancer” technologies that may be much better for detecting specific cancers. This recent publication is interesting in this respect, because this sequencing test seems to be particularly good at detecting lung cancer.

Q: Another approach used in MCED tests is based on analyzing the size of DNA fragments in the blood. Can you explain how this works?

Dr. Delaloge: When cancer is not present, the size of DNA fragments in cells is much more homogeneous. Here also, the benefit of MCED based on this technique rests on the very early detection of cancers that are less common than those for which we already have good screening methods available.

Other approaches, still at the experimental stage, detect certain proteins, certain inflammatory molecules, RNA, etc. But for many researchers, the future will involve pairing tests on the basis of circulating DNA in the blood with the detection of specific molecules indicating the presence of cancer to obtain early screening tests that are even more effective or that possibly even allow us to identify an appropriate treatment at an early stage.

The development of a simple test based on a blood draw that allows us to screen early for all cancers and that would replace all current screening measures is, therefore, not imminent, although it could potentially be on the horizon in years to come. Alongside this, an important issue is the benefit of cancer screening in the general population vs. in a targeted population with a specific risk. The latter option is in development but requires an individualized screening pathway based on blood testing and current screening methods: imaging, etc. It also depends on an individual’s cancer risk profile such as age, personal and family medical history, genetic predisposition, and so on.

According to recent modeling, these multicancer tests could theoretically prevent a minimum of 2,000 deaths from cancer per 100,000 people between ages 50 and 79 years screened per year (17% fewer deaths from cancer per year).

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Multicancer early-detection blood (MCED) tests are the focus of intensive development. What techniques do these tests use? What potential do they show? Suzette Delaloge, MD, MSc, oncologist, breast cancer specialist, and director of the individualized cancer prevention program (Interception) at the Gustave Roussy Institute in Villejuif, France, looks into these “liquid biopsies” and shares her reservations about their potential marketing, especially to the organized care plans.

Question: What are the general principles underpinning these MCED tests?

Suzette Delaloge, MD, MSc: Despite their specificities, the general idea is to detect certain cancer markers in various body fluids (blood, urine, saliva, etc.), for example, molecules released by cancer cells (cytokines, inflammatory proteins, leptin, etc.) or distinctive features of the DNA in tumor cells. In blood, these molecules can be found in plasma or in serum. In urine, it’s more about detecting kidney, bladder, and urinary tract cancers.

Q: What sort of time frame are we looking at for these MCED tests to be used in routine practice?

Dr. Delaloge: They first appeared around 10 years ago. Development of these tests has intensified in recent years. There are numerous research laboratories, both public and private, that are developing different early-detection tests for cancer.

Some of these development processes are about to come to an end and are expected to be in regular, concrete use within 5-10 years. For the most advanced developments, the main biologic material researched and analyzed is DNA from cancer cells. We all have fragments of DNA from dead cells in our plasma (apoptosis), but cancer cells release more of these than others, and most importantly, their DNA has distinctive characteristics. The idea is to develop tests capable of detecting these characteristics.

Liquid biopsies based on genomic biomarkers could make MCED a reality, especially for cancers for which there is no standard screening process. But at this stage of the research, there are limitations, including low sensitivity for detecting stage I cancers in validation studies and an increased risk for overdiagnosis.

Q: What specific set of characteristics are the most advanced approaches based on?

Dr. Delaloge: They’re based on the analysis of DNA methylation, a biological process by which CH3 methyl groups are added to the DNA molecule and that determines gene expression. This phenomenon differs depending on whether the cell is cancerous. Among the tests currently under development making use of this specific characteristic is the Galleri test, which is the most advanced of them all.

A previous British National Health Service study, SYMPLIFY, which was published in 2023 by researchers at the University of Oxford, was conducted in symptomatic patients attending a health center. It offers promising results in a diagnostic situation. It has nothing at all to do with screening here. A large, randomized English study, NHS-Galleri, is underway, this time involving the general population, with the aim of assessing the potential benefit of the same test as screening in 140,000 people between ages 50 and 77 years.

In the SYMPLIFY study, which was carried out in symptomatic patients attending a health center, the Galleri MCED test had a positive predictive value of 75.5%, a negative predictive value of 97.6%, a sensitivity of 66.3%, and a specificity of 98.4%. Sensitivity increased with age and cancer stage from 24.2% at stage I to 95.3% at stage IV. For cases for which a cancer signal was detected in patients with cancer, the prediction of the original site of the cancer by the MCED test was accurate in 85.2% of cases. This large-scale prospective evaluation of an MCED diagnostic test confirms its feasibility in a symptomatic population but is not yet sufficiently accurate to “confirm or rule out the presence of cancer.” According to the authors, “in cases in which the MCED test detects a cancer signal in this context, the probability of a diagnosis of cancer being made is considerably higher and may identify cancers at sites other than those suspected during the initial referral phase, thus reducing delays in diagnosis.” A negative test means a lower likelihood of cancer but not so low that proper investigation can be ruled out. Further tests will be needed to optimize use of a negative predictive value.

Q: Does MCED testing concern all types of cancer?

Dr. Delaloge: The Galleri test is based on full profiling of DNA methylation. This allows for early diagnosis of cancer even before it can be seen on imaging tests. The issue with these tests is that they aren’t that good at early diagnosis of the most common types of cancer (breast, colorectal, cervical, etc.) for which we already have more efficient means such as the fecal immunochemical test for colorectal cancer, mammography, HPV testing, and so on.

These blood tests would thus not be aimed at replacing routine screening but rather at screening asymptomatic individuals or those with nonspecific signs for cancers for which we have few or no screening measures and which are on the rise, such as deep tumors and cancer diagnosed at a late stage, namely pancreas, bile duct, ovarian, esophageal, lung, stomach, etc.

The results from the studies published are promising, but others are underway to confirm the benefit of these MCEDs. The challenge is to identify cancer at an early stage, at a stage where it will be easier to cure the patient and control its growth using treatments that are less onerous for the patient and that have fewer aftereffects but not at the expense of a massive increase in overdiagnosis, as seen with prostate-specific antigen levels in prostate cancer a few years ago!

Q: What would be the focus of these MCED tests?

Dr. Delaloge: We must be alert to the risk for the market development of MCED tests. For now, they are mostly, especially the Galleri test, developed in the general population to screen for types of cancer that could not be detected in any other way but also because it’s the most financially beneficial situation. The designers want to position themselves in the general population, regardless of whether this means they’ll have to test hundreds of people to find one for whom the test is beneficial. What’s more, developing tests in isolation, without considering their place in ad hoc treatment pathways, is not realistic. It’s likely that some of these tests will be marketed within the next 10 years, but the health care systems destined to receive them are not remotely ready to do so.

Q: An even more recent publication, from late July 2023, is even more exciting in relation to early detection of lung cancer using circulating DNA sequencing. What are your thoughts on it?

Dr. Delaloge: Initially overtaken by other technologies in favor of MCED approaches, DNA sequencing as a technique to detect somatic mutations seems to have reentered the competition with this new-generation research. The authors published some very interesting results, especially for stage I lung cancer with a very high sensitivity of 75%. [Editor’s note: A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected more than 90% of patients with lung cancer, including those with stage I and II disease.]

This research illustrates the difficulty of providing high performance while covering a broad range of cancers. Here, the good results mainly concern lung cancer. Researchers and health care authorities must be alert to ensuring that MCED tests prove themselves in terms of sensitivity and specificity in responding to a medical need and in their impact on specific mortality. This craze for MCED tests must not hinder the development of “single-cancer” technologies that may be much better for detecting specific cancers. This recent publication is interesting in this respect, because this sequencing test seems to be particularly good at detecting lung cancer.

Q: Another approach used in MCED tests is based on analyzing the size of DNA fragments in the blood. Can you explain how this works?

Dr. Delaloge: When cancer is not present, the size of DNA fragments in cells is much more homogeneous. Here also, the benefit of MCED based on this technique rests on the very early detection of cancers that are less common than those for which we already have good screening methods available.

Other approaches, still at the experimental stage, detect certain proteins, certain inflammatory molecules, RNA, etc. But for many researchers, the future will involve pairing tests on the basis of circulating DNA in the blood with the detection of specific molecules indicating the presence of cancer to obtain early screening tests that are even more effective or that possibly even allow us to identify an appropriate treatment at an early stage.

The development of a simple test based on a blood draw that allows us to screen early for all cancers and that would replace all current screening measures is, therefore, not imminent, although it could potentially be on the horizon in years to come. Alongside this, an important issue is the benefit of cancer screening in the general population vs. in a targeted population with a specific risk. The latter option is in development but requires an individualized screening pathway based on blood testing and current screening methods: imaging, etc. It also depends on an individual’s cancer risk profile such as age, personal and family medical history, genetic predisposition, and so on.

According to recent modeling, these multicancer tests could theoretically prevent a minimum of 2,000 deaths from cancer per 100,000 people between ages 50 and 79 years screened per year (17% fewer deaths from cancer per year).

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Multicancer early-detection blood (MCED) tests are the focus of intensive development. What techniques do these tests use? What potential do they show? Suzette Delaloge, MD, MSc, oncologist, breast cancer specialist, and director of the individualized cancer prevention program (Interception) at the Gustave Roussy Institute in Villejuif, France, looks into these “liquid biopsies” and shares her reservations about their potential marketing, especially to the organized care plans.

Question: What are the general principles underpinning these MCED tests?

Suzette Delaloge, MD, MSc: Despite their specificities, the general idea is to detect certain cancer markers in various body fluids (blood, urine, saliva, etc.), for example, molecules released by cancer cells (cytokines, inflammatory proteins, leptin, etc.) or distinctive features of the DNA in tumor cells. In blood, these molecules can be found in plasma or in serum. In urine, it’s more about detecting kidney, bladder, and urinary tract cancers.

Q: What sort of time frame are we looking at for these MCED tests to be used in routine practice?

Dr. Delaloge: They first appeared around 10 years ago. Development of these tests has intensified in recent years. There are numerous research laboratories, both public and private, that are developing different early-detection tests for cancer.

Some of these development processes are about to come to an end and are expected to be in regular, concrete use within 5-10 years. For the most advanced developments, the main biologic material researched and analyzed is DNA from cancer cells. We all have fragments of DNA from dead cells in our plasma (apoptosis), but cancer cells release more of these than others, and most importantly, their DNA has distinctive characteristics. The idea is to develop tests capable of detecting these characteristics.

Liquid biopsies based on genomic biomarkers could make MCED a reality, especially for cancers for which there is no standard screening process. But at this stage of the research, there are limitations, including low sensitivity for detecting stage I cancers in validation studies and an increased risk for overdiagnosis.

Q: What specific set of characteristics are the most advanced approaches based on?

Dr. Delaloge: They’re based on the analysis of DNA methylation, a biological process by which CH3 methyl groups are added to the DNA molecule and that determines gene expression. This phenomenon differs depending on whether the cell is cancerous. Among the tests currently under development making use of this specific characteristic is the Galleri test, which is the most advanced of them all.

A previous British National Health Service study, SYMPLIFY, which was published in 2023 by researchers at the University of Oxford, was conducted in symptomatic patients attending a health center. It offers promising results in a diagnostic situation. It has nothing at all to do with screening here. A large, randomized English study, NHS-Galleri, is underway, this time involving the general population, with the aim of assessing the potential benefit of the same test as screening in 140,000 people between ages 50 and 77 years.

In the SYMPLIFY study, which was carried out in symptomatic patients attending a health center, the Galleri MCED test had a positive predictive value of 75.5%, a negative predictive value of 97.6%, a sensitivity of 66.3%, and a specificity of 98.4%. Sensitivity increased with age and cancer stage from 24.2% at stage I to 95.3% at stage IV. For cases for which a cancer signal was detected in patients with cancer, the prediction of the original site of the cancer by the MCED test was accurate in 85.2% of cases. This large-scale prospective evaluation of an MCED diagnostic test confirms its feasibility in a symptomatic population but is not yet sufficiently accurate to “confirm or rule out the presence of cancer.” According to the authors, “in cases in which the MCED test detects a cancer signal in this context, the probability of a diagnosis of cancer being made is considerably higher and may identify cancers at sites other than those suspected during the initial referral phase, thus reducing delays in diagnosis.” A negative test means a lower likelihood of cancer but not so low that proper investigation can be ruled out. Further tests will be needed to optimize use of a negative predictive value.

Q: Does MCED testing concern all types of cancer?

Dr. Delaloge: The Galleri test is based on full profiling of DNA methylation. This allows for early diagnosis of cancer even before it can be seen on imaging tests. The issue with these tests is that they aren’t that good at early diagnosis of the most common types of cancer (breast, colorectal, cervical, etc.) for which we already have more efficient means such as the fecal immunochemical test for colorectal cancer, mammography, HPV testing, and so on.

These blood tests would thus not be aimed at replacing routine screening but rather at screening asymptomatic individuals or those with nonspecific signs for cancers for which we have few or no screening measures and which are on the rise, such as deep tumors and cancer diagnosed at a late stage, namely pancreas, bile duct, ovarian, esophageal, lung, stomach, etc.

The results from the studies published are promising, but others are underway to confirm the benefit of these MCEDs. The challenge is to identify cancer at an early stage, at a stage where it will be easier to cure the patient and control its growth using treatments that are less onerous for the patient and that have fewer aftereffects but not at the expense of a massive increase in overdiagnosis, as seen with prostate-specific antigen levels in prostate cancer a few years ago!

Q: What would be the focus of these MCED tests?

Dr. Delaloge: We must be alert to the risk for the market development of MCED tests. For now, they are mostly, especially the Galleri test, developed in the general population to screen for types of cancer that could not be detected in any other way but also because it’s the most financially beneficial situation. The designers want to position themselves in the general population, regardless of whether this means they’ll have to test hundreds of people to find one for whom the test is beneficial. What’s more, developing tests in isolation, without considering their place in ad hoc treatment pathways, is not realistic. It’s likely that some of these tests will be marketed within the next 10 years, but the health care systems destined to receive them are not remotely ready to do so.

Q: An even more recent publication, from late July 2023, is even more exciting in relation to early detection of lung cancer using circulating DNA sequencing. What are your thoughts on it?

Dr. Delaloge: Initially overtaken by other technologies in favor of MCED approaches, DNA sequencing as a technique to detect somatic mutations seems to have reentered the competition with this new-generation research. The authors published some very interesting results, especially for stage I lung cancer with a very high sensitivity of 75%. [Editor’s note: A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected more than 90% of patients with lung cancer, including those with stage I and II disease.]

This research illustrates the difficulty of providing high performance while covering a broad range of cancers. Here, the good results mainly concern lung cancer. Researchers and health care authorities must be alert to ensuring that MCED tests prove themselves in terms of sensitivity and specificity in responding to a medical need and in their impact on specific mortality. This craze for MCED tests must not hinder the development of “single-cancer” technologies that may be much better for detecting specific cancers. This recent publication is interesting in this respect, because this sequencing test seems to be particularly good at detecting lung cancer.

Q: Another approach used in MCED tests is based on analyzing the size of DNA fragments in the blood. Can you explain how this works?

Dr. Delaloge: When cancer is not present, the size of DNA fragments in cells is much more homogeneous. Here also, the benefit of MCED based on this technique rests on the very early detection of cancers that are less common than those for which we already have good screening methods available.

Other approaches, still at the experimental stage, detect certain proteins, certain inflammatory molecules, RNA, etc. But for many researchers, the future will involve pairing tests on the basis of circulating DNA in the blood with the detection of specific molecules indicating the presence of cancer to obtain early screening tests that are even more effective or that possibly even allow us to identify an appropriate treatment at an early stage.

The development of a simple test based on a blood draw that allows us to screen early for all cancers and that would replace all current screening measures is, therefore, not imminent, although it could potentially be on the horizon in years to come. Alongside this, an important issue is the benefit of cancer screening in the general population vs. in a targeted population with a specific risk. The latter option is in development but requires an individualized screening pathway based on blood testing and current screening methods: imaging, etc. It also depends on an individual’s cancer risk profile such as age, personal and family medical history, genetic predisposition, and so on.

According to recent modeling, these multicancer tests could theoretically prevent a minimum of 2,000 deaths from cancer per 100,000 people between ages 50 and 79 years screened per year (17% fewer deaths from cancer per year).

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

The years go by, and nothing much changes: The first 2 weeks of the new school year have brought with them a rise in emergency department (ED) admissions for asthma in patients under age 15 years. A more relaxed approach to maintenance therapy for the condition over the summer holidays, exposure to allergens at school, and the surge in viral respiratory infections that accompanies the return to group settings explain this trend, which can be foreseen.

As soon as September begins, asthma cases increase rapidly in children. According to Public Health France, which has just relaunched its epidemiological monitoring, these cases reach their peak around 2 weeks after the start of the new term.

In its first weekly review on Aug. 22, 2023, the authority reported a slight uptick in cases in its Indian Ocean overseas departments, and the calm before the storm in mainland France.

Last year, between weeks 35 and 36, the increases were 82% for SOS Médecins (the French home doctor visit service), 169% for EDs, and 33% for hospital admissions.

These data are similar to the figures obtained over the past 3 years. The authors of this monitoring, using the SurSaUD system, France’s program for monitoring emergency cases and deaths, attribute these increases to the surge in viral respiratory infections seen after the return to group settings after the school summer holidays.

Indeed, viral-induced exacerbations are mostly caused by rhinoviruses, which circulate throughout the year, but more so during the autumn and winter months. These are probably the main culprits behind the epidemics seen once schools have reopened. Yet relaxation of maintenance asthma treatment (inhaled corticosteroids alone or in combination with long-acting bronchodilators) during the summer holidays also plays a significant role in this yearly recurrence.
 

Compliance ends with school

Flore Amat, MD, PhD, pediatric respiratory and allergy specialist and coordinating doctor at the Zephyr asthma clinic (Robert-Debré Hospital, Paris Public Hospitals) acknowledged, “The summer holidays are often a time when compliance with maintenance therapy is relaxed.” Aware of this fact, doctors prefer to strike a deal with their young patients. “For some of our young and teenage asthma patients, we support their relaxed approach to medication during the summer holidays,” she admitted. “In July and August, there are fewer viruses circulating, and the weather is often dry, which limits the risk of an asthma attack, meaning we can ease off the maintenance therapy, or even stop taking it altogether. We tell parents and children to start taking them again 2 weeks before school starts; 2 weeks being the minimum time needed for inhaled corticosteroids to start taking effect again.” Unsurprisingly, some forget to do so or simply don’t.

Two other things contribute to the rise in asthma attacks in children in early September. The first relates to exposure to allergens, especially dust mites. “Ninety percent of asthmatic children are allergic,” said Frédéric le Guillou, MD, respiratory medicine specialist and chair of the French Society for Respiratory Health, an organization aimed at patients and health care professionals. “Don’t forget that asthma is the leading chronic condition in childhood, with a prevalence estimated at between 8% and 10% of children and adolescents. So, we’re talking about considerable numbers of children being affected.”

Although dust mites are a year-round problem, their peak period of reproduction mainly occurs during the wetter months (March to April and September to November). This means that there is a risk of relapse in asthmatic children who are allergic to dust mites when school starts again after the summer holidays. “In such children, any signs of unmanageable allergic rhinitis should be examined,” said Dr. Amat, “these signs being permanent nasal congestion, runny nose, et cetera.”

Finally, we can also add “the stress and anxiety generated by the school setting and settling back into a routine” to the list of likely explanations for this peak in asthma attacks, Dr. Amat concluded.
 

Check-up time

Children and teenagers with asthma should have a check-up with their respiratory medicine specialists at the start of the new term to confirm that their condition is under control and to determine whether any changes need to be made to their maintenance therapy. “Looking back at previous Septembers and winters is informative in adapting a patient’s treatment plan,” said Dr. Amat. “If maintenance therapy has been stopped during the summer, take the opportunity to represcribe it or modify it if, for example, the dose of inhaled corticosteroids has not been enough to prevent attacks in years gone by. Adequate control of symptoms over the summer months suggests that treatment should be bolstered with preventive therapy to cope with the autumn and winter months. Finally, the factors aggravating poor management of asthma should be dealt with, such as intranasal antihistamines and corticosteroids in allergic rhinitis, specific immunotherapy in patients with controlled asthma but with significant allergy symptoms.”

The start-of-term visit to the doctor’s office is also the perfect opportunity to carry out respiratory function testing (RFT), if this has not been done for over a year in patients whose asthma is well managed. “RFT is indicated in the 3 months following any changes to maintenance therapy, every 3 to 6 months in patients with poorly controlled asthma, and after stopping maintenance therapy or when considering stopping treatment permanently or for an extended period of time,” noted Dr. Amat.

The distinction between difficult asthma (suboptimal treatment plan, poor compliance, persisting allergen exposure, etc.) and severe asthma may be made during this back-to-school asthma review. In specialist clinics, children with severe asthma (not controlled by combined treatment with maximum-dose corticosteroids and maximum-dose bronchodilators) may, like adults, benefit from some biotherapies.
 

Commentary from Madiha Ellaffi, MD, respiratory medicine specialist

When children experience relatively calm summers without seasonal summer allergies to certain pollens or molds (such as Alternaria, some grasses, etc.) that require maintenance therapy to be continued, we know full well that compliance is often left up to the child. What would be better would be striking a “deal” with these young people: Maintenance treatment can be stopped over the summer, providing that their usual dose is quite low or their asthma is considered mild to moderate, but it must be restarted before going back to school in September. An action plan should be discussed in the event of an asthma attack, and treatment bolstered to overcome this hurdle, should it occur, such as double inhaled corticosteroid doses, etc. Indeed, this period is conducive to asthma exacerbations due to stress, the return of students to confined classrooms, pollutants released by the deep cleaning of school buildings that occurs at the start of term (particularly the release of volatile organic compounds that irritate the airways), and the lack of ventilation in classrooms, which is conducive to the spread of viruses that can cause worsening asthma symptoms. I’d also like to remind parents of the importance of detecting early symptoms (such as wheezing, cough, bronchitis, itchy throat and nose, etc.) in warding off asthma attacks or severe symptoms. I insist on basic measures, such as nasal irrigation, treating allergic rhinitis, which can exacerbate asthma, and ensuring good habits at home to prevent dust mites and mold, such as vacuuming, airing houses, etc. It is sensible to assess the risk of asthma attacks at the start of term according to the child’s allergy profile and their previous history, like starting treatment for allergic rhinitis if not already being taken.

This article was translated from Medscape’s French edition. A version of this article appeared on Medscape.com.

The years go by, and nothing much changes: The first 2 weeks of the new school year have brought with them a rise in emergency department (ED) admissions for asthma in patients under age 15 years. A more relaxed approach to maintenance therapy for the condition over the summer holidays, exposure to allergens at school, and the surge in viral respiratory infections that accompanies the return to group settings explain this trend, which can be foreseen.

As soon as September begins, asthma cases increase rapidly in children. According to Public Health France, which has just relaunched its epidemiological monitoring, these cases reach their peak around 2 weeks after the start of the new term.

In its first weekly review on Aug. 22, 2023, the authority reported a slight uptick in cases in its Indian Ocean overseas departments, and the calm before the storm in mainland France.

Last year, between weeks 35 and 36, the increases were 82% for SOS Médecins (the French home doctor visit service), 169% for EDs, and 33% for hospital admissions.

These data are similar to the figures obtained over the past 3 years. The authors of this monitoring, using the SurSaUD system, France’s program for monitoring emergency cases and deaths, attribute these increases to the surge in viral respiratory infections seen after the return to group settings after the school summer holidays.

Indeed, viral-induced exacerbations are mostly caused by rhinoviruses, which circulate throughout the year, but more so during the autumn and winter months. These are probably the main culprits behind the epidemics seen once schools have reopened. Yet relaxation of maintenance asthma treatment (inhaled corticosteroids alone or in combination with long-acting bronchodilators) during the summer holidays also plays a significant role in this yearly recurrence.
 

Compliance ends with school

Flore Amat, MD, PhD, pediatric respiratory and allergy specialist and coordinating doctor at the Zephyr asthma clinic (Robert-Debré Hospital, Paris Public Hospitals) acknowledged, “The summer holidays are often a time when compliance with maintenance therapy is relaxed.” Aware of this fact, doctors prefer to strike a deal with their young patients. “For some of our young and teenage asthma patients, we support their relaxed approach to medication during the summer holidays,” she admitted. “In July and August, there are fewer viruses circulating, and the weather is often dry, which limits the risk of an asthma attack, meaning we can ease off the maintenance therapy, or even stop taking it altogether. We tell parents and children to start taking them again 2 weeks before school starts; 2 weeks being the minimum time needed for inhaled corticosteroids to start taking effect again.” Unsurprisingly, some forget to do so or simply don’t.

Two other things contribute to the rise in asthma attacks in children in early September. The first relates to exposure to allergens, especially dust mites. “Ninety percent of asthmatic children are allergic,” said Frédéric le Guillou, MD, respiratory medicine specialist and chair of the French Society for Respiratory Health, an organization aimed at patients and health care professionals. “Don’t forget that asthma is the leading chronic condition in childhood, with a prevalence estimated at between 8% and 10% of children and adolescents. So, we’re talking about considerable numbers of children being affected.”

Although dust mites are a year-round problem, their peak period of reproduction mainly occurs during the wetter months (March to April and September to November). This means that there is a risk of relapse in asthmatic children who are allergic to dust mites when school starts again after the summer holidays. “In such children, any signs of unmanageable allergic rhinitis should be examined,” said Dr. Amat, “these signs being permanent nasal congestion, runny nose, et cetera.”

Finally, we can also add “the stress and anxiety generated by the school setting and settling back into a routine” to the list of likely explanations for this peak in asthma attacks, Dr. Amat concluded.
 

Check-up time

Children and teenagers with asthma should have a check-up with their respiratory medicine specialists at the start of the new term to confirm that their condition is under control and to determine whether any changes need to be made to their maintenance therapy. “Looking back at previous Septembers and winters is informative in adapting a patient’s treatment plan,” said Dr. Amat. “If maintenance therapy has been stopped during the summer, take the opportunity to represcribe it or modify it if, for example, the dose of inhaled corticosteroids has not been enough to prevent attacks in years gone by. Adequate control of symptoms over the summer months suggests that treatment should be bolstered with preventive therapy to cope with the autumn and winter months. Finally, the factors aggravating poor management of asthma should be dealt with, such as intranasal antihistamines and corticosteroids in allergic rhinitis, specific immunotherapy in patients with controlled asthma but with significant allergy symptoms.”

The start-of-term visit to the doctor’s office is also the perfect opportunity to carry out respiratory function testing (RFT), if this has not been done for over a year in patients whose asthma is well managed. “RFT is indicated in the 3 months following any changes to maintenance therapy, every 3 to 6 months in patients with poorly controlled asthma, and after stopping maintenance therapy or when considering stopping treatment permanently or for an extended period of time,” noted Dr. Amat.

The distinction between difficult asthma (suboptimal treatment plan, poor compliance, persisting allergen exposure, etc.) and severe asthma may be made during this back-to-school asthma review. In specialist clinics, children with severe asthma (not controlled by combined treatment with maximum-dose corticosteroids and maximum-dose bronchodilators) may, like adults, benefit from some biotherapies.
 

Commentary from Madiha Ellaffi, MD, respiratory medicine specialist

When children experience relatively calm summers without seasonal summer allergies to certain pollens or molds (such as Alternaria, some grasses, etc.) that require maintenance therapy to be continued, we know full well that compliance is often left up to the child. What would be better would be striking a “deal” with these young people: Maintenance treatment can be stopped over the summer, providing that their usual dose is quite low or their asthma is considered mild to moderate, but it must be restarted before going back to school in September. An action plan should be discussed in the event of an asthma attack, and treatment bolstered to overcome this hurdle, should it occur, such as double inhaled corticosteroid doses, etc. Indeed, this period is conducive to asthma exacerbations due to stress, the return of students to confined classrooms, pollutants released by the deep cleaning of school buildings that occurs at the start of term (particularly the release of volatile organic compounds that irritate the airways), and the lack of ventilation in classrooms, which is conducive to the spread of viruses that can cause worsening asthma symptoms. I’d also like to remind parents of the importance of detecting early symptoms (such as wheezing, cough, bronchitis, itchy throat and nose, etc.) in warding off asthma attacks or severe symptoms. I insist on basic measures, such as nasal irrigation, treating allergic rhinitis, which can exacerbate asthma, and ensuring good habits at home to prevent dust mites and mold, such as vacuuming, airing houses, etc. It is sensible to assess the risk of asthma attacks at the start of term according to the child’s allergy profile and their previous history, like starting treatment for allergic rhinitis if not already being taken.

This article was translated from Medscape’s French edition. A version of this article appeared on Medscape.com.

The years go by, and nothing much changes: The first 2 weeks of the new school year have brought with them a rise in emergency department (ED) admissions for asthma in patients under age 15 years. A more relaxed approach to maintenance therapy for the condition over the summer holidays, exposure to allergens at school, and the surge in viral respiratory infections that accompanies the return to group settings explain this trend, which can be foreseen.

As soon as September begins, asthma cases increase rapidly in children. According to Public Health France, which has just relaunched its epidemiological monitoring, these cases reach their peak around 2 weeks after the start of the new term.

In its first weekly review on Aug. 22, 2023, the authority reported a slight uptick in cases in its Indian Ocean overseas departments, and the calm before the storm in mainland France.

Last year, between weeks 35 and 36, the increases were 82% for SOS Médecins (the French home doctor visit service), 169% for EDs, and 33% for hospital admissions.

These data are similar to the figures obtained over the past 3 years. The authors of this monitoring, using the SurSaUD system, France’s program for monitoring emergency cases and deaths, attribute these increases to the surge in viral respiratory infections seen after the return to group settings after the school summer holidays.

Indeed, viral-induced exacerbations are mostly caused by rhinoviruses, which circulate throughout the year, but more so during the autumn and winter months. These are probably the main culprits behind the epidemics seen once schools have reopened. Yet relaxation of maintenance asthma treatment (inhaled corticosteroids alone or in combination with long-acting bronchodilators) during the summer holidays also plays a significant role in this yearly recurrence.
 

Compliance ends with school

Flore Amat, MD, PhD, pediatric respiratory and allergy specialist and coordinating doctor at the Zephyr asthma clinic (Robert-Debré Hospital, Paris Public Hospitals) acknowledged, “The summer holidays are often a time when compliance with maintenance therapy is relaxed.” Aware of this fact, doctors prefer to strike a deal with their young patients. “For some of our young and teenage asthma patients, we support their relaxed approach to medication during the summer holidays,” she admitted. “In July and August, there are fewer viruses circulating, and the weather is often dry, which limits the risk of an asthma attack, meaning we can ease off the maintenance therapy, or even stop taking it altogether. We tell parents and children to start taking them again 2 weeks before school starts; 2 weeks being the minimum time needed for inhaled corticosteroids to start taking effect again.” Unsurprisingly, some forget to do so or simply don’t.

Two other things contribute to the rise in asthma attacks in children in early September. The first relates to exposure to allergens, especially dust mites. “Ninety percent of asthmatic children are allergic,” said Frédéric le Guillou, MD, respiratory medicine specialist and chair of the French Society for Respiratory Health, an organization aimed at patients and health care professionals. “Don’t forget that asthma is the leading chronic condition in childhood, with a prevalence estimated at between 8% and 10% of children and adolescents. So, we’re talking about considerable numbers of children being affected.”

Although dust mites are a year-round problem, their peak period of reproduction mainly occurs during the wetter months (March to April and September to November). This means that there is a risk of relapse in asthmatic children who are allergic to dust mites when school starts again after the summer holidays. “In such children, any signs of unmanageable allergic rhinitis should be examined,” said Dr. Amat, “these signs being permanent nasal congestion, runny nose, et cetera.”

Finally, we can also add “the stress and anxiety generated by the school setting and settling back into a routine” to the list of likely explanations for this peak in asthma attacks, Dr. Amat concluded.
 

Check-up time

Children and teenagers with asthma should have a check-up with their respiratory medicine specialists at the start of the new term to confirm that their condition is under control and to determine whether any changes need to be made to their maintenance therapy. “Looking back at previous Septembers and winters is informative in adapting a patient’s treatment plan,” said Dr. Amat. “If maintenance therapy has been stopped during the summer, take the opportunity to represcribe it or modify it if, for example, the dose of inhaled corticosteroids has not been enough to prevent attacks in years gone by. Adequate control of symptoms over the summer months suggests that treatment should be bolstered with preventive therapy to cope with the autumn and winter months. Finally, the factors aggravating poor management of asthma should be dealt with, such as intranasal antihistamines and corticosteroids in allergic rhinitis, specific immunotherapy in patients with controlled asthma but with significant allergy symptoms.”

The start-of-term visit to the doctor’s office is also the perfect opportunity to carry out respiratory function testing (RFT), if this has not been done for over a year in patients whose asthma is well managed. “RFT is indicated in the 3 months following any changes to maintenance therapy, every 3 to 6 months in patients with poorly controlled asthma, and after stopping maintenance therapy or when considering stopping treatment permanently or for an extended period of time,” noted Dr. Amat.

The distinction between difficult asthma (suboptimal treatment plan, poor compliance, persisting allergen exposure, etc.) and severe asthma may be made during this back-to-school asthma review. In specialist clinics, children with severe asthma (not controlled by combined treatment with maximum-dose corticosteroids and maximum-dose bronchodilators) may, like adults, benefit from some biotherapies.
 

Commentary from Madiha Ellaffi, MD, respiratory medicine specialist

When children experience relatively calm summers without seasonal summer allergies to certain pollens or molds (such as Alternaria, some grasses, etc.) that require maintenance therapy to be continued, we know full well that compliance is often left up to the child. What would be better would be striking a “deal” with these young people: Maintenance treatment can be stopped over the summer, providing that their usual dose is quite low or their asthma is considered mild to moderate, but it must be restarted before going back to school in September. An action plan should be discussed in the event of an asthma attack, and treatment bolstered to overcome this hurdle, should it occur, such as double inhaled corticosteroid doses, etc. Indeed, this period is conducive to asthma exacerbations due to stress, the return of students to confined classrooms, pollutants released by the deep cleaning of school buildings that occurs at the start of term (particularly the release of volatile organic compounds that irritate the airways), and the lack of ventilation in classrooms, which is conducive to the spread of viruses that can cause worsening asthma symptoms. I’d also like to remind parents of the importance of detecting early symptoms (such as wheezing, cough, bronchitis, itchy throat and nose, etc.) in warding off asthma attacks or severe symptoms. I insist on basic measures, such as nasal irrigation, treating allergic rhinitis, which can exacerbate asthma, and ensuring good habits at home to prevent dust mites and mold, such as vacuuming, airing houses, etc. It is sensible to assess the risk of asthma attacks at the start of term according to the child’s allergy profile and their previous history, like starting treatment for allergic rhinitis if not already being taken.

This article was translated from Medscape’s French edition. A version of this article appeared on Medscape.com.

MARSEILLE, FRANCE – Setmelanotide can lead to significant weight loss that lasts for at least 3 years, according to results presented at the latest French Pediatric Society conference. The treatment is effective for adults and children alike.

Setmelanotide is the culmination of two decades of research involving the identification of genes involved in early-onset obesity and the characterization of the melanocortin 4 receptor. It became available via early access in 2021.

Currently limited to use in treating obesity linked to a biallelic POMC/PCSK1 or LEPR deficiency, setmelanotide is being tested with respect to other mutations responsible for severe obesity, raising hopes that it will soon be indicated for use in a larger number of patients.

Fewer than 1% of patients who suffer from severe obesity have monogenic forms of obesity. In recent years, the hope for a targeted treatment for patients with these monogenic forms has become a reality.

Although only a small number of patients currently meet the criteria for setmelanotide treatment (namely, those with obesity linked to a biallelic POMC/PCSK1 enzyme or LEPR deficiency and patients with Bardet-Biedl syndrome), there is a real hope that patients with other forms of severe obesity will be able to benefit from this product, including those with heterozygous (not just homozygous) monoallelic variants, who account for more than 10% of patients with severe early-onset obesity.
 

Restoring satiety signaling

“Setmelanotide is a melanocortin 4 receptor agonist,” said Béatrice Dubern, MD, PhD, pediatrician at Trousseau Hospital, Paris, and member of the French medical research institute (INSERM)/Sorbonne University team on nutrition and obesity. “Its mode of action rests on activation of the leptin-melanocortin signaling pathway in the hypothalamus, which regulates hunger, satiety, energy expenditure, and, therefore, body weight. Rare genetic variants in the leptin-melanocortin pathway are associated with polyphagia and severe early-onset obesity. It is believed that more than 60 genes involved in this leptin-melanocortin pathway are currently associated with obesity.”

In July 2021, the European Medicines Agency approved setmelanotide for daily use via subcutaneous administration.
 

Weight loss maintained

In phase 3 studies, setmelanotide (melanocortin 4 receptor agonist) demonstrated its effectiveness in reducing weight and hunger for patients with obesity caused by a POMC/PCSK1 or LEPR deficiency.

Twenty-four patients aged 6 years and older showed a significant response to setmelanotide after 1 year of treatment and were included in the extension study. “Significant response” was defined as a reduction in body weight greater than or equal to 10% after 52 weeks for patients aged 18 years and older or a reduction in body mass index (BMI) z-score greater than or equal to 0.3 after 52 weeks for patients younger than 18 years.

Among all patients, the mean variation (standard deviation) in BMI was −24.8% (8.2%, n = 24), −21% (13%, n = 23), and −24% (17.9%, n = 15) at 12, 24, and 36 months, respectively.

For patients aged greater than or equal to 18 years (n = 11), the mean variation (standard deviation) in weight was −25.1% (7.7%, n = 11), −22.9% (12.5%, n = 11), and −24.4% (13.2%, n = 8) at 12, 24, and 36 months, respectively.

For children and adolescents (patients aged < 18 years, n = 13), the mean reduction (standard deviation) in BMI z-score was −1.31 ([0.66], n = 13), −1.10 ([0.79], n = 11), and −1.01 (1.22], n = 4) at 12, 24, and 36 months, respectively.

For patients younger than 18 years, the mean variation in BMI z-score was −1.01 SD after three years on setmelanotide (standard deviation, 1.22 [n = 4]). The mean BMI z-score was +2.42 SD (standard deviation, 1.22 [n = 4]) after 3 years of treatment with setmelanotide.

In sum, the patients who achieved a reduction in body weight of at least 10% or greater than or equal to 0.3 mean variation in BMI z-score after 1 year experienced long-lasting, clinically significant benefit after 3 years. The finding supports the long-term use of setmelanotide for this group.

“We feared that setmelanotide’s effectiveness would decrease over time, but after 3 years, this had not happened, and we are hopeful that this sustained efficacy will be long lasting. The first two patients who took the drug in 2016 have not noticed any loss of efficacy as it stands,” said Dr. Dubern.

This is all the more encouraging. In the study presented at the 2023 pediatric conference, setmelanotide’s safety profile was reassuring, and it was consistent with previous studies. Side effects reported in greater than or equal to 15% of patients include injection site reactions, skin hyperpigmentation, nausea, diarrhea, mood disturbances, abdominal pain, vomiting, gastroenteritis, and spontaneous erection.

In addition to the lack of control group, Dr. Dubern acknowledged one other constraint of this study. “Only the patients who responded to treatment with setmelanotide during early-phase trials (85.7%) were enrolled.”

Dr. Dubern summarized the clinical implications: “In patients with early-onset obesity, starting before 5 years of age, doctors should really be considering the possibility that genetics might be involved in such cases. For confirmation and to seek expert opinion, specialist obesity clinics can be found throughout France. Additionally, the INSERM NutriOmics research team headed by Prof Karine Clément, MD, PhD, Sorbonne University, in conjunction with Prof Christine Poitou, MD, PhD, has developed a diagnostic tool [called] ObsGen for practitioners faced with patients with potentially genetic causes of obesity. We can answer any questions they have about the likelihood of a particular patient having a genetic form of obesity and guide their next steps. Treating patients with genetic obesity early on helps limit the condition worsening during adolescence, prevents related complications, and can reduce the stigmatization and suffering experienced by these people. It’s a huge issue. A clinical trial with setmelanotide is currently being carried out in children over 2 years of age.”
 

Hypothalamic obesity

During the pediatric conference, another speaker presented the results of a phase 2 study that evaluated the efficacy and tolerability of setmelanotide as a new treatment for hypothalamic obesity. Lesions in the hypothalamus can alter melanocortin 4 receptor pathway signaling and thus lead to hypothalamic obesity. Eighteen patients aged 6-40 years with a BMI greater than or equal to the 95th percentile (for patients aged 6-18 years) or greater than or equal to 35 kg/m² (for adults aged ≥ 18 years) and hypothalamic obesity (craniopharyngioma or other benign brain tumors, surgical removal, and/or chemotherapy) were enrolled. A significant proportion of patients achieved a reduction of greater than or equal to 5% of their BMI (n = 16, 88.9%, CI 90%, 69%-89%, P < .0001), and 72.2% achieved a reduction of greater than or equal to 10% by week 16. The mean change in BMI was −14.9% (9.6%, n = 17). These early results may justify further studies of setmelanotide in treating hypothalamic obesity.

Dr. Dubern has collaborated with Rhythm Pharmaceuticals and Novo Nordisk.

This article was translated from the Medscape French Edition and a version appeared on Medscape.com.

MARSEILLE, FRANCE – Setmelanotide can lead to significant weight loss that lasts for at least 3 years, according to results presented at the latest French Pediatric Society conference. The treatment is effective for adults and children alike.

Setmelanotide is the culmination of two decades of research involving the identification of genes involved in early-onset obesity and the characterization of the melanocortin 4 receptor. It became available via early access in 2021.

Currently limited to use in treating obesity linked to a biallelic POMC/PCSK1 or LEPR deficiency, setmelanotide is being tested with respect to other mutations responsible for severe obesity, raising hopes that it will soon be indicated for use in a larger number of patients.

Fewer than 1% of patients who suffer from severe obesity have monogenic forms of obesity. In recent years, the hope for a targeted treatment for patients with these monogenic forms has become a reality.

Although only a small number of patients currently meet the criteria for setmelanotide treatment (namely, those with obesity linked to a biallelic POMC/PCSK1 enzyme or LEPR deficiency and patients with Bardet-Biedl syndrome), there is a real hope that patients with other forms of severe obesity will be able to benefit from this product, including those with heterozygous (not just homozygous) monoallelic variants, who account for more than 10% of patients with severe early-onset obesity.
 

Restoring satiety signaling

“Setmelanotide is a melanocortin 4 receptor agonist,” said Béatrice Dubern, MD, PhD, pediatrician at Trousseau Hospital, Paris, and member of the French medical research institute (INSERM)/Sorbonne University team on nutrition and obesity. “Its mode of action rests on activation of the leptin-melanocortin signaling pathway in the hypothalamus, which regulates hunger, satiety, energy expenditure, and, therefore, body weight. Rare genetic variants in the leptin-melanocortin pathway are associated with polyphagia and severe early-onset obesity. It is believed that more than 60 genes involved in this leptin-melanocortin pathway are currently associated with obesity.”

In July 2021, the European Medicines Agency approved setmelanotide for daily use via subcutaneous administration.
 

Weight loss maintained

In phase 3 studies, setmelanotide (melanocortin 4 receptor agonist) demonstrated its effectiveness in reducing weight and hunger for patients with obesity caused by a POMC/PCSK1 or LEPR deficiency.

Twenty-four patients aged 6 years and older showed a significant response to setmelanotide after 1 year of treatment and were included in the extension study. “Significant response” was defined as a reduction in body weight greater than or equal to 10% after 52 weeks for patients aged 18 years and older or a reduction in body mass index (BMI) z-score greater than or equal to 0.3 after 52 weeks for patients younger than 18 years.

Among all patients, the mean variation (standard deviation) in BMI was −24.8% (8.2%, n = 24), −21% (13%, n = 23), and −24% (17.9%, n = 15) at 12, 24, and 36 months, respectively.

For patients aged greater than or equal to 18 years (n = 11), the mean variation (standard deviation) in weight was −25.1% (7.7%, n = 11), −22.9% (12.5%, n = 11), and −24.4% (13.2%, n = 8) at 12, 24, and 36 months, respectively.

For children and adolescents (patients aged < 18 years, n = 13), the mean reduction (standard deviation) in BMI z-score was −1.31 ([0.66], n = 13), −1.10 ([0.79], n = 11), and −1.01 (1.22], n = 4) at 12, 24, and 36 months, respectively.

For patients younger than 18 years, the mean variation in BMI z-score was −1.01 SD after three years on setmelanotide (standard deviation, 1.22 [n = 4]). The mean BMI z-score was +2.42 SD (standard deviation, 1.22 [n = 4]) after 3 years of treatment with setmelanotide.

In sum, the patients who achieved a reduction in body weight of at least 10% or greater than or equal to 0.3 mean variation in BMI z-score after 1 year experienced long-lasting, clinically significant benefit after 3 years. The finding supports the long-term use of setmelanotide for this group.

“We feared that setmelanotide’s effectiveness would decrease over time, but after 3 years, this had not happened, and we are hopeful that this sustained efficacy will be long lasting. The first two patients who took the drug in 2016 have not noticed any loss of efficacy as it stands,” said Dr. Dubern.

This is all the more encouraging. In the study presented at the 2023 pediatric conference, setmelanotide’s safety profile was reassuring, and it was consistent with previous studies. Side effects reported in greater than or equal to 15% of patients include injection site reactions, skin hyperpigmentation, nausea, diarrhea, mood disturbances, abdominal pain, vomiting, gastroenteritis, and spontaneous erection.

In addition to the lack of control group, Dr. Dubern acknowledged one other constraint of this study. “Only the patients who responded to treatment with setmelanotide during early-phase trials (85.7%) were enrolled.”

Dr. Dubern summarized the clinical implications: “In patients with early-onset obesity, starting before 5 years of age, doctors should really be considering the possibility that genetics might be involved in such cases. For confirmation and to seek expert opinion, specialist obesity clinics can be found throughout France. Additionally, the INSERM NutriOmics research team headed by Prof Karine Clément, MD, PhD, Sorbonne University, in conjunction with Prof Christine Poitou, MD, PhD, has developed a diagnostic tool [called] ObsGen for practitioners faced with patients with potentially genetic causes of obesity. We can answer any questions they have about the likelihood of a particular patient having a genetic form of obesity and guide their next steps. Treating patients with genetic obesity early on helps limit the condition worsening during adolescence, prevents related complications, and can reduce the stigmatization and suffering experienced by these people. It’s a huge issue. A clinical trial with setmelanotide is currently being carried out in children over 2 years of age.”
 

Hypothalamic obesity

During the pediatric conference, another speaker presented the results of a phase 2 study that evaluated the efficacy and tolerability of setmelanotide as a new treatment for hypothalamic obesity. Lesions in the hypothalamus can alter melanocortin 4 receptor pathway signaling and thus lead to hypothalamic obesity. Eighteen patients aged 6-40 years with a BMI greater than or equal to the 95th percentile (for patients aged 6-18 years) or greater than or equal to 35 kg/m² (for adults aged ≥ 18 years) and hypothalamic obesity (craniopharyngioma or other benign brain tumors, surgical removal, and/or chemotherapy) were enrolled. A significant proportion of patients achieved a reduction of greater than or equal to 5% of their BMI (n = 16, 88.9%, CI 90%, 69%-89%, P < .0001), and 72.2% achieved a reduction of greater than or equal to 10% by week 16. The mean change in BMI was −14.9% (9.6%, n = 17). These early results may justify further studies of setmelanotide in treating hypothalamic obesity.

Dr. Dubern has collaborated with Rhythm Pharmaceuticals and Novo Nordisk.

This article was translated from the Medscape French Edition and a version appeared on Medscape.com.

MARSEILLE, FRANCE – Setmelanotide can lead to significant weight loss that lasts for at least 3 years, according to results presented at the latest French Pediatric Society conference. The treatment is effective for adults and children alike.

Setmelanotide is the culmination of two decades of research involving the identification of genes involved in early-onset obesity and the characterization of the melanocortin 4 receptor. It became available via early access in 2021.

Currently limited to use in treating obesity linked to a biallelic POMC/PCSK1 or LEPR deficiency, setmelanotide is being tested with respect to other mutations responsible for severe obesity, raising hopes that it will soon be indicated for use in a larger number of patients.

Fewer than 1% of patients who suffer from severe obesity have monogenic forms of obesity. In recent years, the hope for a targeted treatment for patients with these monogenic forms has become a reality.

Although only a small number of patients currently meet the criteria for setmelanotide treatment (namely, those with obesity linked to a biallelic POMC/PCSK1 enzyme or LEPR deficiency and patients with Bardet-Biedl syndrome), there is a real hope that patients with other forms of severe obesity will be able to benefit from this product, including those with heterozygous (not just homozygous) monoallelic variants, who account for more than 10% of patients with severe early-onset obesity.
 

Restoring satiety signaling

“Setmelanotide is a melanocortin 4 receptor agonist,” said Béatrice Dubern, MD, PhD, pediatrician at Trousseau Hospital, Paris, and member of the French medical research institute (INSERM)/Sorbonne University team on nutrition and obesity. “Its mode of action rests on activation of the leptin-melanocortin signaling pathway in the hypothalamus, which regulates hunger, satiety, energy expenditure, and, therefore, body weight. Rare genetic variants in the leptin-melanocortin pathway are associated with polyphagia and severe early-onset obesity. It is believed that more than 60 genes involved in this leptin-melanocortin pathway are currently associated with obesity.”

In July 2021, the European Medicines Agency approved setmelanotide for daily use via subcutaneous administration.
 

Weight loss maintained

In phase 3 studies, setmelanotide (melanocortin 4 receptor agonist) demonstrated its effectiveness in reducing weight and hunger for patients with obesity caused by a POMC/PCSK1 or LEPR deficiency.

Twenty-four patients aged 6 years and older showed a significant response to setmelanotide after 1 year of treatment and were included in the extension study. “Significant response” was defined as a reduction in body weight greater than or equal to 10% after 52 weeks for patients aged 18 years and older or a reduction in body mass index (BMI) z-score greater than or equal to 0.3 after 52 weeks for patients younger than 18 years.

Among all patients, the mean variation (standard deviation) in BMI was −24.8% (8.2%, n = 24), −21% (13%, n = 23), and −24% (17.9%, n = 15) at 12, 24, and 36 months, respectively.

For patients aged greater than or equal to 18 years (n = 11), the mean variation (standard deviation) in weight was −25.1% (7.7%, n = 11), −22.9% (12.5%, n = 11), and −24.4% (13.2%, n = 8) at 12, 24, and 36 months, respectively.

For children and adolescents (patients aged < 18 years, n = 13), the mean reduction (standard deviation) in BMI z-score was −1.31 ([0.66], n = 13), −1.10 ([0.79], n = 11), and −1.01 (1.22], n = 4) at 12, 24, and 36 months, respectively.

For patients younger than 18 years, the mean variation in BMI z-score was −1.01 SD after three years on setmelanotide (standard deviation, 1.22 [n = 4]). The mean BMI z-score was +2.42 SD (standard deviation, 1.22 [n = 4]) after 3 years of treatment with setmelanotide.

In sum, the patients who achieved a reduction in body weight of at least 10% or greater than or equal to 0.3 mean variation in BMI z-score after 1 year experienced long-lasting, clinically significant benefit after 3 years. The finding supports the long-term use of setmelanotide for this group.

“We feared that setmelanotide’s effectiveness would decrease over time, but after 3 years, this had not happened, and we are hopeful that this sustained efficacy will be long lasting. The first two patients who took the drug in 2016 have not noticed any loss of efficacy as it stands,” said Dr. Dubern.

This is all the more encouraging. In the study presented at the 2023 pediatric conference, setmelanotide’s safety profile was reassuring, and it was consistent with previous studies. Side effects reported in greater than or equal to 15% of patients include injection site reactions, skin hyperpigmentation, nausea, diarrhea, mood disturbances, abdominal pain, vomiting, gastroenteritis, and spontaneous erection.

In addition to the lack of control group, Dr. Dubern acknowledged one other constraint of this study. “Only the patients who responded to treatment with setmelanotide during early-phase trials (85.7%) were enrolled.”

Dr. Dubern summarized the clinical implications: “In patients with early-onset obesity, starting before 5 years of age, doctors should really be considering the possibility that genetics might be involved in such cases. For confirmation and to seek expert opinion, specialist obesity clinics can be found throughout France. Additionally, the INSERM NutriOmics research team headed by Prof Karine Clément, MD, PhD, Sorbonne University, in conjunction with Prof Christine Poitou, MD, PhD, has developed a diagnostic tool [called] ObsGen for practitioners faced with patients with potentially genetic causes of obesity. We can answer any questions they have about the likelihood of a particular patient having a genetic form of obesity and guide their next steps. Treating patients with genetic obesity early on helps limit the condition worsening during adolescence, prevents related complications, and can reduce the stigmatization and suffering experienced by these people. It’s a huge issue. A clinical trial with setmelanotide is currently being carried out in children over 2 years of age.”
 

Hypothalamic obesity

During the pediatric conference, another speaker presented the results of a phase 2 study that evaluated the efficacy and tolerability of setmelanotide as a new treatment for hypothalamic obesity. Lesions in the hypothalamus can alter melanocortin 4 receptor pathway signaling and thus lead to hypothalamic obesity. Eighteen patients aged 6-40 years with a BMI greater than or equal to the 95th percentile (for patients aged 6-18 years) or greater than or equal to 35 kg/m² (for adults aged ≥ 18 years) and hypothalamic obesity (craniopharyngioma or other benign brain tumors, surgical removal, and/or chemotherapy) were enrolled. A significant proportion of patients achieved a reduction of greater than or equal to 5% of their BMI (n = 16, 88.9%, CI 90%, 69%-89%, P < .0001), and 72.2% achieved a reduction of greater than or equal to 10% by week 16. The mean change in BMI was −14.9% (9.6%, n = 17). These early results may justify further studies of setmelanotide in treating hypothalamic obesity.

Dr. Dubern has collaborated with Rhythm Pharmaceuticals and Novo Nordisk.

This article was translated from the Medscape French Edition and a version appeared on Medscape.com.