Immunology

Although in many cases, food-allergen tolerance can be achieved with oral immunotherapy, primary prevention of food allergies remains crucial, according to the French Society of Allergology. In new recommendations that were presented at a session of the Congress of French Pediatric Societies, the academic society advocated early introduction of allergens for all children, starting at 4 months of age.

The latest prevention data from two major studies, LEAP and EAT, have prompted European and French experts to rethink their stance on food diversification. The new French proposals were recently published under the coordination of Dominique Sabouraud-Leclerc, MD, pediatrics department, Reims (France) University Hospital, on behalf of the Food Allergy Working Group of the French Society of Allergology.

For all newborns, regardless of whether they have a history of atopic or nonatopic dermatitis, food diversification is now recommended from 4 months of age instead of 6 months, as was previously recommended. If the child does not develop atopic dermatitis or develops only a mild form, peanuts, eggs, and nuts may be introduced at home.

However, if the child experiences severe atopic dermatitis, an allergy testing panel for peanuts, nuts, eggs, and cow’s milk proteins should be performed. An oral food challenge may be conducted at the allergist’s discretion.

Regarding peanuts, the working group proposed introducing a purée in the form of either a mixture of peanuts/hazelnuts/cashew nuts (1 level teaspoon five times a week; 2 g of protein/food per week) or a 100% peanut paste (1 scant teaspoon four times a week; 2 g of peanut protein/week). If the family is worried, the allergist can suggest monitoring the child in the clinic waiting room for 30 minutes after the first dose.

“We shouldn’t delay the introduction of the primary allergens anymore, regardless of whether children are at risk for a food allergy, and particularly a peanut allergy,” explained Stéphanie Lejeune, MD, pediatric pulmonologist and allergist at Lille (France) Regional University Hospital, who presented these new findings at the congress. “In fact, if we only target at-risk children, we overlook children with no family history who will nevertheless develop food allergies. The idea is to introduce everything, especially peanuts, between 4 and 6 months of age and to no longer do so gradually, one food after another, as was being done until now, beginning at 6 months and over. We must give priority to regularity over quantity.”

Although this approach is based on clinical trials, no real-life data are currently available.
 

LEAP and EAT studies support early introduction of peanuts

A study from 2021 summed up the risk factors for peanut allergy. About 61% of infants (4-11 months) had atopic dermatitis, 18% had a food allergy, 62% had a first-degree relative with a peanut allergy, and 11% had a confirmed peanut allergy. The risk of peanut allergy increased with age and severe eczema.

In 2015, the LEAP study, which was conducted in the United Kingdom with 640 infants aged 4-11 months who had risk factors for peanut allergy, revolutionized peanut-allergy primary prevention. Regardless of whether the children were sensitized or not, the number of children who developed a peanut allergy was systematically lower in the group that ingested the allergen in comparison with the “avoidance” group.

Additionally, the LEAP-ON study showed that protection against peanut allergy persisted for 12 months after cessation of consumption between ages 5 and 6 years among children who had consumed peanuts previously.

Early diversification in the general population was investigated in the EAT study, which involved 1303 breastfed infants. Of these infants, 24% had atopic dermatitis (median SCORAD score, 7.5). They were divided into two arms: avoidance and breast feeding until 6 months (standard introduction) or early introduction at 3 months (boiled egg, milk, peanuts, sesame, white fish, wheat, 2 g of protein twice a week). In the per-protocol analysis, there were 13 cases of peanut allergy in the standard introduction group; there were no cases in the early introduction group.

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

Although in many cases, food-allergen tolerance can be achieved with oral immunotherapy, primary prevention of food allergies remains crucial, according to the French Society of Allergology. In new recommendations that were presented at a session of the Congress of French Pediatric Societies, the academic society advocated early introduction of allergens for all children, starting at 4 months of age.

The latest prevention data from two major studies, LEAP and EAT, have prompted European and French experts to rethink their stance on food diversification. The new French proposals were recently published under the coordination of Dominique Sabouraud-Leclerc, MD, pediatrics department, Reims (France) University Hospital, on behalf of the Food Allergy Working Group of the French Society of Allergology.

For all newborns, regardless of whether they have a history of atopic or nonatopic dermatitis, food diversification is now recommended from 4 months of age instead of 6 months, as was previously recommended. If the child does not develop atopic dermatitis or develops only a mild form, peanuts, eggs, and nuts may be introduced at home.

However, if the child experiences severe atopic dermatitis, an allergy testing panel for peanuts, nuts, eggs, and cow’s milk proteins should be performed. An oral food challenge may be conducted at the allergist’s discretion.

Regarding peanuts, the working group proposed introducing a purée in the form of either a mixture of peanuts/hazelnuts/cashew nuts (1 level teaspoon five times a week; 2 g of protein/food per week) or a 100% peanut paste (1 scant teaspoon four times a week; 2 g of peanut protein/week). If the family is worried, the allergist can suggest monitoring the child in the clinic waiting room for 30 minutes after the first dose.

“We shouldn’t delay the introduction of the primary allergens anymore, regardless of whether children are at risk for a food allergy, and particularly a peanut allergy,” explained Stéphanie Lejeune, MD, pediatric pulmonologist and allergist at Lille (France) Regional University Hospital, who presented these new findings at the congress. “In fact, if we only target at-risk children, we overlook children with no family history who will nevertheless develop food allergies. The idea is to introduce everything, especially peanuts, between 4 and 6 months of age and to no longer do so gradually, one food after another, as was being done until now, beginning at 6 months and over. We must give priority to regularity over quantity.”

Although this approach is based on clinical trials, no real-life data are currently available.
 

LEAP and EAT studies support early introduction of peanuts

A study from 2021 summed up the risk factors for peanut allergy. About 61% of infants (4-11 months) had atopic dermatitis, 18% had a food allergy, 62% had a first-degree relative with a peanut allergy, and 11% had a confirmed peanut allergy. The risk of peanut allergy increased with age and severe eczema.

In 2015, the LEAP study, which was conducted in the United Kingdom with 640 infants aged 4-11 months who had risk factors for peanut allergy, revolutionized peanut-allergy primary prevention. Regardless of whether the children were sensitized or not, the number of children who developed a peanut allergy was systematically lower in the group that ingested the allergen in comparison with the “avoidance” group.

Additionally, the LEAP-ON study showed that protection against peanut allergy persisted for 12 months after cessation of consumption between ages 5 and 6 years among children who had consumed peanuts previously.

Early diversification in the general population was investigated in the EAT study, which involved 1303 breastfed infants. Of these infants, 24% had atopic dermatitis (median SCORAD score, 7.5). They were divided into two arms: avoidance and breast feeding until 6 months (standard introduction) or early introduction at 3 months (boiled egg, milk, peanuts, sesame, white fish, wheat, 2 g of protein twice a week). In the per-protocol analysis, there were 13 cases of peanut allergy in the standard introduction group; there were no cases in the early introduction group.

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

Although in many cases, food-allergen tolerance can be achieved with oral immunotherapy, primary prevention of food allergies remains crucial, according to the French Society of Allergology. In new recommendations that were presented at a session of the Congress of French Pediatric Societies, the academic society advocated early introduction of allergens for all children, starting at 4 months of age.

The latest prevention data from two major studies, LEAP and EAT, have prompted European and French experts to rethink their stance on food diversification. The new French proposals were recently published under the coordination of Dominique Sabouraud-Leclerc, MD, pediatrics department, Reims (France) University Hospital, on behalf of the Food Allergy Working Group of the French Society of Allergology.

For all newborns, regardless of whether they have a history of atopic or nonatopic dermatitis, food diversification is now recommended from 4 months of age instead of 6 months, as was previously recommended. If the child does not develop atopic dermatitis or develops only a mild form, peanuts, eggs, and nuts may be introduced at home.

However, if the child experiences severe atopic dermatitis, an allergy testing panel for peanuts, nuts, eggs, and cow’s milk proteins should be performed. An oral food challenge may be conducted at the allergist’s discretion.

Regarding peanuts, the working group proposed introducing a purée in the form of either a mixture of peanuts/hazelnuts/cashew nuts (1 level teaspoon five times a week; 2 g of protein/food per week) or a 100% peanut paste (1 scant teaspoon four times a week; 2 g of peanut protein/week). If the family is worried, the allergist can suggest monitoring the child in the clinic waiting room for 30 minutes after the first dose.

“We shouldn’t delay the introduction of the primary allergens anymore, regardless of whether children are at risk for a food allergy, and particularly a peanut allergy,” explained Stéphanie Lejeune, MD, pediatric pulmonologist and allergist at Lille (France) Regional University Hospital, who presented these new findings at the congress. “In fact, if we only target at-risk children, we overlook children with no family history who will nevertheless develop food allergies. The idea is to introduce everything, especially peanuts, between 4 and 6 months of age and to no longer do so gradually, one food after another, as was being done until now, beginning at 6 months and over. We must give priority to regularity over quantity.”

Although this approach is based on clinical trials, no real-life data are currently available.
 

LEAP and EAT studies support early introduction of peanuts

A study from 2021 summed up the risk factors for peanut allergy. About 61% of infants (4-11 months) had atopic dermatitis, 18% had a food allergy, 62% had a first-degree relative with a peanut allergy, and 11% had a confirmed peanut allergy. The risk of peanut allergy increased with age and severe eczema.

In 2015, the LEAP study, which was conducted in the United Kingdom with 640 infants aged 4-11 months who had risk factors for peanut allergy, revolutionized peanut-allergy primary prevention. Regardless of whether the children were sensitized or not, the number of children who developed a peanut allergy was systematically lower in the group that ingested the allergen in comparison with the “avoidance” group.

Additionally, the LEAP-ON study showed that protection against peanut allergy persisted for 12 months after cessation of consumption between ages 5 and 6 years among children who had consumed peanuts previously.

Early diversification in the general population was investigated in the EAT study, which involved 1303 breastfed infants. Of these infants, 24% had atopic dermatitis (median SCORAD score, 7.5). They were divided into two arms: avoidance and breast feeding until 6 months (standard introduction) or early introduction at 3 months (boiled egg, milk, peanuts, sesame, white fish, wheat, 2 g of protein twice a week). In the per-protocol analysis, there were 13 cases of peanut allergy in the standard introduction group; there were no cases in the early introduction group.

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

According to a consensus study, many infants in some countries are misdiagnosed with allergy to cow, sheep, or goat milk, and they’re prescribed specialized formulas they don’t need.

“Milk allergy overdiagnosis is common in some regions and can potentially harm mothers and infants,” the authors write in Clinical & Experimental Allergy. “These new consensus recommendations on the safe detection and management of milk allergy in children under 2 years aim to reduce harms associated with milk allergy overdiagnosis.”

“This guidance, developed by experts without commercial ties to the formula industry, aims to reduce milk allergy overdiagnosis and [to] support ... breastfeeding and less use of specialized formula, compared with current guidelines,” they add.

Up to 1% of European infants 2 years of age and younger are considered allergic to cow’s milk. Prescriptions for specialized formula for bottle-fed infants allergic to cow’s milk in Australia, England, and Norway have grown to over 10 times the expected volumes.

Lead study author Hilary I. Allen, National Heart and Lung Institute, Imperial College London, and her colleagues on several continents developed practical guidance for providers on safely detecting and managing milk allergy in infants.

Due to lack of high-certainty research evidence in this area, they used the Delphi consensus method.

The study involved two rounds of anonymous consensus-building surveys and one formal meeting in 2021.

The team identified experts from diverse geographic and cultural settings by searching medical databases for the term “milk hypersensitivity.” They asked those experts to recommend colleagues. The researchers also contacted experts with ties to international professional organizations, such as the International Board of Lactation Consultant Examiners, as well as societies associated with the World Allergy Organization.

The 17 study participants included clinicians and researchers in general practice, health visiting, lactation support, midwifery, nutrition, and relevant areas of pediatrics from Africa, Asia, Australia, Europe, the Middle East, and North America. Experts with recent conflicts of interest with the breastmilk substitute (formula) industry were excluded from the study. Five authors of earlier milk allergy guidelines and seven parents contributed feedback.

In each survey round, participants used a nine-point scale to rank the importance of each proposed statement that addressed prevention of overdiagnosis or underdiagnosis, support of breastfeeding women, and the role of specialized formula products.

Based on the number of total points participants assigned, each statement was classified as “essential,” “recommended,” “no consensus,” or “excluded” due to lack of relevance.

The experts agreed on 38 essential statements in several categories, including:

• Maternal dietary restriction is often not necessary to manage milk allergy
• In infants with chronic symptoms who are exclusively breastfed, milk allergy diagnosis should be considered only in specific, rare circumstances
• Milk allergy diagnosis does not usually need to be considered for stool changes, aversive feeding, or occasional spots of blood in stool, if not related in time with milk protein ingestion

The consensus recommendations provide more restrictive criteria than earlier guidelines for detecting milk allergy, fewer maternal dietary exclusions, and less use of specialized formula.
 

During an infant formula shortage in the U.S., a timely study

Jodi A. Shroba, MSN, APRN, CPNP, coordinator for the Food Allergy Program, Children’s Mercy Kansas City, Missouri, welcomed the study’s engagement of specialists in various fields and avoidance of bias from formula companies.

“Food allergies have received a lot of attention, especially through websites and social media,” Ms. Shroba, who was not involved in the study, told this news organization in an email. “Unfortunately, a lot of that information is incorrect and can lead to misunderstanding and misdiagnosis.”

“This article helps guide practitioners through identifying the concerning symptoms of milk allergy versus normal infant symptoms,” she said. “It can help providers discern when testing, elimination diets, and changes in formula are warranted.

“This guidance emphasizes the reproducibility and specificity of symptoms, which are key elements of a food allergy diagnosis,” she explained. “By eliminating unnecessary milk allergy labeling, we can keep infants on appropriate diets for their age, such as breastfeeding or milk-based formulas. Proper diagnosis can also reduce unnecessary financial strain of specialty formulas, stress to the family regarding feedings, and a restrictive diet for the breastfeeding mother.”

The study will be useful to a wide range of health care providers, Jennifer Anne Dantzer, MD, assistant professor of pediatrics, Johns Hopkins Medicine, Baltimore, said in an email.

“With the current formula shortage, there has perhaps never been a more important time to do this study and provide additional guidance on who does or does not need special formula,” noted Dr. Dantzer, who also was not involved in the study. “A milk allergy diagnosis impacts the child and the family, so it is very important to avoid overdiagnosis and to support the breastfeeding mother.”

“These findings should provide reassurance that dietary exclusions for the breastfeeding mother are not needed for most children with milk allergy,” she said. “If a milk allergy is suspected, the child should be referred to an allergist.”

The authors recommend further related research into the safety and effectiveness of using the guidance in practice.

One coauthor reports financial relationships with a biotech company. Ms. Allen and her remaining coauthors, as well as Ms. Shroba and Dr. Dantzer, report no relevant financial relationships. The study was funded through fellowships.

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

According to a consensus study, many infants in some countries are misdiagnosed with allergy to cow, sheep, or goat milk, and they’re prescribed specialized formulas they don’t need.

“Milk allergy overdiagnosis is common in some regions and can potentially harm mothers and infants,” the authors write in Clinical & Experimental Allergy. “These new consensus recommendations on the safe detection and management of milk allergy in children under 2 years aim to reduce harms associated with milk allergy overdiagnosis.”

“This guidance, developed by experts without commercial ties to the formula industry, aims to reduce milk allergy overdiagnosis and [to] support ... breastfeeding and less use of specialized formula, compared with current guidelines,” they add.

Up to 1% of European infants 2 years of age and younger are considered allergic to cow’s milk. Prescriptions for specialized formula for bottle-fed infants allergic to cow’s milk in Australia, England, and Norway have grown to over 10 times the expected volumes.

Lead study author Hilary I. Allen, National Heart and Lung Institute, Imperial College London, and her colleagues on several continents developed practical guidance for providers on safely detecting and managing milk allergy in infants.

Due to lack of high-certainty research evidence in this area, they used the Delphi consensus method.

The study involved two rounds of anonymous consensus-building surveys and one formal meeting in 2021.

The team identified experts from diverse geographic and cultural settings by searching medical databases for the term “milk hypersensitivity.” They asked those experts to recommend colleagues. The researchers also contacted experts with ties to international professional organizations, such as the International Board of Lactation Consultant Examiners, as well as societies associated with the World Allergy Organization.

The 17 study participants included clinicians and researchers in general practice, health visiting, lactation support, midwifery, nutrition, and relevant areas of pediatrics from Africa, Asia, Australia, Europe, the Middle East, and North America. Experts with recent conflicts of interest with the breastmilk substitute (formula) industry were excluded from the study. Five authors of earlier milk allergy guidelines and seven parents contributed feedback.

In each survey round, participants used a nine-point scale to rank the importance of each proposed statement that addressed prevention of overdiagnosis or underdiagnosis, support of breastfeeding women, and the role of specialized formula products.

Based on the number of total points participants assigned, each statement was classified as “essential,” “recommended,” “no consensus,” or “excluded” due to lack of relevance.

The experts agreed on 38 essential statements in several categories, including:

• Maternal dietary restriction is often not necessary to manage milk allergy
• In infants with chronic symptoms who are exclusively breastfed, milk allergy diagnosis should be considered only in specific, rare circumstances
• Milk allergy diagnosis does not usually need to be considered for stool changes, aversive feeding, or occasional spots of blood in stool, if not related in time with milk protein ingestion

The consensus recommendations provide more restrictive criteria than earlier guidelines for detecting milk allergy, fewer maternal dietary exclusions, and less use of specialized formula.
 

During an infant formula shortage in the U.S., a timely study

Jodi A. Shroba, MSN, APRN, CPNP, coordinator for the Food Allergy Program, Children’s Mercy Kansas City, Missouri, welcomed the study’s engagement of specialists in various fields and avoidance of bias from formula companies.

“Food allergies have received a lot of attention, especially through websites and social media,” Ms. Shroba, who was not involved in the study, told this news organization in an email. “Unfortunately, a lot of that information is incorrect and can lead to misunderstanding and misdiagnosis.”

“This article helps guide practitioners through identifying the concerning symptoms of milk allergy versus normal infant symptoms,” she said. “It can help providers discern when testing, elimination diets, and changes in formula are warranted.

“This guidance emphasizes the reproducibility and specificity of symptoms, which are key elements of a food allergy diagnosis,” she explained. “By eliminating unnecessary milk allergy labeling, we can keep infants on appropriate diets for their age, such as breastfeeding or milk-based formulas. Proper diagnosis can also reduce unnecessary financial strain of specialty formulas, stress to the family regarding feedings, and a restrictive diet for the breastfeeding mother.”

The study will be useful to a wide range of health care providers, Jennifer Anne Dantzer, MD, assistant professor of pediatrics, Johns Hopkins Medicine, Baltimore, said in an email.

“With the current formula shortage, there has perhaps never been a more important time to do this study and provide additional guidance on who does or does not need special formula,” noted Dr. Dantzer, who also was not involved in the study. “A milk allergy diagnosis impacts the child and the family, so it is very important to avoid overdiagnosis and to support the breastfeeding mother.”

“These findings should provide reassurance that dietary exclusions for the breastfeeding mother are not needed for most children with milk allergy,” she said. “If a milk allergy is suspected, the child should be referred to an allergist.”

The authors recommend further related research into the safety and effectiveness of using the guidance in practice.

One coauthor reports financial relationships with a biotech company. Ms. Allen and her remaining coauthors, as well as Ms. Shroba and Dr. Dantzer, report no relevant financial relationships. The study was funded through fellowships.

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

According to a consensus study, many infants in some countries are misdiagnosed with allergy to cow, sheep, or goat milk, and they’re prescribed specialized formulas they don’t need.

“Milk allergy overdiagnosis is common in some regions and can potentially harm mothers and infants,” the authors write in Clinical & Experimental Allergy. “These new consensus recommendations on the safe detection and management of milk allergy in children under 2 years aim to reduce harms associated with milk allergy overdiagnosis.”

“This guidance, developed by experts without commercial ties to the formula industry, aims to reduce milk allergy overdiagnosis and [to] support ... breastfeeding and less use of specialized formula, compared with current guidelines,” they add.

Up to 1% of European infants 2 years of age and younger are considered allergic to cow’s milk. Prescriptions for specialized formula for bottle-fed infants allergic to cow’s milk in Australia, England, and Norway have grown to over 10 times the expected volumes.

Lead study author Hilary I. Allen, National Heart and Lung Institute, Imperial College London, and her colleagues on several continents developed practical guidance for providers on safely detecting and managing milk allergy in infants.

Due to lack of high-certainty research evidence in this area, they used the Delphi consensus method.

The study involved two rounds of anonymous consensus-building surveys and one formal meeting in 2021.

The team identified experts from diverse geographic and cultural settings by searching medical databases for the term “milk hypersensitivity.” They asked those experts to recommend colleagues. The researchers also contacted experts with ties to international professional organizations, such as the International Board of Lactation Consultant Examiners, as well as societies associated with the World Allergy Organization.

The 17 study participants included clinicians and researchers in general practice, health visiting, lactation support, midwifery, nutrition, and relevant areas of pediatrics from Africa, Asia, Australia, Europe, the Middle East, and North America. Experts with recent conflicts of interest with the breastmilk substitute (formula) industry were excluded from the study. Five authors of earlier milk allergy guidelines and seven parents contributed feedback.

In each survey round, participants used a nine-point scale to rank the importance of each proposed statement that addressed prevention of overdiagnosis or underdiagnosis, support of breastfeeding women, and the role of specialized formula products.

Based on the number of total points participants assigned, each statement was classified as “essential,” “recommended,” “no consensus,” or “excluded” due to lack of relevance.

The experts agreed on 38 essential statements in several categories, including:

• Maternal dietary restriction is often not necessary to manage milk allergy
• In infants with chronic symptoms who are exclusively breastfed, milk allergy diagnosis should be considered only in specific, rare circumstances
• Milk allergy diagnosis does not usually need to be considered for stool changes, aversive feeding, or occasional spots of blood in stool, if not related in time with milk protein ingestion

The consensus recommendations provide more restrictive criteria than earlier guidelines for detecting milk allergy, fewer maternal dietary exclusions, and less use of specialized formula.
 

During an infant formula shortage in the U.S., a timely study

Jodi A. Shroba, MSN, APRN, CPNP, coordinator for the Food Allergy Program, Children’s Mercy Kansas City, Missouri, welcomed the study’s engagement of specialists in various fields and avoidance of bias from formula companies.

“Food allergies have received a lot of attention, especially through websites and social media,” Ms. Shroba, who was not involved in the study, told this news organization in an email. “Unfortunately, a lot of that information is incorrect and can lead to misunderstanding and misdiagnosis.”

“This article helps guide practitioners through identifying the concerning symptoms of milk allergy versus normal infant symptoms,” she said. “It can help providers discern when testing, elimination diets, and changes in formula are warranted.

“This guidance emphasizes the reproducibility and specificity of symptoms, which are key elements of a food allergy diagnosis,” she explained. “By eliminating unnecessary milk allergy labeling, we can keep infants on appropriate diets for their age, such as breastfeeding or milk-based formulas. Proper diagnosis can also reduce unnecessary financial strain of specialty formulas, stress to the family regarding feedings, and a restrictive diet for the breastfeeding mother.”

The study will be useful to a wide range of health care providers, Jennifer Anne Dantzer, MD, assistant professor of pediatrics, Johns Hopkins Medicine, Baltimore, said in an email.

“With the current formula shortage, there has perhaps never been a more important time to do this study and provide additional guidance on who does or does not need special formula,” noted Dr. Dantzer, who also was not involved in the study. “A milk allergy diagnosis impacts the child and the family, so it is very important to avoid overdiagnosis and to support the breastfeeding mother.”

“These findings should provide reassurance that dietary exclusions for the breastfeeding mother are not needed for most children with milk allergy,” she said. “If a milk allergy is suspected, the child should be referred to an allergist.”

The authors recommend further related research into the safety and effectiveness of using the guidance in practice.

One coauthor reports financial relationships with a biotech company. Ms. Allen and her remaining coauthors, as well as Ms. Shroba and Dr. Dantzer, report no relevant financial relationships. The study was funded through fellowships.

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

What would you do if you believed you had a serious health issue, but the best way to find out for sure might kill you?

That’s the reality for patients who wish to confirm or rule out a food allergy, says Sindy Tang, PhD, an associate professor of mechanical engineering at Stanford (Calif.) University.

And it’s the reason Dr. Tang and her colleagues are developing a food allergy test that’s not only safer, but also more reliable than today’s tests. In a paper in the journal Lab on a Chip, Dr. Tang and her colleagues outline the basis for this future test, which isolates a food allergy marker from the blood using a magnetic field.
 

How today’s food allergy tests fall short

The gold standard for food allergy diagnosis is something called the oral food challenge. That’s when the patient eats gradually increasing amounts of a problem food – say, peanuts – every 15 to 30 minutes to see if symptoms occur. This means highly allergic patients may risk anaphylaxis, an allergic reaction that causes inflammation so severe that breathing becomes restricted and blood pressure drops. Because of that, a clinical team must be at the ready with treatments like oxygen, epinephrine, or albuterol.

“The test is very accurate, but it’s also potentially unsafe and even fatal in rare cases,” Dr. Tang says. “That’s led to many sham tests advertised online that claim to use hair samples for food tests, but those are inaccurate and potentially dangerous, since they may give someone a false sense of confidence about a food they should avoid.”

Less risky tests are available, such as skin-prick tests – those involve scratching a small amount of the food into a patient’s arm – as well as blood tests that measure allergen-specific antibodies.

“Unfortunately, both of those are not that accurate and have high false-positive rates,” Dr. Tang says. “The best method is the oral food challenge, which many patients are afraid to do, not surprisingly.”
 

The future of food allergy testing: faster, safer, more reliable

In their study, the Stanford researchers focused on a type of white blood cell known as basophils, which release histamine when triggered by allergens. By using magnetic nanoparticles that bind to some blood cells but not basophils, they were able to separate basophils from the blood with a magnetic field in just 10 minutes.

Once isolated, the basophils are exposed to potential allergens. If they react, that’s a sign of an allergy.

Basophils have been isolated in labs before but not nearly this quickly and efficiently, Dr. Tang says.

“For true basophil activation, you need the blood to be fresh, which is challenging when you have to send it to a lab,” Dr. Tang says. “Being able to do this kind of test within a clinic or an in-house lab would be a big step forward.”
 

Next steps

While this represents a breakthrough in basophil activation testing, more research is needed to fully develop the system for clinical use. It must be standardized, automated, and miniaturized, the researchers say.

That said, the results give hope to those with food allergies that tomorrow’s gold-standard test will require only a blood sample without an emergency team standing by.

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

What would you do if you believed you had a serious health issue, but the best way to find out for sure might kill you?

That’s the reality for patients who wish to confirm or rule out a food allergy, says Sindy Tang, PhD, an associate professor of mechanical engineering at Stanford (Calif.) University.

And it’s the reason Dr. Tang and her colleagues are developing a food allergy test that’s not only safer, but also more reliable than today’s tests. In a paper in the journal Lab on a Chip, Dr. Tang and her colleagues outline the basis for this future test, which isolates a food allergy marker from the blood using a magnetic field.
 

How today’s food allergy tests fall short

The gold standard for food allergy diagnosis is something called the oral food challenge. That’s when the patient eats gradually increasing amounts of a problem food – say, peanuts – every 15 to 30 minutes to see if symptoms occur. This means highly allergic patients may risk anaphylaxis, an allergic reaction that causes inflammation so severe that breathing becomes restricted and blood pressure drops. Because of that, a clinical team must be at the ready with treatments like oxygen, epinephrine, or albuterol.

“The test is very accurate, but it’s also potentially unsafe and even fatal in rare cases,” Dr. Tang says. “That’s led to many sham tests advertised online that claim to use hair samples for food tests, but those are inaccurate and potentially dangerous, since they may give someone a false sense of confidence about a food they should avoid.”

Less risky tests are available, such as skin-prick tests – those involve scratching a small amount of the food into a patient’s arm – as well as blood tests that measure allergen-specific antibodies.

“Unfortunately, both of those are not that accurate and have high false-positive rates,” Dr. Tang says. “The best method is the oral food challenge, which many patients are afraid to do, not surprisingly.”
 

The future of food allergy testing: faster, safer, more reliable

In their study, the Stanford researchers focused on a type of white blood cell known as basophils, which release histamine when triggered by allergens. By using magnetic nanoparticles that bind to some blood cells but not basophils, they were able to separate basophils from the blood with a magnetic field in just 10 minutes.

Once isolated, the basophils are exposed to potential allergens. If they react, that’s a sign of an allergy.

Basophils have been isolated in labs before but not nearly this quickly and efficiently, Dr. Tang says.

“For true basophil activation, you need the blood to be fresh, which is challenging when you have to send it to a lab,” Dr. Tang says. “Being able to do this kind of test within a clinic or an in-house lab would be a big step forward.”
 

Next steps

While this represents a breakthrough in basophil activation testing, more research is needed to fully develop the system for clinical use. It must be standardized, automated, and miniaturized, the researchers say.

That said, the results give hope to those with food allergies that tomorrow’s gold-standard test will require only a blood sample without an emergency team standing by.

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

What would you do if you believed you had a serious health issue, but the best way to find out for sure might kill you?

That’s the reality for patients who wish to confirm or rule out a food allergy, says Sindy Tang, PhD, an associate professor of mechanical engineering at Stanford (Calif.) University.

And it’s the reason Dr. Tang and her colleagues are developing a food allergy test that’s not only safer, but also more reliable than today’s tests. In a paper in the journal Lab on a Chip, Dr. Tang and her colleagues outline the basis for this future test, which isolates a food allergy marker from the blood using a magnetic field.
 

How today’s food allergy tests fall short

The gold standard for food allergy diagnosis is something called the oral food challenge. That’s when the patient eats gradually increasing amounts of a problem food – say, peanuts – every 15 to 30 minutes to see if symptoms occur. This means highly allergic patients may risk anaphylaxis, an allergic reaction that causes inflammation so severe that breathing becomes restricted and blood pressure drops. Because of that, a clinical team must be at the ready with treatments like oxygen, epinephrine, or albuterol.

“The test is very accurate, but it’s also potentially unsafe and even fatal in rare cases,” Dr. Tang says. “That’s led to many sham tests advertised online that claim to use hair samples for food tests, but those are inaccurate and potentially dangerous, since they may give someone a false sense of confidence about a food they should avoid.”

Less risky tests are available, such as skin-prick tests – those involve scratching a small amount of the food into a patient’s arm – as well as blood tests that measure allergen-specific antibodies.

“Unfortunately, both of those are not that accurate and have high false-positive rates,” Dr. Tang says. “The best method is the oral food challenge, which many patients are afraid to do, not surprisingly.”
 

The future of food allergy testing: faster, safer, more reliable

In their study, the Stanford researchers focused on a type of white blood cell known as basophils, which release histamine when triggered by allergens. By using magnetic nanoparticles that bind to some blood cells but not basophils, they were able to separate basophils from the blood with a magnetic field in just 10 minutes.

Once isolated, the basophils are exposed to potential allergens. If they react, that’s a sign of an allergy.

Basophils have been isolated in labs before but not nearly this quickly and efficiently, Dr. Tang says.

“For true basophil activation, you need the blood to be fresh, which is challenging when you have to send it to a lab,” Dr. Tang says. “Being able to do this kind of test within a clinic or an in-house lab would be a big step forward.”
 

Next steps

While this represents a breakthrough in basophil activation testing, more research is needed to fully develop the system for clinical use. It must be standardized, automated, and miniaturized, the researchers say.

That said, the results give hope to those with food allergies that tomorrow’s gold-standard test will require only a blood sample without an emergency team standing by.

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

From Sharp Memorial Hospital, San Diego, CA (Drs. Poremba, Dehner, Perreiter, Semma, and Mills), Sharp Rees-Stealy Medical Group, San Diego, CA (Dr. Sakoulas), and Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA (Dr. Sakoulas).

Abstract

Objective: To compare the costs of hospitalization of patients with moderate-to-severe COVID-19 who received intravenous immunoglobulin (IVIG) with those of patients of similar comorbidity and illness severity who did not.

Design: Analysis 1 was a case-control study of 10 nonventilated, moderately to severely hypoxic patients with COVID-19 who received IVIG (Privigen [CSL Behring]) matched 1:2 with 20 control patients of similar age, body mass index, degree of hypoxemia, and comorbidities. Analysis 2 consisted of patients enrolled in a previously published, randomized, open-label prospective study of 14 patients with COVID-19 receiving standard of care vs 13 patients who received standard of care plus IVIG (Octagam 10% [Octapharma]).

Setting and participants: Patients with COVID-19 with moderate-to-severe hypoxemia hospitalized at a single site located in San Diego, California.

Measurements: Direct cost of hospitalization.

Results: In the first (case-control) population, mean total direct costs, including IVIG, for the treatment group were $21,982 per IVIG-treated case vs $42,431 per case for matched non-IVIG-receiving controls, representing a net cost reduction of $20,449 (48%) per case. For the second (randomized) group, mean total direct costs, including IVIG, for the treatment group were $28,268 per case vs $62,707 per case for untreated controls, representing a net cost reduction of $34,439 (55%) per case. Of the patients who did not receive IVIG, 24% had hospital costs exceeding $80,000; none of the IVIG-treated patients had costs exceeding this amount (P = .016, Fisher exact test).

Conclusion: If allocated early to the appropriate patient type (moderate-to-severe illness without end-organ comorbidities and age <70 years), IVIG can significantly reduce hospital costs in COVID-19 care. More important, in our study it reduced the demand for scarce critical care resources during the COVID-19 pandemic.

Keywords: IVIG, SARS-CoV-2, cost saving, direct hospital costs.

Intravenous immunoglobulin (IVIG) has been available in most hospitals for 4 decades, with broad therapeutic applications in the treatment of Kawasaki disease and a variety of inflammatory, infectious, autoimmune, and viral diseases, via multifactorial mechanisms of immune modulation.¹ Reports of COVID-19−associated multisystem inflammatory syndrome in adults and children have supported the use of IVIG in treatment.^2,3 Previous studies of IVIG treatment for COVID-19 have produced mixed results. Although retrospective studies have largely been positive,^4-8 prospective clinical trials have been mixed, with some favorable results^9-11 and another, more recent study showing no benefit.¹² However, there is still considerable debate regarding whether some subgroups of patients with COVID-19 may benefit from IVIG; the studies that support this argument, however, have been diluted by broad clinical trials that lack granularity among the heterogeneity of patient characteristics and the timing of IVIG administration.^13,14 One study suggests that patients with COVID-19 who may be particularly poised to benefit from IVIG are those who are younger, have fewer comorbidities, and are treated early.⁸

At our institution, we selectively utilized IVIG to treat patients within 48 hours of rapidly increasing oxygen requirements due to COVID-19, targeting those younger than 70 years, with no previous irreversible end-organ damage, no significant comorbidities (renal failure, heart failure, dementia, active cancer malignancies), and no active treatment for cancer. We analyzed the costs of care of these IVIG (Privigen) recipients and compared them to costs for patients with COVID-19 matched by comorbidities, age, and illness severity who did not receive IVIG. To look for consistency, we examined the cost of care of COVID-19 patients who received IVIG (Octagam) as compared to controls from a previously published pilot trial.¹⁰

Methods

Setting and Treatment

All patients in this study were hospitalized at a single site located in San Diego, California. Treatment patients in both cohorts received IVIG 0.5 g/kg adjusted for body weight daily for 3 consecutive days.

Patient Cohort #1: Retrospective Case-Control Trial

Intravenous immunoglobulin (Privigen 10%, CSL Behring) was utilized off-label to treat moderately to severely ill non-intensive care unit (ICU) patients with COVID-19 requiring ≥3 L of oxygen by nasal cannula who were not mechanically ventilated but were considered at high risk for respiratory failure. Preset exclusion criteria for off-label use of IVIG in the treatment of COVID-19 were age >70 years, active malignancy, organ transplant recipient, renal failure, heart failure, or dementia. Controls were obtained from a list of all admitted patients with COVID-19, matched to cases 2:1 on the basis of age (±10 years), body mass index (±1), gender, comorbidities present at admission (eg, hypertension, diabetes mellitus, lung disease, or history of tobacco use), and maximum oxygen requirements within the first 48 hours of admission. In situations where more than 2 potential matched controls were identified for a patient, the 2 controls closest in age to the treatment patient were selected. One IVIG patient was excluded because only 1 matched-age control could be found. Pregnant patients who otherwise fulfilled the criteria for IVIG administration were also excluded from this analysis.

Patient Cohort #2: Prospective, Randomized, Open-Label Trial

Use of IVIG (Octagam 10%, Octapharma) in COVID-19 was studied in a previously published, prospective, open-label randomized trial.¹⁰ This pilot trial included 16 IVIG-treated patients and 17 control patients, of which 13 and 14 patients, respectively, had hospital cost data available for analysis.¹⁰ Most notably, COVID-19 patients in this study were required to have ≥4 L of oxygen via nasal cannula to maintain arterial oxygen saturationof ≤96%.

Outcomes

Cost data were independently obtained from our finance team, which provided us with the total direct cost and the total pharmaceutical cost associated with each admission. We also compared total length of stay (LOS) and ICU LOS between treatment arms, as these were presumed to be the major drivers of cost difference.

Statistics

Nonparametric comparisons of medians were performed with the Mann-Whitney U test. Comparison of means was done by Student t test. Categorical data were analyzed by Fisher exact test.

This analysis was initiated as an internal quality assessment. It received approval from the Sharp Healthcare Institutional Review Board ([email protected]), and was granted a waiver of subject authorization and consent given the retrospective nature of the study.

Results

Case-Control Analysis

A total of 10 hypoxic patients with COVID-19 received Privigen IVIG outside of clinical trial settings. None of the patients was vaccinated against SARS-CoV-2, as hospitalization occurred prior to vaccine availability. In addition, the original SARS-CoV-2 strain was circulating while these patients were hospitalized, preceding subsequent emerging variants. Oxygen requirements within the first 48 hours ranged from 3 L via nasal cannula to requiring bi-level positive pressure airway therapy with 100% oxygen; median age was 56 years and median Charlson comorbidity index was 1. These 10 patients were each matched to 2 control patients hospitalized during a comparable time period and who, based on oxygen requirements, did not receive IVIG. The 20 control patients had a median age of 58.5 years and a Charlson comorbidity index of 1 (Table 1). Rates of comorbidities, such as hypertension, diabetes mellitus, and obesity, were identical in the 2 groups. None of the patients in either group died during the index hospitalization. Fewer control patients received glucocorticoids, which was reflective of lower illness severity/degree of hypoxia in some controls.

Health care utilization in terms of costs and hospital LOS between the 2 groups are shown in Table 2. The mean total direct hospital cost per case, including IVIG and other drug costs, for the 10 IVIG-treated COVID-19 patients was $21,982 vs $42,431 for the matched controls, a reduction of $20,449 (48%) per case (P = .6187) with IVIG. This difference was heavily driven by 4 control patients (20%) with hospital costs >$80,000, marked by need for ICU transfer, mechanical ventilation during admission, and longer hospital stays. This reduction in progression to mechanical ventilation was consistent with our previously published, open-label, randomized prospective IVIG study, the financial assessment of which is reviewed below. While total direct costs were lower in the treatment arm, the mean drug cost for the treatment arm was $3122 greater than the mean drug cost in the control arm (P = .001622), consistent with the high cost of IVIG therapy (Table 2).

LOS information was obtained, as this was thought to be a primary driver of direct costs. The average LOS in the IVIG arm was 8.4 days, and the average LOS in the control arm was 13.6 days (P = NS). The average ICU LOS in the IVIG arm was 0 days, while the average ICU LOS in the control arm was 5.3 days (P = .04). As with the differences in cost, the differences in LOS were primarily driven by the 4 outlier cases in our control arm, who each had a LOS >25 days, as well as an ICU LOS >20 days.

Randomized, Open-Label, Patient Cohort Analysis

Patient characteristics, LOS, and rates of mechanical ventilation for the IVIG and control patients were previously published and showed a reduction in mechanical ventilation and hospital LOS with IVIG treatment.¹⁰ In this group of patients, 1 patient treated with IVIG (6%) and 3 patients not treated with IVIG (18%) died. To determine the consistency of these results from the case-control patients with a set of patients obtained from clinical trial randomization, we examined the health care costs of patients from the prior study.¹⁰ As with the case-control group, patients in this portion of the analysis were hospitalized before vaccines were available and prior to any identified variants.

Comparing the hospital cost of the IVIG-treated patients to the control patients from this trial revealed results similar to the matched case-control analysis discussed earlier. Average total direct cost per case, including IVIG, for the IVIG treatment group was $28,268, vs $62,707 per case for non-IVIG controls. This represented a net cost reduction of $34,439 (55%) per case, very similar to that of the prior cohort.

IVIG Reduces Costly Outlier Cases

The case-control and randomized trial groups, yielding a combined 23 IVIG and 34 control patients, showed a median cost per case of $22,578 (range $10,115-$70,929) and $22,645 (range $4723-$279,797) for the IVIG and control groups, respectively. Cases with a cost >$80,000 were 0/23 (0%) vs 8/34 (24%) in the IVIG and control groups, respectively (P = .016, Fisher exact test).

Improving care while simultaneously keeping care costs below reimbursement payment levels received from third-party payers is paramount to the financial survival of health care systems. IVIG appears to do this by reducing the number of patients with COVID-19 who progress to ICU care. We compared the costs of care of our combined case-control and randomized trial cohorts to published data on average reimbursements hospitals receive for COVID-19 care from Medicaid, Medicare, and private insurance (Figure).¹⁵ IVIG demonstrated a reduction in cases where costs exceed reimbursement. Indeed, a comparison of net revenue per case of the case-control group showed significantly higher revenue for the IVIG group compared to controls ($52,704 vs $34,712, P = .0338, Table 2).

Discussion

As reflected in at least 1 other study,¹⁶ our hospital had been successfully utilizing IVIG in the treatment of viral acute respiratory distress syndrome (ARDS) prior to COVID-19. Therefore, we moved quickly to perform a randomized, open-label pilot study of IVIG (Octagam 10%) in COVID-19, and noted significant clinical benefit that might translate into hospital cost savings.¹⁰ Over the course of the pandemic, evidence has accumulated that IVIG may play an important role in COVID-19 therapeutics, as summarized in a recent review.¹⁷ However, despite promising but inconsistent results, the relatively high acquisition costs of IVIG raised questions as to its pharmacoeconomic value, particularly with such a high volume of COVID-19 patients with hypoxia, in light of limited clinical data.

COVID-19 therapeutics data can be categorized into either high-quality trials showing marginal benefit for some agents or low-quality trials showing greater benefit for other agents, with IVIG studies falling into the latter category.¹⁸ This phenomenon may speak to the pathophysiological heterogeneity of the COVID-19 patient population. High-quality trials enrolling broad patient types lack the granularity to capture and single out relevant patient subsets who would derive maximal therapeutic benefit, with those subsets diluted by other patient types for which no benefit is seen. Meanwhile, the more granular low-quality trials are criticized as underpowered and lacking in translatability to practice.

Positive results from our pilot trial allowed the use of IVIG (Privigen) off-label in hospitalized COVID-19 patients restricted to specific criteria. Patients had to be moderately to severely ill, requiring >3 L of oxygen via nasal cannula; show high risk of clinical deterioration based on respiratory rate and decline in respiratory status; and have underlying comorbidities (such as hypertension, obesity, or diabetes mellitus). However, older patients (>age 70 years) and those with underlying comorbidities marked by organ failure (such as heart failure, renal failure, dementia, or receipt of organ transplant) and active malignancy were excluded, as their clinical outcome in COVID-19 may be considered less modifiable by therapeutics, while simultaneously carrying potentially a higher risk of adverse events from IVIG (volume overload, renal failure). These exclusions are reflected in the overall low Charlson comorbidity index (mean of 1) of the patients in the case-control study arm. As anticipated, we found a net cost reduction: $20,449 (48%) per case among the 10 IVIG-treated patients compared to the 20 matched controls.

We then went back to the patients from the randomized prospective trial and compared costs for the 13 of 16 IVIG patients and 14 of 17 of the control patients for whom data were available. Among untreated controls, we found a net cost reduction of $34,439 (55%) per case. The higher costs seen in the randomized patient cohort compared to the latter case-control group may be due to a combination of the fact that the treated patients had slightly higher comorbidity indices than the case-control group (median Charlson comorbidity index of 2 in both groups) and the fact that they were treated earlier in the pandemic (May/June 2020), as opposed to the case-control group patients, who were treated in November/December 2020.

It was notable that the cost savings across both groups were derived largely from the reduction in the approximately 20% to 25% of control patients who went on to critical illness, including mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and prolonged ICU stays. Indeed, 8 of 34 of the control patients—but none of the 23 IVIG-treated patients—generated hospital costs in excess of $80,000, a difference that was statistically significant even for such a small sample size. Therefore, reducing these very costly outlier events translated into net savings across the board.

In addition to lowering costs, reducing progression to critical illness is extremely important during heavy waves of COVID-19, when the sheer volume of patients results in severe strain due to the relative scarcity of ICU beds, mechanical ventilators, and ECMO. Therefore, reducing the need for these resources would have a vital role that cannot be measured economically.

The major limitations of this study include the small sample size and the potential lack of generalizability of these results to all hospital centers and treating providers. Our group has considerable experience in IVIG utilization in COVID-19 and, as a result, has identified a “sweet spot,” where benefits were seen clinically and economically. However, it remains to be determined whether IVIG will benefit patients with greater illness severity, such as those in the ICU, on mechanical ventilation, or ECMO. Furthermore, while a significant morbidity and mortality burden of COVID-19 rests in extremely elderly patients and those with end-organ comorbidities such as renal failure and heart failure, it is uncertain whether their COVID-19 adverse outcomes can be improved with IVIG or other therapies. We believe such patients may limit the pharmacoeconomic value of IVIG due to their generally poorer prognosis, regardless of intervention. On the other hand, COVID-19 patients who are not that severely ill, with minimal to no hypoxia, generally will do well regardless of therapy. Therefore, IVIG intervention may be an unnecessary treatment expense. Evidence for this was suggested in our pilot trial¹⁰ and supported in a recent meta-analysis of IVIG therapy in COVID-19.¹⁹

Several other therapeutic options with high acquisition costs have seen an increase in use during the COVID-19 pandemic despite relatively lukewarm data. Remdesivir, the first drug found to have a beneficial effect on hospitalized patients with COVID-19, is priced at $3120 for a complete 5-day treatment course in the United States. This was in line with initial pricing models from the Institute for Clinical and Economic Review (ICER) in May 2020, assuming a mortality benefit with remdesivir use. After the SOLIDARITY trial was published, which showed no mortality benefit associated with remdesivir, ICER updated their pricing models in June 2020 and released a statement that the price of remdesivir was too high to align with demonstrated benefits.^20,21 More recent data demonstrate that remdesivir may be beneficial, but only if administered to patients with fewer than 6 days of symptoms.²² However, only a minority of patients present to the hospital early enough in their illness for remdesivir to be beneficial.²²

Tocilizumab, an interleukin-6 inhibitor, saw an increase in use during the pandemic. An 800-mg treatment course for COVID-19 costs $3584. The efficacy of this treatment option came into question after the COVACTA trial failed to show a difference in clinical status or mortality in COVID-19 patients who received tocilizumab vs placebo.^23,24 A more recent study pointed to a survival benefit of tocilizumab in COVID-19, driven by a very large sample size (>4000), yielding statistically significant, but perhaps clinically less significant, effects on survival.²⁵ This latter study points to the extremely large sample sizes required to capture statistically significant benefits of expensive interventions in COVID-19, which our data demonstrate may benefit only a fraction of patients (20%-25% of patients in the case of IVIG). A more granular clinical assessment of these other interventions is needed to be able to capture the patient subtypes where tocilizumab, remdesivir, and other therapies will be cost effective in the treatment of COVID-19 or other virally mediated cases of ARDS.

Conclusion

While IVIG has a high acquisition cost, the drug’s use in hypoxic COVID-19 patients resulted in reduced costs per COVID-19 case of approximately 50% and use of less critical care resources. The difference was consistent between 2 cohorts (randomized trial vs off-label use in prespecified COVID-19 patient types), IVIG products used (Octagam 10% and Privigen), and time period in the pandemic (waves 1 and 2 in May/June 2020 vs wave 3 in November/December 2020), thereby adjusting for potential differences in circulating viral strains. Furthermore, patients from both groups predated SARS-CoV-2 vaccine availability and major circulating viral variants (eg, delta, omicron), thereby eliminating confounding on outcomes posed by these factors. Control patients’ higher costs of care were driven largely by the approximately 25% of patients who required costly hospital critical care resources, a group mitigated by IVIG. When allocated to the appropriate patient type (patients with moderate-to-severe but not critical illness, <age 70 without preexisting comorbidities of end-organ failure or active cancer), IVIG can reduce hospital costs for COVID-19 care. Identification of specific patient populations where IVIG has the most anticipated benefits in viral illness is needed.

Corresponding author: George Sakoulas, MD, Sharp Rees-Stealy Medical Group, 2020 Genesee Avenue, 2nd Floor, San Diego, CA 92123; [email protected]

Disclosures: Dr Sakoulas has worked as a consultant for Abbvie, Paratek, and Octapharma, has served as a speaker for Abbvie and Paratek, and has received research funding from Octapharma. The other authors did not report any disclosures.

From Sharp Memorial Hospital, San Diego, CA (Drs. Poremba, Dehner, Perreiter, Semma, and Mills), Sharp Rees-Stealy Medical Group, San Diego, CA (Dr. Sakoulas), and Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA (Dr. Sakoulas).

Abstract

Objective: To compare the costs of hospitalization of patients with moderate-to-severe COVID-19 who received intravenous immunoglobulin (IVIG) with those of patients of similar comorbidity and illness severity who did not.

Design: Analysis 1 was a case-control study of 10 nonventilated, moderately to severely hypoxic patients with COVID-19 who received IVIG (Privigen [CSL Behring]) matched 1:2 with 20 control patients of similar age, body mass index, degree of hypoxemia, and comorbidities. Analysis 2 consisted of patients enrolled in a previously published, randomized, open-label prospective study of 14 patients with COVID-19 receiving standard of care vs 13 patients who received standard of care plus IVIG (Octagam 10% [Octapharma]).

Setting and participants: Patients with COVID-19 with moderate-to-severe hypoxemia hospitalized at a single site located in San Diego, California.

Measurements: Direct cost of hospitalization.

Results: In the first (case-control) population, mean total direct costs, including IVIG, for the treatment group were $21,982 per IVIG-treated case vs $42,431 per case for matched non-IVIG-receiving controls, representing a net cost reduction of $20,449 (48%) per case. For the second (randomized) group, mean total direct costs, including IVIG, for the treatment group were $28,268 per case vs $62,707 per case for untreated controls, representing a net cost reduction of $34,439 (55%) per case. Of the patients who did not receive IVIG, 24% had hospital costs exceeding $80,000; none of the IVIG-treated patients had costs exceeding this amount (P = .016, Fisher exact test).

Conclusion: If allocated early to the appropriate patient type (moderate-to-severe illness without end-organ comorbidities and age <70 years), IVIG can significantly reduce hospital costs in COVID-19 care. More important, in our study it reduced the demand for scarce critical care resources during the COVID-19 pandemic.

Keywords: IVIG, SARS-CoV-2, cost saving, direct hospital costs.

Intravenous immunoglobulin (IVIG) has been available in most hospitals for 4 decades, with broad therapeutic applications in the treatment of Kawasaki disease and a variety of inflammatory, infectious, autoimmune, and viral diseases, via multifactorial mechanisms of immune modulation.¹ Reports of COVID-19−associated multisystem inflammatory syndrome in adults and children have supported the use of IVIG in treatment.^2,3 Previous studies of IVIG treatment for COVID-19 have produced mixed results. Although retrospective studies have largely been positive,^4-8 prospective clinical trials have been mixed, with some favorable results^9-11 and another, more recent study showing no benefit.¹² However, there is still considerable debate regarding whether some subgroups of patients with COVID-19 may benefit from IVIG; the studies that support this argument, however, have been diluted by broad clinical trials that lack granularity among the heterogeneity of patient characteristics and the timing of IVIG administration.^13,14 One study suggests that patients with COVID-19 who may be particularly poised to benefit from IVIG are those who are younger, have fewer comorbidities, and are treated early.⁸

At our institution, we selectively utilized IVIG to treat patients within 48 hours of rapidly increasing oxygen requirements due to COVID-19, targeting those younger than 70 years, with no previous irreversible end-organ damage, no significant comorbidities (renal failure, heart failure, dementia, active cancer malignancies), and no active treatment for cancer. We analyzed the costs of care of these IVIG (Privigen) recipients and compared them to costs for patients with COVID-19 matched by comorbidities, age, and illness severity who did not receive IVIG. To look for consistency, we examined the cost of care of COVID-19 patients who received IVIG (Octagam) as compared to controls from a previously published pilot trial.¹⁰

Methods

Setting and Treatment

All patients in this study were hospitalized at a single site located in San Diego, California. Treatment patients in both cohorts received IVIG 0.5 g/kg adjusted for body weight daily for 3 consecutive days.

Patient Cohort #1: Retrospective Case-Control Trial

Intravenous immunoglobulin (Privigen 10%, CSL Behring) was utilized off-label to treat moderately to severely ill non-intensive care unit (ICU) patients with COVID-19 requiring ≥3 L of oxygen by nasal cannula who were not mechanically ventilated but were considered at high risk for respiratory failure. Preset exclusion criteria for off-label use of IVIG in the treatment of COVID-19 were age >70 years, active malignancy, organ transplant recipient, renal failure, heart failure, or dementia. Controls were obtained from a list of all admitted patients with COVID-19, matched to cases 2:1 on the basis of age (±10 years), body mass index (±1), gender, comorbidities present at admission (eg, hypertension, diabetes mellitus, lung disease, or history of tobacco use), and maximum oxygen requirements within the first 48 hours of admission. In situations where more than 2 potential matched controls were identified for a patient, the 2 controls closest in age to the treatment patient were selected. One IVIG patient was excluded because only 1 matched-age control could be found. Pregnant patients who otherwise fulfilled the criteria for IVIG administration were also excluded from this analysis.

Patient Cohort #2: Prospective, Randomized, Open-Label Trial

Use of IVIG (Octagam 10%, Octapharma) in COVID-19 was studied in a previously published, prospective, open-label randomized trial.¹⁰ This pilot trial included 16 IVIG-treated patients and 17 control patients, of which 13 and 14 patients, respectively, had hospital cost data available for analysis.¹⁰ Most notably, COVID-19 patients in this study were required to have ≥4 L of oxygen via nasal cannula to maintain arterial oxygen saturationof ≤96%.

Outcomes

Cost data were independently obtained from our finance team, which provided us with the total direct cost and the total pharmaceutical cost associated with each admission. We also compared total length of stay (LOS) and ICU LOS between treatment arms, as these were presumed to be the major drivers of cost difference.

Statistics

Nonparametric comparisons of medians were performed with the Mann-Whitney U test. Comparison of means was done by Student t test. Categorical data were analyzed by Fisher exact test.

This analysis was initiated as an internal quality assessment. It received approval from the Sharp Healthcare Institutional Review Board ([email protected]), and was granted a waiver of subject authorization and consent given the retrospective nature of the study.

Results

Case-Control Analysis

A total of 10 hypoxic patients with COVID-19 received Privigen IVIG outside of clinical trial settings. None of the patients was vaccinated against SARS-CoV-2, as hospitalization occurred prior to vaccine availability. In addition, the original SARS-CoV-2 strain was circulating while these patients were hospitalized, preceding subsequent emerging variants. Oxygen requirements within the first 48 hours ranged from 3 L via nasal cannula to requiring bi-level positive pressure airway therapy with 100% oxygen; median age was 56 years and median Charlson comorbidity index was 1. These 10 patients were each matched to 2 control patients hospitalized during a comparable time period and who, based on oxygen requirements, did not receive IVIG. The 20 control patients had a median age of 58.5 years and a Charlson comorbidity index of 1 (Table 1). Rates of comorbidities, such as hypertension, diabetes mellitus, and obesity, were identical in the 2 groups. None of the patients in either group died during the index hospitalization. Fewer control patients received glucocorticoids, which was reflective of lower illness severity/degree of hypoxia in some controls.

Health care utilization in terms of costs and hospital LOS between the 2 groups are shown in Table 2. The mean total direct hospital cost per case, including IVIG and other drug costs, for the 10 IVIG-treated COVID-19 patients was $21,982 vs $42,431 for the matched controls, a reduction of $20,449 (48%) per case (P = .6187) with IVIG. This difference was heavily driven by 4 control patients (20%) with hospital costs >$80,000, marked by need for ICU transfer, mechanical ventilation during admission, and longer hospital stays. This reduction in progression to mechanical ventilation was consistent with our previously published, open-label, randomized prospective IVIG study, the financial assessment of which is reviewed below. While total direct costs were lower in the treatment arm, the mean drug cost for the treatment arm was $3122 greater than the mean drug cost in the control arm (P = .001622), consistent with the high cost of IVIG therapy (Table 2).

LOS information was obtained, as this was thought to be a primary driver of direct costs. The average LOS in the IVIG arm was 8.4 days, and the average LOS in the control arm was 13.6 days (P = NS). The average ICU LOS in the IVIG arm was 0 days, while the average ICU LOS in the control arm was 5.3 days (P = .04). As with the differences in cost, the differences in LOS were primarily driven by the 4 outlier cases in our control arm, who each had a LOS >25 days, as well as an ICU LOS >20 days.

Randomized, Open-Label, Patient Cohort Analysis

Patient characteristics, LOS, and rates of mechanical ventilation for the IVIG and control patients were previously published and showed a reduction in mechanical ventilation and hospital LOS with IVIG treatment.¹⁰ In this group of patients, 1 patient treated with IVIG (6%) and 3 patients not treated with IVIG (18%) died. To determine the consistency of these results from the case-control patients with a set of patients obtained from clinical trial randomization, we examined the health care costs of patients from the prior study.¹⁰ As with the case-control group, patients in this portion of the analysis were hospitalized before vaccines were available and prior to any identified variants.

Comparing the hospital cost of the IVIG-treated patients to the control patients from this trial revealed results similar to the matched case-control analysis discussed earlier. Average total direct cost per case, including IVIG, for the IVIG treatment group was $28,268, vs $62,707 per case for non-IVIG controls. This represented a net cost reduction of $34,439 (55%) per case, very similar to that of the prior cohort.

IVIG Reduces Costly Outlier Cases

The case-control and randomized trial groups, yielding a combined 23 IVIG and 34 control patients, showed a median cost per case of $22,578 (range $10,115-$70,929) and $22,645 (range $4723-$279,797) for the IVIG and control groups, respectively. Cases with a cost >$80,000 were 0/23 (0%) vs 8/34 (24%) in the IVIG and control groups, respectively (P = .016, Fisher exact test).

Improving care while simultaneously keeping care costs below reimbursement payment levels received from third-party payers is paramount to the financial survival of health care systems. IVIG appears to do this by reducing the number of patients with COVID-19 who progress to ICU care. We compared the costs of care of our combined case-control and randomized trial cohorts to published data on average reimbursements hospitals receive for COVID-19 care from Medicaid, Medicare, and private insurance (Figure).¹⁵ IVIG demonstrated a reduction in cases where costs exceed reimbursement. Indeed, a comparison of net revenue per case of the case-control group showed significantly higher revenue for the IVIG group compared to controls ($52,704 vs $34,712, P = .0338, Table 2).

Discussion

As reflected in at least 1 other study,¹⁶ our hospital had been successfully utilizing IVIG in the treatment of viral acute respiratory distress syndrome (ARDS) prior to COVID-19. Therefore, we moved quickly to perform a randomized, open-label pilot study of IVIG (Octagam 10%) in COVID-19, and noted significant clinical benefit that might translate into hospital cost savings.¹⁰ Over the course of the pandemic, evidence has accumulated that IVIG may play an important role in COVID-19 therapeutics, as summarized in a recent review.¹⁷ However, despite promising but inconsistent results, the relatively high acquisition costs of IVIG raised questions as to its pharmacoeconomic value, particularly with such a high volume of COVID-19 patients with hypoxia, in light of limited clinical data.

COVID-19 therapeutics data can be categorized into either high-quality trials showing marginal benefit for some agents or low-quality trials showing greater benefit for other agents, with IVIG studies falling into the latter category.¹⁸ This phenomenon may speak to the pathophysiological heterogeneity of the COVID-19 patient population. High-quality trials enrolling broad patient types lack the granularity to capture and single out relevant patient subsets who would derive maximal therapeutic benefit, with those subsets diluted by other patient types for which no benefit is seen. Meanwhile, the more granular low-quality trials are criticized as underpowered and lacking in translatability to practice.

Positive results from our pilot trial allowed the use of IVIG (Privigen) off-label in hospitalized COVID-19 patients restricted to specific criteria. Patients had to be moderately to severely ill, requiring >3 L of oxygen via nasal cannula; show high risk of clinical deterioration based on respiratory rate and decline in respiratory status; and have underlying comorbidities (such as hypertension, obesity, or diabetes mellitus). However, older patients (>age 70 years) and those with underlying comorbidities marked by organ failure (such as heart failure, renal failure, dementia, or receipt of organ transplant) and active malignancy were excluded, as their clinical outcome in COVID-19 may be considered less modifiable by therapeutics, while simultaneously carrying potentially a higher risk of adverse events from IVIG (volume overload, renal failure). These exclusions are reflected in the overall low Charlson comorbidity index (mean of 1) of the patients in the case-control study arm. As anticipated, we found a net cost reduction: $20,449 (48%) per case among the 10 IVIG-treated patients compared to the 20 matched controls.

We then went back to the patients from the randomized prospective trial and compared costs for the 13 of 16 IVIG patients and 14 of 17 of the control patients for whom data were available. Among untreated controls, we found a net cost reduction of $34,439 (55%) per case. The higher costs seen in the randomized patient cohort compared to the latter case-control group may be due to a combination of the fact that the treated patients had slightly higher comorbidity indices than the case-control group (median Charlson comorbidity index of 2 in both groups) and the fact that they were treated earlier in the pandemic (May/June 2020), as opposed to the case-control group patients, who were treated in November/December 2020.

It was notable that the cost savings across both groups were derived largely from the reduction in the approximately 20% to 25% of control patients who went on to critical illness, including mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and prolonged ICU stays. Indeed, 8 of 34 of the control patients—but none of the 23 IVIG-treated patients—generated hospital costs in excess of $80,000, a difference that was statistically significant even for such a small sample size. Therefore, reducing these very costly outlier events translated into net savings across the board.

In addition to lowering costs, reducing progression to critical illness is extremely important during heavy waves of COVID-19, when the sheer volume of patients results in severe strain due to the relative scarcity of ICU beds, mechanical ventilators, and ECMO. Therefore, reducing the need for these resources would have a vital role that cannot be measured economically.

The major limitations of this study include the small sample size and the potential lack of generalizability of these results to all hospital centers and treating providers. Our group has considerable experience in IVIG utilization in COVID-19 and, as a result, has identified a “sweet spot,” where benefits were seen clinically and economically. However, it remains to be determined whether IVIG will benefit patients with greater illness severity, such as those in the ICU, on mechanical ventilation, or ECMO. Furthermore, while a significant morbidity and mortality burden of COVID-19 rests in extremely elderly patients and those with end-organ comorbidities such as renal failure and heart failure, it is uncertain whether their COVID-19 adverse outcomes can be improved with IVIG or other therapies. We believe such patients may limit the pharmacoeconomic value of IVIG due to their generally poorer prognosis, regardless of intervention. On the other hand, COVID-19 patients who are not that severely ill, with minimal to no hypoxia, generally will do well regardless of therapy. Therefore, IVIG intervention may be an unnecessary treatment expense. Evidence for this was suggested in our pilot trial¹⁰ and supported in a recent meta-analysis of IVIG therapy in COVID-19.¹⁹

Several other therapeutic options with high acquisition costs have seen an increase in use during the COVID-19 pandemic despite relatively lukewarm data. Remdesivir, the first drug found to have a beneficial effect on hospitalized patients with COVID-19, is priced at $3120 for a complete 5-day treatment course in the United States. This was in line with initial pricing models from the Institute for Clinical and Economic Review (ICER) in May 2020, assuming a mortality benefit with remdesivir use. After the SOLIDARITY trial was published, which showed no mortality benefit associated with remdesivir, ICER updated their pricing models in June 2020 and released a statement that the price of remdesivir was too high to align with demonstrated benefits.^20,21 More recent data demonstrate that remdesivir may be beneficial, but only if administered to patients with fewer than 6 days of symptoms.²² However, only a minority of patients present to the hospital early enough in their illness for remdesivir to be beneficial.²²

Tocilizumab, an interleukin-6 inhibitor, saw an increase in use during the pandemic. An 800-mg treatment course for COVID-19 costs $3584. The efficacy of this treatment option came into question after the COVACTA trial failed to show a difference in clinical status or mortality in COVID-19 patients who received tocilizumab vs placebo.^23,24 A more recent study pointed to a survival benefit of tocilizumab in COVID-19, driven by a very large sample size (>4000), yielding statistically significant, but perhaps clinically less significant, effects on survival.²⁵ This latter study points to the extremely large sample sizes required to capture statistically significant benefits of expensive interventions in COVID-19, which our data demonstrate may benefit only a fraction of patients (20%-25% of patients in the case of IVIG). A more granular clinical assessment of these other interventions is needed to be able to capture the patient subtypes where tocilizumab, remdesivir, and other therapies will be cost effective in the treatment of COVID-19 or other virally mediated cases of ARDS.

Conclusion

While IVIG has a high acquisition cost, the drug’s use in hypoxic COVID-19 patients resulted in reduced costs per COVID-19 case of approximately 50% and use of less critical care resources. The difference was consistent between 2 cohorts (randomized trial vs off-label use in prespecified COVID-19 patient types), IVIG products used (Octagam 10% and Privigen), and time period in the pandemic (waves 1 and 2 in May/June 2020 vs wave 3 in November/December 2020), thereby adjusting for potential differences in circulating viral strains. Furthermore, patients from both groups predated SARS-CoV-2 vaccine availability and major circulating viral variants (eg, delta, omicron), thereby eliminating confounding on outcomes posed by these factors. Control patients’ higher costs of care were driven largely by the approximately 25% of patients who required costly hospital critical care resources, a group mitigated by IVIG. When allocated to the appropriate patient type (patients with moderate-to-severe but not critical illness, <age 70 without preexisting comorbidities of end-organ failure or active cancer), IVIG can reduce hospital costs for COVID-19 care. Identification of specific patient populations where IVIG has the most anticipated benefits in viral illness is needed.

Corresponding author: George Sakoulas, MD, Sharp Rees-Stealy Medical Group, 2020 Genesee Avenue, 2nd Floor, San Diego, CA 92123; [email protected]

Disclosures: Dr Sakoulas has worked as a consultant for Abbvie, Paratek, and Octapharma, has served as a speaker for Abbvie and Paratek, and has received research funding from Octapharma. The other authors did not report any disclosures.

From Sharp Memorial Hospital, San Diego, CA (Drs. Poremba, Dehner, Perreiter, Semma, and Mills), Sharp Rees-Stealy Medical Group, San Diego, CA (Dr. Sakoulas), and Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA (Dr. Sakoulas).

Abstract

Objective: To compare the costs of hospitalization of patients with moderate-to-severe COVID-19 who received intravenous immunoglobulin (IVIG) with those of patients of similar comorbidity and illness severity who did not.

Design: Analysis 1 was a case-control study of 10 nonventilated, moderately to severely hypoxic patients with COVID-19 who received IVIG (Privigen [CSL Behring]) matched 1:2 with 20 control patients of similar age, body mass index, degree of hypoxemia, and comorbidities. Analysis 2 consisted of patients enrolled in a previously published, randomized, open-label prospective study of 14 patients with COVID-19 receiving standard of care vs 13 patients who received standard of care plus IVIG (Octagam 10% [Octapharma]).

Setting and participants: Patients with COVID-19 with moderate-to-severe hypoxemia hospitalized at a single site located in San Diego, California.

Measurements: Direct cost of hospitalization.

Results: In the first (case-control) population, mean total direct costs, including IVIG, for the treatment group were $21,982 per IVIG-treated case vs $42,431 per case for matched non-IVIG-receiving controls, representing a net cost reduction of $20,449 (48%) per case. For the second (randomized) group, mean total direct costs, including IVIG, for the treatment group were $28,268 per case vs $62,707 per case for untreated controls, representing a net cost reduction of $34,439 (55%) per case. Of the patients who did not receive IVIG, 24% had hospital costs exceeding $80,000; none of the IVIG-treated patients had costs exceeding this amount (P = .016, Fisher exact test).

Conclusion: If allocated early to the appropriate patient type (moderate-to-severe illness without end-organ comorbidities and age <70 years), IVIG can significantly reduce hospital costs in COVID-19 care. More important, in our study it reduced the demand for scarce critical care resources during the COVID-19 pandemic.

Keywords: IVIG, SARS-CoV-2, cost saving, direct hospital costs.

Intravenous immunoglobulin (IVIG) has been available in most hospitals for 4 decades, with broad therapeutic applications in the treatment of Kawasaki disease and a variety of inflammatory, infectious, autoimmune, and viral diseases, via multifactorial mechanisms of immune modulation.¹ Reports of COVID-19−associated multisystem inflammatory syndrome in adults and children have supported the use of IVIG in treatment.^2,3 Previous studies of IVIG treatment for COVID-19 have produced mixed results. Although retrospective studies have largely been positive,^4-8 prospective clinical trials have been mixed, with some favorable results^9-11 and another, more recent study showing no benefit.¹² However, there is still considerable debate regarding whether some subgroups of patients with COVID-19 may benefit from IVIG; the studies that support this argument, however, have been diluted by broad clinical trials that lack granularity among the heterogeneity of patient characteristics and the timing of IVIG administration.^13,14 One study suggests that patients with COVID-19 who may be particularly poised to benefit from IVIG are those who are younger, have fewer comorbidities, and are treated early.⁸

At our institution, we selectively utilized IVIG to treat patients within 48 hours of rapidly increasing oxygen requirements due to COVID-19, targeting those younger than 70 years, with no previous irreversible end-organ damage, no significant comorbidities (renal failure, heart failure, dementia, active cancer malignancies), and no active treatment for cancer. We analyzed the costs of care of these IVIG (Privigen) recipients and compared them to costs for patients with COVID-19 matched by comorbidities, age, and illness severity who did not receive IVIG. To look for consistency, we examined the cost of care of COVID-19 patients who received IVIG (Octagam) as compared to controls from a previously published pilot trial.¹⁰

Methods

Setting and Treatment

All patients in this study were hospitalized at a single site located in San Diego, California. Treatment patients in both cohorts received IVIG 0.5 g/kg adjusted for body weight daily for 3 consecutive days.

Patient Cohort #1: Retrospective Case-Control Trial

Intravenous immunoglobulin (Privigen 10%, CSL Behring) was utilized off-label to treat moderately to severely ill non-intensive care unit (ICU) patients with COVID-19 requiring ≥3 L of oxygen by nasal cannula who were not mechanically ventilated but were considered at high risk for respiratory failure. Preset exclusion criteria for off-label use of IVIG in the treatment of COVID-19 were age >70 years, active malignancy, organ transplant recipient, renal failure, heart failure, or dementia. Controls were obtained from a list of all admitted patients with COVID-19, matched to cases 2:1 on the basis of age (±10 years), body mass index (±1), gender, comorbidities present at admission (eg, hypertension, diabetes mellitus, lung disease, or history of tobacco use), and maximum oxygen requirements within the first 48 hours of admission. In situations where more than 2 potential matched controls were identified for a patient, the 2 controls closest in age to the treatment patient were selected. One IVIG patient was excluded because only 1 matched-age control could be found. Pregnant patients who otherwise fulfilled the criteria for IVIG administration were also excluded from this analysis.

Patient Cohort #2: Prospective, Randomized, Open-Label Trial

Use of IVIG (Octagam 10%, Octapharma) in COVID-19 was studied in a previously published, prospective, open-label randomized trial.¹⁰ This pilot trial included 16 IVIG-treated patients and 17 control patients, of which 13 and 14 patients, respectively, had hospital cost data available for analysis.¹⁰ Most notably, COVID-19 patients in this study were required to have ≥4 L of oxygen via nasal cannula to maintain arterial oxygen saturationof ≤96%.

Outcomes

Cost data were independently obtained from our finance team, which provided us with the total direct cost and the total pharmaceutical cost associated with each admission. We also compared total length of stay (LOS) and ICU LOS between treatment arms, as these were presumed to be the major drivers of cost difference.

Statistics

Nonparametric comparisons of medians were performed with the Mann-Whitney U test. Comparison of means was done by Student t test. Categorical data were analyzed by Fisher exact test.

This analysis was initiated as an internal quality assessment. It received approval from the Sharp Healthcare Institutional Review Board ([email protected]), and was granted a waiver of subject authorization and consent given the retrospective nature of the study.

Results

Case-Control Analysis

A total of 10 hypoxic patients with COVID-19 received Privigen IVIG outside of clinical trial settings. None of the patients was vaccinated against SARS-CoV-2, as hospitalization occurred prior to vaccine availability. In addition, the original SARS-CoV-2 strain was circulating while these patients were hospitalized, preceding subsequent emerging variants. Oxygen requirements within the first 48 hours ranged from 3 L via nasal cannula to requiring bi-level positive pressure airway therapy with 100% oxygen; median age was 56 years and median Charlson comorbidity index was 1. These 10 patients were each matched to 2 control patients hospitalized during a comparable time period and who, based on oxygen requirements, did not receive IVIG. The 20 control patients had a median age of 58.5 years and a Charlson comorbidity index of 1 (Table 1). Rates of comorbidities, such as hypertension, diabetes mellitus, and obesity, were identical in the 2 groups. None of the patients in either group died during the index hospitalization. Fewer control patients received glucocorticoids, which was reflective of lower illness severity/degree of hypoxia in some controls.

Health care utilization in terms of costs and hospital LOS between the 2 groups are shown in Table 2. The mean total direct hospital cost per case, including IVIG and other drug costs, for the 10 IVIG-treated COVID-19 patients was $21,982 vs $42,431 for the matched controls, a reduction of $20,449 (48%) per case (P = .6187) with IVIG. This difference was heavily driven by 4 control patients (20%) with hospital costs >$80,000, marked by need for ICU transfer, mechanical ventilation during admission, and longer hospital stays. This reduction in progression to mechanical ventilation was consistent with our previously published, open-label, randomized prospective IVIG study, the financial assessment of which is reviewed below. While total direct costs were lower in the treatment arm, the mean drug cost for the treatment arm was $3122 greater than the mean drug cost in the control arm (P = .001622), consistent with the high cost of IVIG therapy (Table 2).

LOS information was obtained, as this was thought to be a primary driver of direct costs. The average LOS in the IVIG arm was 8.4 days, and the average LOS in the control arm was 13.6 days (P = NS). The average ICU LOS in the IVIG arm was 0 days, while the average ICU LOS in the control arm was 5.3 days (P = .04). As with the differences in cost, the differences in LOS were primarily driven by the 4 outlier cases in our control arm, who each had a LOS >25 days, as well as an ICU LOS >20 days.

Randomized, Open-Label, Patient Cohort Analysis

Patient characteristics, LOS, and rates of mechanical ventilation for the IVIG and control patients were previously published and showed a reduction in mechanical ventilation and hospital LOS with IVIG treatment.¹⁰ In this group of patients, 1 patient treated with IVIG (6%) and 3 patients not treated with IVIG (18%) died. To determine the consistency of these results from the case-control patients with a set of patients obtained from clinical trial randomization, we examined the health care costs of patients from the prior study.¹⁰ As with the case-control group, patients in this portion of the analysis were hospitalized before vaccines were available and prior to any identified variants.

Comparing the hospital cost of the IVIG-treated patients to the control patients from this trial revealed results similar to the matched case-control analysis discussed earlier. Average total direct cost per case, including IVIG, for the IVIG treatment group was $28,268, vs $62,707 per case for non-IVIG controls. This represented a net cost reduction of $34,439 (55%) per case, very similar to that of the prior cohort.

IVIG Reduces Costly Outlier Cases

The case-control and randomized trial groups, yielding a combined 23 IVIG and 34 control patients, showed a median cost per case of $22,578 (range $10,115-$70,929) and $22,645 (range $4723-$279,797) for the IVIG and control groups, respectively. Cases with a cost >$80,000 were 0/23 (0%) vs 8/34 (24%) in the IVIG and control groups, respectively (P = .016, Fisher exact test).

Improving care while simultaneously keeping care costs below reimbursement payment levels received from third-party payers is paramount to the financial survival of health care systems. IVIG appears to do this by reducing the number of patients with COVID-19 who progress to ICU care. We compared the costs of care of our combined case-control and randomized trial cohorts to published data on average reimbursements hospitals receive for COVID-19 care from Medicaid, Medicare, and private insurance (Figure).¹⁵ IVIG demonstrated a reduction in cases where costs exceed reimbursement. Indeed, a comparison of net revenue per case of the case-control group showed significantly higher revenue for the IVIG group compared to controls ($52,704 vs $34,712, P = .0338, Table 2).

Discussion

As reflected in at least 1 other study,¹⁶ our hospital had been successfully utilizing IVIG in the treatment of viral acute respiratory distress syndrome (ARDS) prior to COVID-19. Therefore, we moved quickly to perform a randomized, open-label pilot study of IVIG (Octagam 10%) in COVID-19, and noted significant clinical benefit that might translate into hospital cost savings.¹⁰ Over the course of the pandemic, evidence has accumulated that IVIG may play an important role in COVID-19 therapeutics, as summarized in a recent review.¹⁷ However, despite promising but inconsistent results, the relatively high acquisition costs of IVIG raised questions as to its pharmacoeconomic value, particularly with such a high volume of COVID-19 patients with hypoxia, in light of limited clinical data.

COVID-19 therapeutics data can be categorized into either high-quality trials showing marginal benefit for some agents or low-quality trials showing greater benefit for other agents, with IVIG studies falling into the latter category.¹⁸ This phenomenon may speak to the pathophysiological heterogeneity of the COVID-19 patient population. High-quality trials enrolling broad patient types lack the granularity to capture and single out relevant patient subsets who would derive maximal therapeutic benefit, with those subsets diluted by other patient types for which no benefit is seen. Meanwhile, the more granular low-quality trials are criticized as underpowered and lacking in translatability to practice.

Positive results from our pilot trial allowed the use of IVIG (Privigen) off-label in hospitalized COVID-19 patients restricted to specific criteria. Patients had to be moderately to severely ill, requiring >3 L of oxygen via nasal cannula; show high risk of clinical deterioration based on respiratory rate and decline in respiratory status; and have underlying comorbidities (such as hypertension, obesity, or diabetes mellitus). However, older patients (>age 70 years) and those with underlying comorbidities marked by organ failure (such as heart failure, renal failure, dementia, or receipt of organ transplant) and active malignancy were excluded, as their clinical outcome in COVID-19 may be considered less modifiable by therapeutics, while simultaneously carrying potentially a higher risk of adverse events from IVIG (volume overload, renal failure). These exclusions are reflected in the overall low Charlson comorbidity index (mean of 1) of the patients in the case-control study arm. As anticipated, we found a net cost reduction: $20,449 (48%) per case among the 10 IVIG-treated patients compared to the 20 matched controls.

We then went back to the patients from the randomized prospective trial and compared costs for the 13 of 16 IVIG patients and 14 of 17 of the control patients for whom data were available. Among untreated controls, we found a net cost reduction of $34,439 (55%) per case. The higher costs seen in the randomized patient cohort compared to the latter case-control group may be due to a combination of the fact that the treated patients had slightly higher comorbidity indices than the case-control group (median Charlson comorbidity index of 2 in both groups) and the fact that they were treated earlier in the pandemic (May/June 2020), as opposed to the case-control group patients, who were treated in November/December 2020.

It was notable that the cost savings across both groups were derived largely from the reduction in the approximately 20% to 25% of control patients who went on to critical illness, including mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and prolonged ICU stays. Indeed, 8 of 34 of the control patients—but none of the 23 IVIG-treated patients—generated hospital costs in excess of $80,000, a difference that was statistically significant even for such a small sample size. Therefore, reducing these very costly outlier events translated into net savings across the board.

In addition to lowering costs, reducing progression to critical illness is extremely important during heavy waves of COVID-19, when the sheer volume of patients results in severe strain due to the relative scarcity of ICU beds, mechanical ventilators, and ECMO. Therefore, reducing the need for these resources would have a vital role that cannot be measured economically.

The major limitations of this study include the small sample size and the potential lack of generalizability of these results to all hospital centers and treating providers. Our group has considerable experience in IVIG utilization in COVID-19 and, as a result, has identified a “sweet spot,” where benefits were seen clinically and economically. However, it remains to be determined whether IVIG will benefit patients with greater illness severity, such as those in the ICU, on mechanical ventilation, or ECMO. Furthermore, while a significant morbidity and mortality burden of COVID-19 rests in extremely elderly patients and those with end-organ comorbidities such as renal failure and heart failure, it is uncertain whether their COVID-19 adverse outcomes can be improved with IVIG or other therapies. We believe such patients may limit the pharmacoeconomic value of IVIG due to their generally poorer prognosis, regardless of intervention. On the other hand, COVID-19 patients who are not that severely ill, with minimal to no hypoxia, generally will do well regardless of therapy. Therefore, IVIG intervention may be an unnecessary treatment expense. Evidence for this was suggested in our pilot trial¹⁰ and supported in a recent meta-analysis of IVIG therapy in COVID-19.¹⁹

Several other therapeutic options with high acquisition costs have seen an increase in use during the COVID-19 pandemic despite relatively lukewarm data. Remdesivir, the first drug found to have a beneficial effect on hospitalized patients with COVID-19, is priced at $3120 for a complete 5-day treatment course in the United States. This was in line with initial pricing models from the Institute for Clinical and Economic Review (ICER) in May 2020, assuming a mortality benefit with remdesivir use. After the SOLIDARITY trial was published, which showed no mortality benefit associated with remdesivir, ICER updated their pricing models in June 2020 and released a statement that the price of remdesivir was too high to align with demonstrated benefits.^20,21 More recent data demonstrate that remdesivir may be beneficial, but only if administered to patients with fewer than 6 days of symptoms.²² However, only a minority of patients present to the hospital early enough in their illness for remdesivir to be beneficial.²²

Tocilizumab, an interleukin-6 inhibitor, saw an increase in use during the pandemic. An 800-mg treatment course for COVID-19 costs $3584. The efficacy of this treatment option came into question after the COVACTA trial failed to show a difference in clinical status or mortality in COVID-19 patients who received tocilizumab vs placebo.^23,24 A more recent study pointed to a survival benefit of tocilizumab in COVID-19, driven by a very large sample size (>4000), yielding statistically significant, but perhaps clinically less significant, effects on survival.²⁵ This latter study points to the extremely large sample sizes required to capture statistically significant benefits of expensive interventions in COVID-19, which our data demonstrate may benefit only a fraction of patients (20%-25% of patients in the case of IVIG). A more granular clinical assessment of these other interventions is needed to be able to capture the patient subtypes where tocilizumab, remdesivir, and other therapies will be cost effective in the treatment of COVID-19 or other virally mediated cases of ARDS.

Conclusion

While IVIG has a high acquisition cost, the drug’s use in hypoxic COVID-19 patients resulted in reduced costs per COVID-19 case of approximately 50% and use of less critical care resources. The difference was consistent between 2 cohorts (randomized trial vs off-label use in prespecified COVID-19 patient types), IVIG products used (Octagam 10% and Privigen), and time period in the pandemic (waves 1 and 2 in May/June 2020 vs wave 3 in November/December 2020), thereby adjusting for potential differences in circulating viral strains. Furthermore, patients from both groups predated SARS-CoV-2 vaccine availability and major circulating viral variants (eg, delta, omicron), thereby eliminating confounding on outcomes posed by these factors. Control patients’ higher costs of care were driven largely by the approximately 25% of patients who required costly hospital critical care resources, a group mitigated by IVIG. When allocated to the appropriate patient type (patients with moderate-to-severe but not critical illness, <age 70 without preexisting comorbidities of end-organ failure or active cancer), IVIG can reduce hospital costs for COVID-19 care. Identification of specific patient populations where IVIG has the most anticipated benefits in viral illness is needed.

Corresponding author: George Sakoulas, MD, Sharp Rees-Stealy Medical Group, 2020 Genesee Avenue, 2nd Floor, San Diego, CA 92123; [email protected]

Disclosures: Dr Sakoulas has worked as a consultant for Abbvie, Paratek, and Octapharma, has served as a speaker for Abbvie and Paratek, and has received research funding from Octapharma. The other authors did not report any disclosures.

Cesarean births are not likely linked to an elevated risk of food allergy during the first year of life, an Australian study found.

Published online in the Journal of Allergy and Clinical Immunology, the findings may help assess the risks and benefits of cesarean delivery and reassure women who require it that their babies are not more likely to develop food allergy, according to Rachel L. Peters, PhD, an epidemiologist at the Murdoch Child Research Institute (MCRI) in Melbourne, and colleagues.

Dr. Peters’ group undertook the analysis to clarify a possible association between mode of delivery and food allergy risk, which has remained unclear owing to the absence of studies with both challenge-proven food allergy outcomes and detailed information on the type and timing of cesarean delivery.

“The infant immune system undergoes rapid development during the neonatal period,” Dr. Peters said in an MCRI press release, and the mode of delivery may interfere with the normal development of the immune system. “Babies born by cesarean have less exposure to the bacteria from the mother’s gut and vagina, which influence the composition of the baby’s microbiome and immune system development. However, this doesn’t appear to play a major role in the development of food allergy,” she said.
 

The HealthNuts study

In the period 2007-2011, the longitudinal population-based HealthNuts cohort study enrolled 5,276 12-month-olds who underwent skin prick testing and oral food challenge for sensitization to egg, peanut, sesame, and either shellfish or cow’s milk. It linked the resulting data to additional birth statistics from the Victorian Perinatal Data Collection when children turned 6.

Birth data were obtained on 2,045 babies, and in this subgroup with linked data, 30% were born by cesarean – similar to the 31.7% of U.S. cesarean births in 2019 – and 12.7% of these had food allergy versus 13.2% of those delivered vaginally.

Compared with vaginal birth, C-section was not associated with the risk of food allergy (adjusted odds ratio [aOR] 0.95, 95% confidence interval [CI], 0.70-0.30).

Nor did the timing of the C-section have an effect. Cesarean delivery either before labor or after onset of labor was not associated with the risk of food allergy (aOR, 0.83, 95% CI, 0.55-1.23) and aOR, 1.13, 95% CI, 0.75-1.72), respectively.

Compared with vaginal delivery, elective or emergency cesarean was not associated with food allergy risk (aOR, 1.05, 95% CI, 0.71-1.55, and aOR, 0.86, 95% CI, 0.56-1.31).

Similarly, no evidence emerged of an effect modification by breastfeeding, older siblings, pet dog ownership, or maternal allergy.

“This study is helpful because in addition to blood and skin tests, it also used food challenge, which is the gold standard,” Terri Brown-Whitehorn, MD, an attending physician in the division of allergy and immunology at Children’s Hospital of Philadelphia, said in an interview. “If no actual food is given, the other tests could lead to false positives.”

Dr. Brown-Whitehorn, who was not involved in the MCRI research, said the findings are not likely to affect most decisions about C-sections because most are not voluntary. “But if a mother had a first baby by emergency cesarean section, she might be given the option of having the next one by the same method.”

She said the current advice is to introduce even high-risk foods to a child’s diet early on to ward off the development of food allergies.

According to the microbial exposure hypothesis, it was previously thought that a potential link between cesarean birth and allergy might reflect differences in early exposure to maternal flora beneficial to the immune system in the vagina during delivery. A C-section might bypass the opportunity for neonatal gut colonization with maternal gut and vaginal flora, thereby raising allergy risk. A 2018 meta-analysis, for example, suggested cesarean birth could raise the risk for food allergies by 21%.

In other research from HealthNuts, 30% of child peanut allergy and 90% of egg allergy appear to resolve naturally by age 6. These numbers are somewhat higher than what Dr. Brown-Whitehorn sees. “We find that about 20% of peanut allergies and about 70% or 80% – maybe a bit less – of egg allergies resolve by age 6.”

This research was supported by the National Health & Medical Research Council of Australia, the Ilhan Food Allergy Foundation, AnaphylaxiStop, the Charles and Sylvia Viertel Medical Research Foundation, the Victorian Government’s Operational Infrastructure Support Program, and the Melbourne Children’s Clinician-Scientist Fellowship.

Dr. Peters disclosed no competing interests. Several coauthors reported research support or employment with private companies and one is the inventor of an MCRI-held patent. Dr. Brown-Whitehorn had no competing interests to disclose.

Cesarean births are not likely linked to an elevated risk of food allergy during the first year of life, an Australian study found.

Published online in the Journal of Allergy and Clinical Immunology, the findings may help assess the risks and benefits of cesarean delivery and reassure women who require it that their babies are not more likely to develop food allergy, according to Rachel L. Peters, PhD, an epidemiologist at the Murdoch Child Research Institute (MCRI) in Melbourne, and colleagues.

Dr. Peters’ group undertook the analysis to clarify a possible association between mode of delivery and food allergy risk, which has remained unclear owing to the absence of studies with both challenge-proven food allergy outcomes and detailed information on the type and timing of cesarean delivery.

“The infant immune system undergoes rapid development during the neonatal period,” Dr. Peters said in an MCRI press release, and the mode of delivery may interfere with the normal development of the immune system. “Babies born by cesarean have less exposure to the bacteria from the mother’s gut and vagina, which influence the composition of the baby’s microbiome and immune system development. However, this doesn’t appear to play a major role in the development of food allergy,” she said.
 

The HealthNuts study

In the period 2007-2011, the longitudinal population-based HealthNuts cohort study enrolled 5,276 12-month-olds who underwent skin prick testing and oral food challenge for sensitization to egg, peanut, sesame, and either shellfish or cow’s milk. It linked the resulting data to additional birth statistics from the Victorian Perinatal Data Collection when children turned 6.

Birth data were obtained on 2,045 babies, and in this subgroup with linked data, 30% were born by cesarean – similar to the 31.7% of U.S. cesarean births in 2019 – and 12.7% of these had food allergy versus 13.2% of those delivered vaginally.

Compared with vaginal birth, C-section was not associated with the risk of food allergy (adjusted odds ratio [aOR] 0.95, 95% confidence interval [CI], 0.70-0.30).

Nor did the timing of the C-section have an effect. Cesarean delivery either before labor or after onset of labor was not associated with the risk of food allergy (aOR, 0.83, 95% CI, 0.55-1.23) and aOR, 1.13, 95% CI, 0.75-1.72), respectively.

Compared with vaginal delivery, elective or emergency cesarean was not associated with food allergy risk (aOR, 1.05, 95% CI, 0.71-1.55, and aOR, 0.86, 95% CI, 0.56-1.31).

Similarly, no evidence emerged of an effect modification by breastfeeding, older siblings, pet dog ownership, or maternal allergy.

“This study is helpful because in addition to blood and skin tests, it also used food challenge, which is the gold standard,” Terri Brown-Whitehorn, MD, an attending physician in the division of allergy and immunology at Children’s Hospital of Philadelphia, said in an interview. “If no actual food is given, the other tests could lead to false positives.”

Dr. Brown-Whitehorn, who was not involved in the MCRI research, said the findings are not likely to affect most decisions about C-sections because most are not voluntary. “But if a mother had a first baby by emergency cesarean section, she might be given the option of having the next one by the same method.”

She said the current advice is to introduce even high-risk foods to a child’s diet early on to ward off the development of food allergies.

According to the microbial exposure hypothesis, it was previously thought that a potential link between cesarean birth and allergy might reflect differences in early exposure to maternal flora beneficial to the immune system in the vagina during delivery. A C-section might bypass the opportunity for neonatal gut colonization with maternal gut and vaginal flora, thereby raising allergy risk. A 2018 meta-analysis, for example, suggested cesarean birth could raise the risk for food allergies by 21%.

In other research from HealthNuts, 30% of child peanut allergy and 90% of egg allergy appear to resolve naturally by age 6. These numbers are somewhat higher than what Dr. Brown-Whitehorn sees. “We find that about 20% of peanut allergies and about 70% or 80% – maybe a bit less – of egg allergies resolve by age 6.”

This research was supported by the National Health & Medical Research Council of Australia, the Ilhan Food Allergy Foundation, AnaphylaxiStop, the Charles and Sylvia Viertel Medical Research Foundation, the Victorian Government’s Operational Infrastructure Support Program, and the Melbourne Children’s Clinician-Scientist Fellowship.

Dr. Peters disclosed no competing interests. Several coauthors reported research support or employment with private companies and one is the inventor of an MCRI-held patent. Dr. Brown-Whitehorn had no competing interests to disclose.

Cesarean births are not likely linked to an elevated risk of food allergy during the first year of life, an Australian study found.

Published online in the Journal of Allergy and Clinical Immunology, the findings may help assess the risks and benefits of cesarean delivery and reassure women who require it that their babies are not more likely to develop food allergy, according to Rachel L. Peters, PhD, an epidemiologist at the Murdoch Child Research Institute (MCRI) in Melbourne, and colleagues.

Dr. Peters’ group undertook the analysis to clarify a possible association between mode of delivery and food allergy risk, which has remained unclear owing to the absence of studies with both challenge-proven food allergy outcomes and detailed information on the type and timing of cesarean delivery.

“The infant immune system undergoes rapid development during the neonatal period,” Dr. Peters said in an MCRI press release, and the mode of delivery may interfere with the normal development of the immune system. “Babies born by cesarean have less exposure to the bacteria from the mother’s gut and vagina, which influence the composition of the baby’s microbiome and immune system development. However, this doesn’t appear to play a major role in the development of food allergy,” she said.
 

The HealthNuts study

In the period 2007-2011, the longitudinal population-based HealthNuts cohort study enrolled 5,276 12-month-olds who underwent skin prick testing and oral food challenge for sensitization to egg, peanut, sesame, and either shellfish or cow’s milk. It linked the resulting data to additional birth statistics from the Victorian Perinatal Data Collection when children turned 6.

Birth data were obtained on 2,045 babies, and in this subgroup with linked data, 30% were born by cesarean – similar to the 31.7% of U.S. cesarean births in 2019 – and 12.7% of these had food allergy versus 13.2% of those delivered vaginally.

Compared with vaginal birth, C-section was not associated with the risk of food allergy (adjusted odds ratio [aOR] 0.95, 95% confidence interval [CI], 0.70-0.30).

Nor did the timing of the C-section have an effect. Cesarean delivery either before labor or after onset of labor was not associated with the risk of food allergy (aOR, 0.83, 95% CI, 0.55-1.23) and aOR, 1.13, 95% CI, 0.75-1.72), respectively.

Compared with vaginal delivery, elective or emergency cesarean was not associated with food allergy risk (aOR, 1.05, 95% CI, 0.71-1.55, and aOR, 0.86, 95% CI, 0.56-1.31).

Similarly, no evidence emerged of an effect modification by breastfeeding, older siblings, pet dog ownership, or maternal allergy.

“This study is helpful because in addition to blood and skin tests, it also used food challenge, which is the gold standard,” Terri Brown-Whitehorn, MD, an attending physician in the division of allergy and immunology at Children’s Hospital of Philadelphia, said in an interview. “If no actual food is given, the other tests could lead to false positives.”

Dr. Brown-Whitehorn, who was not involved in the MCRI research, said the findings are not likely to affect most decisions about C-sections because most are not voluntary. “But if a mother had a first baby by emergency cesarean section, she might be given the option of having the next one by the same method.”

She said the current advice is to introduce even high-risk foods to a child’s diet early on to ward off the development of food allergies.

According to the microbial exposure hypothesis, it was previously thought that a potential link between cesarean birth and allergy might reflect differences in early exposure to maternal flora beneficial to the immune system in the vagina during delivery. A C-section might bypass the opportunity for neonatal gut colonization with maternal gut and vaginal flora, thereby raising allergy risk. A 2018 meta-analysis, for example, suggested cesarean birth could raise the risk for food allergies by 21%.

In other research from HealthNuts, 30% of child peanut allergy and 90% of egg allergy appear to resolve naturally by age 6. These numbers are somewhat higher than what Dr. Brown-Whitehorn sees. “We find that about 20% of peanut allergies and about 70% or 80% – maybe a bit less – of egg allergies resolve by age 6.”

This research was supported by the National Health & Medical Research Council of Australia, the Ilhan Food Allergy Foundation, AnaphylaxiStop, the Charles and Sylvia Viertel Medical Research Foundation, the Victorian Government’s Operational Infrastructure Support Program, and the Melbourne Children’s Clinician-Scientist Fellowship.

Dr. Peters disclosed no competing interests. Several coauthors reported research support or employment with private companies and one is the inventor of an MCRI-held patent. Dr. Brown-Whitehorn had no competing interests to disclose.

According to the latest evidence, the ketogenic diet is emerging as an effective strategy not only to promote weight loss, but also to manage many comorbidities associated with obesity, including COVID-19. This development was revealed during the 8th International Scientific Symposium New Frontiers in Scientific Research, organized by PronoKal Group and held in Barcelona. During this conference, international multidisciplinary experts in the study and management of obesity presented the latest data on the benefits of treatment based on a very-low-calorie ketogenic diet.

“Nutritional ketosis has gained great interest in recent years because it is shown to have beneficial properties for health and promotes healthy aging, increasing longevity,” said Ana Belén Crujeiras, BSc, PhD, principal investigator of the Health Research Institute of Santiago de Compostela-Galician Health Service (IDIS-SERGAS) Group of Epigenomics in Endocrinology and Nutrition and the Biomedical Research Networking Center for Obesity and Nutrition Physiopathology (CIBEROBN). “Furthermore, in the case of obesity, we have more and more evidence that it is an effective treatment, mainly because to achieve this metabolic state (ketosis), routes that require the combustion of fats are activated, and this induces body weight loss.”

The specialist stressed that several strategies are used to induce nutritional ketosis. They are characterized by low carbohydrate consumption (low-carbohydrate and high-fat diet; low-carbohydrate, low-fat diet; and intermittent fasting). But Dr. Crujeiras warned that to use it as a treatment for a disease such as obesity, it must be backed by strong and solid scientific evidence, moving away from the concept of fad diets.

In this sense, since 2010, Dr. Crujeiras’ team has developed several studies focused on analyzing the efficacy and safety of treatment with a very-low-calorie ketogenic diet, the results of which have been published in high-impact journals.

Dr. Crujeiras commented on the main conclusions drawn from these investigations. “Our work has shown that the very-low-calorie ketogenic diet is effective for rapid weight loss and maintenance of lost weight, as well as reducing fat mass, primarily visceral fat mass.

“In this sense, a very interesting result is that despite the strong weight loss it induces, it preserves muscle mass and function and improves resting metabolic rate. These two variables are important, because all therapeutic strategies that exist to lose weight lead to a significant reduction in fat-free mass and also a reduction in energy expenditure at rest. This factor is associated with the risk of regaining lost weight, which is currently the great challenge in the treatment of obesity,” she added.
 

Specific methylation pattern

Dr. Crujeiras indicated that other notable evidence is the favorable impact on an emotional and psychological level. “To determine whether the caloric restriction of this diet and the strong weight loss that it involves were associated with an increased desire to eat, we also carried out an analysis with psychobiological tests. These results led us to conclude that this guideline is accompanied by a reduction of anxiety about food and an improvement in psychobiological parameters, thus increasing the quality of life of these patients.”

The specialist also mentioned that studies currently in progress show that the beneficial effect of this diet could be mediated by epigenetic mechanisms. “In our group, we have identified a specific DNA methylation pattern in people with obesity and we wondered if the very-low-calorie ketogenic diet would be able to reverse that methylome.

“We conducted a study in which we collected blood samples from patients on the very-low-calorie ketogenic diet (600 to 800 kcal/day) drawn before treatment, at peak ketosis, and at the end of treatment. After determining the global pattern of DNA in all patients with obesity targeted with this strategy and through bioinformatic analysis, we were able to obtain a methylation pattern. The results showed that after weight loss on the very-low-calorie ketogenic diet, the methylome that obese people initially had [was] reversed and matched that of normal-weight people.

“Continuing with this bioinformatic analysis more comprehensively, we wanted to see what kind of genes were differentially methylated, especially by the action of the ketosis itself. We found that most of the genes that exhibited differential methylation (in total, 292 identified) belonged to pathways that were involved in the regulation of metabolism, adipose tissue function, CNS function, and also carcinogenesis,” she continued.
 

Immunomodulatory effect

Dr. Crujeiras said that her research group also observed the modulatory role of the very-low-calorie ketogenic diet in the functioning of the immune system, “something that was not seen after similar weight loss induced by bariatric surgery. We analyzed this data in the context of the situation created by COVID-19, taking into account the evidence that people with obesity, compared to those with normal weight, have a higher risk of becoming infected and of having a poor evolution of the infection.”

In this regard, Dr. Crujeiras’ team launched an investigation to study the ACE2 gene methylation pattern, comparing obesity with normal weight and the situation after following a very-low-calorie ketogenic diet or undergoing bariatric surgery. “We observed that the methylation pattern of this gene in obese people was increased, compared to normal-weight people,” she explained, “and this increase was observed mainly in visceral adipose tissue. However, we did not see this in subcutaneous adipose tissue, which is in agreement with the hypothesis that visceral adipose tissue is that mostly associated with obesity-related comorbidities.

“Likewise, the very-low-calorie ketogenic diet was associated with decreased ACE2 methylation, along with increased exposure of this gene. However, after bariatric surgery, no significant changes were observed, so we deduce that we are protecting the patient in some way from inflammation and, therefore, from the potential of serious illness if they become infected.

“In light of these results, we wanted to dig deeper into what was happening with the immune system of obese patients and that inflammation after a very-low-calorie ketogenic diet. We conducted a new study, currently under review in the journal Clinical Nutrition, with the same approach, comparing this diet with a standard hypocaloric balanced diet and bariatric surgery, in which we analyzed a wide battery of cytokines (32). We have observed a differential pattern between the very-low-calorie ketogenic diet and bariatric surgery.

“The results confirm our hypothesis that the very-low-calorie ketogenic diet remodels the inflammatory status of obese patients, and we were also able to verify that the increase in ketone bodies has immunomodulatory properties that were previously demonstrated in preclinical and animal models, which is associated with increased immune function in these patients,” added Dr. Crujeiras.
 

Personalization and weight regain

In regard to the next steps to take in the knowledge and clinical application of the benefits of this dietary strategy, Dr. Crujeiras said that despite the fact that this diet is known to be effective, it is currently prescribed in a standard manner to all patients, “but there is some variability in the response and also a high risk of regaining weight, as is the case with any nutritional intervention strategy, with that ‘regain’ of lost weight being the main challenge in the treatment of obesity. In this sense, the epigenomic and epigenetic markers that we have identified could help us optimize treatment.”

She added that the future lies in establishing an algorithm that encompasses the patient’s exposome data, along with their genetic and epigenetic profile, to properly classify patients and prescribe a personalized precision therapeutic strategy.

Luca Busetto, MD, cochair of the Obesity Management Task Force (OMTF) of the European Association for the Study of Obesity (EASO), also insisted on the challenge posed by the individualized application of the very-low-calorie ketogenic diet, emphasizing that this diet should always be prescribed by a doctor after an appropriate assessment of the patient. “Obesity is not a matter of willpower or motivation, and most people with obesity have struggled their entire lives and failed because their biology tends to cause weight regain. Therefore, we should try to offer them the options that we currently have, including the very-low-calorie ketogenic diet, adapting them as much as possible to the profile of each patient.”

During his speech, Dr. Busetto presented the recent European guidelines for the management of obesity in adults with a very-low-calorie ketogenic diet, endorsed by EASO, and analyzed the main strengths of these recommendations.

Dr. Busetto remarked that three important points clearly justify the use of the very-low-calorie ketogenic diet. The first is the speed with which the initial weight loss occurs. Recent studies have looked at the benefits of a significant loss of excess weight early in a weight-loss diet, and although this is an association rather than a cause, the results strongly suggest that rapid initial weight loss increases the chance of the result being maintained in the long term. This clashes with the traditional recommendation of losing weight little by little as a strategy to achieve long-term results, but it must be taken into account that there are many myths in the treatment of obesity that current evidence is dismantling with new data – and this is one of them.

Secondly, the effect of the very-low-calorie ketogenic diet can be added to other treatments. This has been demonstrated by studies carried out with liraglutide that showed that this dietary strategy optimizes results, compared with patients who had been treated only with this drug. The third point that justifies the use of the very-low-calorie ketogenic diet is the management of obesity comorbidities. Several investigations demonstrate the effectiveness of this diet in this regard, especially in the case of type 2 diabetes. Data suggest that the substantial weight reductions achieved with it also favor the remission of these comorbidities in many patients.
 

EASO ‘approval’

Dr. Busetto pointed out that, based on this evidence, the OMTF proposed the development of standards to be included in the EASO guidelines, since there had been no specific recommendation on the very-low-calorie ketogenic diet.

“The main objective of these European guidelines was to provide data referenced by scientific evidence and to suggest a common protocol for the use of this dietary strategy,” he added.

For this, a very exhaustive meta-analysis was carried out, researching all the publications that compared the very-low-calorie ketogenic diet with other diets. The results showed the superiority of the former method for the reduction of body mass index and weight and fat mass, with no difference in lean (muscle) mass, despite significant weight loss in these patients.

This evidence also demonstrates a reduction and an improvement in metabolic markers, specifically glucose metabolism and lipid metabolism.

“The final conclusions of the study corroborate that the very-low-calorie ketogenic diet can be recommended as an effective and safe tool for people with obesity, especially those with severe obesity or comorbidities (joint disease, preoperative period to bariatric surgery, metabolic and cardiovascular diseases) who need immediate, substantial weight loss. In addition, it can be prescribed to specific groups of patients with obesity after considering potential contraindications and under medical follow-up,” said Dr. Busetto.

In Dr. Busetto’s opinion, it would be convenient to refer to this approach as a method, instead of as a diet, “because, in reality, the state of ketosis is limited in time, and if the ketogenic phase is stopped without a continuity plan, obviously weight is regained. In addition, the method approach may increase adherence by patients.”

Finally, Dr. Busetto emphasized the importance of integrating this type of treatment into a long-term lifestyle strategy (including habits, exercise, and nutritional advice). “We must start from the basis that obesity is a chronic and relapsing disease, whose management should also be chronic and probably maintained throughout life.”

Dr. Crujeiras and Dr. Busetto have disclosed no relevant financial relationships. PronoKal Group has recently become part of Nestlé Health Science.

A version of this article appeared on Medscape.com. It was translated from Medscape Spanish Edition.

According to the latest evidence, the ketogenic diet is emerging as an effective strategy not only to promote weight loss, but also to manage many comorbidities associated with obesity, including COVID-19. This development was revealed during the 8th International Scientific Symposium New Frontiers in Scientific Research, organized by PronoKal Group and held in Barcelona. During this conference, international multidisciplinary experts in the study and management of obesity presented the latest data on the benefits of treatment based on a very-low-calorie ketogenic diet.

“Nutritional ketosis has gained great interest in recent years because it is shown to have beneficial properties for health and promotes healthy aging, increasing longevity,” said Ana Belén Crujeiras, BSc, PhD, principal investigator of the Health Research Institute of Santiago de Compostela-Galician Health Service (IDIS-SERGAS) Group of Epigenomics in Endocrinology and Nutrition and the Biomedical Research Networking Center for Obesity and Nutrition Physiopathology (CIBEROBN). “Furthermore, in the case of obesity, we have more and more evidence that it is an effective treatment, mainly because to achieve this metabolic state (ketosis), routes that require the combustion of fats are activated, and this induces body weight loss.”

The specialist stressed that several strategies are used to induce nutritional ketosis. They are characterized by low carbohydrate consumption (low-carbohydrate and high-fat diet; low-carbohydrate, low-fat diet; and intermittent fasting). But Dr. Crujeiras warned that to use it as a treatment for a disease such as obesity, it must be backed by strong and solid scientific evidence, moving away from the concept of fad diets.

In this sense, since 2010, Dr. Crujeiras’ team has developed several studies focused on analyzing the efficacy and safety of treatment with a very-low-calorie ketogenic diet, the results of which have been published in high-impact journals.

Dr. Crujeiras commented on the main conclusions drawn from these investigations. “Our work has shown that the very-low-calorie ketogenic diet is effective for rapid weight loss and maintenance of lost weight, as well as reducing fat mass, primarily visceral fat mass.

“In this sense, a very interesting result is that despite the strong weight loss it induces, it preserves muscle mass and function and improves resting metabolic rate. These two variables are important, because all therapeutic strategies that exist to lose weight lead to a significant reduction in fat-free mass and also a reduction in energy expenditure at rest. This factor is associated with the risk of regaining lost weight, which is currently the great challenge in the treatment of obesity,” she added.
 

Specific methylation pattern

Dr. Crujeiras indicated that other notable evidence is the favorable impact on an emotional and psychological level. “To determine whether the caloric restriction of this diet and the strong weight loss that it involves were associated with an increased desire to eat, we also carried out an analysis with psychobiological tests. These results led us to conclude that this guideline is accompanied by a reduction of anxiety about food and an improvement in psychobiological parameters, thus increasing the quality of life of these patients.”

The specialist also mentioned that studies currently in progress show that the beneficial effect of this diet could be mediated by epigenetic mechanisms. “In our group, we have identified a specific DNA methylation pattern in people with obesity and we wondered if the very-low-calorie ketogenic diet would be able to reverse that methylome.

“We conducted a study in which we collected blood samples from patients on the very-low-calorie ketogenic diet (600 to 800 kcal/day) drawn before treatment, at peak ketosis, and at the end of treatment. After determining the global pattern of DNA in all patients with obesity targeted with this strategy and through bioinformatic analysis, we were able to obtain a methylation pattern. The results showed that after weight loss on the very-low-calorie ketogenic diet, the methylome that obese people initially had [was] reversed and matched that of normal-weight people.

“Continuing with this bioinformatic analysis more comprehensively, we wanted to see what kind of genes were differentially methylated, especially by the action of the ketosis itself. We found that most of the genes that exhibited differential methylation (in total, 292 identified) belonged to pathways that were involved in the regulation of metabolism, adipose tissue function, CNS function, and also carcinogenesis,” she continued.
 

Immunomodulatory effect

Dr. Crujeiras said that her research group also observed the modulatory role of the very-low-calorie ketogenic diet in the functioning of the immune system, “something that was not seen after similar weight loss induced by bariatric surgery. We analyzed this data in the context of the situation created by COVID-19, taking into account the evidence that people with obesity, compared to those with normal weight, have a higher risk of becoming infected and of having a poor evolution of the infection.”

In this regard, Dr. Crujeiras’ team launched an investigation to study the ACE2 gene methylation pattern, comparing obesity with normal weight and the situation after following a very-low-calorie ketogenic diet or undergoing bariatric surgery. “We observed that the methylation pattern of this gene in obese people was increased, compared to normal-weight people,” she explained, “and this increase was observed mainly in visceral adipose tissue. However, we did not see this in subcutaneous adipose tissue, which is in agreement with the hypothesis that visceral adipose tissue is that mostly associated with obesity-related comorbidities.

“Likewise, the very-low-calorie ketogenic diet was associated with decreased ACE2 methylation, along with increased exposure of this gene. However, after bariatric surgery, no significant changes were observed, so we deduce that we are protecting the patient in some way from inflammation and, therefore, from the potential of serious illness if they become infected.

“In light of these results, we wanted to dig deeper into what was happening with the immune system of obese patients and that inflammation after a very-low-calorie ketogenic diet. We conducted a new study, currently under review in the journal Clinical Nutrition, with the same approach, comparing this diet with a standard hypocaloric balanced diet and bariatric surgery, in which we analyzed a wide battery of cytokines (32). We have observed a differential pattern between the very-low-calorie ketogenic diet and bariatric surgery.

“The results confirm our hypothesis that the very-low-calorie ketogenic diet remodels the inflammatory status of obese patients, and we were also able to verify that the increase in ketone bodies has immunomodulatory properties that were previously demonstrated in preclinical and animal models, which is associated with increased immune function in these patients,” added Dr. Crujeiras.
 

Personalization and weight regain

In regard to the next steps to take in the knowledge and clinical application of the benefits of this dietary strategy, Dr. Crujeiras said that despite the fact that this diet is known to be effective, it is currently prescribed in a standard manner to all patients, “but there is some variability in the response and also a high risk of regaining weight, as is the case with any nutritional intervention strategy, with that ‘regain’ of lost weight being the main challenge in the treatment of obesity. In this sense, the epigenomic and epigenetic markers that we have identified could help us optimize treatment.”

She added that the future lies in establishing an algorithm that encompasses the patient’s exposome data, along with their genetic and epigenetic profile, to properly classify patients and prescribe a personalized precision therapeutic strategy.

Luca Busetto, MD, cochair of the Obesity Management Task Force (OMTF) of the European Association for the Study of Obesity (EASO), also insisted on the challenge posed by the individualized application of the very-low-calorie ketogenic diet, emphasizing that this diet should always be prescribed by a doctor after an appropriate assessment of the patient. “Obesity is not a matter of willpower or motivation, and most people with obesity have struggled their entire lives and failed because their biology tends to cause weight regain. Therefore, we should try to offer them the options that we currently have, including the very-low-calorie ketogenic diet, adapting them as much as possible to the profile of each patient.”

During his speech, Dr. Busetto presented the recent European guidelines for the management of obesity in adults with a very-low-calorie ketogenic diet, endorsed by EASO, and analyzed the main strengths of these recommendations.

Dr. Busetto remarked that three important points clearly justify the use of the very-low-calorie ketogenic diet. The first is the speed with which the initial weight loss occurs. Recent studies have looked at the benefits of a significant loss of excess weight early in a weight-loss diet, and although this is an association rather than a cause, the results strongly suggest that rapid initial weight loss increases the chance of the result being maintained in the long term. This clashes with the traditional recommendation of losing weight little by little as a strategy to achieve long-term results, but it must be taken into account that there are many myths in the treatment of obesity that current evidence is dismantling with new data – and this is one of them.

Secondly, the effect of the very-low-calorie ketogenic diet can be added to other treatments. This has been demonstrated by studies carried out with liraglutide that showed that this dietary strategy optimizes results, compared with patients who had been treated only with this drug. The third point that justifies the use of the very-low-calorie ketogenic diet is the management of obesity comorbidities. Several investigations demonstrate the effectiveness of this diet in this regard, especially in the case of type 2 diabetes. Data suggest that the substantial weight reductions achieved with it also favor the remission of these comorbidities in many patients.
 

EASO ‘approval’

Dr. Busetto pointed out that, based on this evidence, the OMTF proposed the development of standards to be included in the EASO guidelines, since there had been no specific recommendation on the very-low-calorie ketogenic diet.

“The main objective of these European guidelines was to provide data referenced by scientific evidence and to suggest a common protocol for the use of this dietary strategy,” he added.

For this, a very exhaustive meta-analysis was carried out, researching all the publications that compared the very-low-calorie ketogenic diet with other diets. The results showed the superiority of the former method for the reduction of body mass index and weight and fat mass, with no difference in lean (muscle) mass, despite significant weight loss in these patients.

This evidence also demonstrates a reduction and an improvement in metabolic markers, specifically glucose metabolism and lipid metabolism.

“The final conclusions of the study corroborate that the very-low-calorie ketogenic diet can be recommended as an effective and safe tool for people with obesity, especially those with severe obesity or comorbidities (joint disease, preoperative period to bariatric surgery, metabolic and cardiovascular diseases) who need immediate, substantial weight loss. In addition, it can be prescribed to specific groups of patients with obesity after considering potential contraindications and under medical follow-up,” said Dr. Busetto.

In Dr. Busetto’s opinion, it would be convenient to refer to this approach as a method, instead of as a diet, “because, in reality, the state of ketosis is limited in time, and if the ketogenic phase is stopped without a continuity plan, obviously weight is regained. In addition, the method approach may increase adherence by patients.”

Finally, Dr. Busetto emphasized the importance of integrating this type of treatment into a long-term lifestyle strategy (including habits, exercise, and nutritional advice). “We must start from the basis that obesity is a chronic and relapsing disease, whose management should also be chronic and probably maintained throughout life.”

Dr. Crujeiras and Dr. Busetto have disclosed no relevant financial relationships. PronoKal Group has recently become part of Nestlé Health Science.

A version of this article appeared on Medscape.com. It was translated from Medscape Spanish Edition.

According to the latest evidence, the ketogenic diet is emerging as an effective strategy not only to promote weight loss, but also to manage many comorbidities associated with obesity, including COVID-19. This development was revealed during the 8th International Scientific Symposium New Frontiers in Scientific Research, organized by PronoKal Group and held in Barcelona. During this conference, international multidisciplinary experts in the study and management of obesity presented the latest data on the benefits of treatment based on a very-low-calorie ketogenic diet.

“Nutritional ketosis has gained great interest in recent years because it is shown to have beneficial properties for health and promotes healthy aging, increasing longevity,” said Ana Belén Crujeiras, BSc, PhD, principal investigator of the Health Research Institute of Santiago de Compostela-Galician Health Service (IDIS-SERGAS) Group of Epigenomics in Endocrinology and Nutrition and the Biomedical Research Networking Center for Obesity and Nutrition Physiopathology (CIBEROBN). “Furthermore, in the case of obesity, we have more and more evidence that it is an effective treatment, mainly because to achieve this metabolic state (ketosis), routes that require the combustion of fats are activated, and this induces body weight loss.”

The specialist stressed that several strategies are used to induce nutritional ketosis. They are characterized by low carbohydrate consumption (low-carbohydrate and high-fat diet; low-carbohydrate, low-fat diet; and intermittent fasting). But Dr. Crujeiras warned that to use it as a treatment for a disease such as obesity, it must be backed by strong and solid scientific evidence, moving away from the concept of fad diets.

In this sense, since 2010, Dr. Crujeiras’ team has developed several studies focused on analyzing the efficacy and safety of treatment with a very-low-calorie ketogenic diet, the results of which have been published in high-impact journals.

Dr. Crujeiras commented on the main conclusions drawn from these investigations. “Our work has shown that the very-low-calorie ketogenic diet is effective for rapid weight loss and maintenance of lost weight, as well as reducing fat mass, primarily visceral fat mass.

“In this sense, a very interesting result is that despite the strong weight loss it induces, it preserves muscle mass and function and improves resting metabolic rate. These two variables are important, because all therapeutic strategies that exist to lose weight lead to a significant reduction in fat-free mass and also a reduction in energy expenditure at rest. This factor is associated with the risk of regaining lost weight, which is currently the great challenge in the treatment of obesity,” she added.
 

Specific methylation pattern

Dr. Crujeiras indicated that other notable evidence is the favorable impact on an emotional and psychological level. “To determine whether the caloric restriction of this diet and the strong weight loss that it involves were associated with an increased desire to eat, we also carried out an analysis with psychobiological tests. These results led us to conclude that this guideline is accompanied by a reduction of anxiety about food and an improvement in psychobiological parameters, thus increasing the quality of life of these patients.”

The specialist also mentioned that studies currently in progress show that the beneficial effect of this diet could be mediated by epigenetic mechanisms. “In our group, we have identified a specific DNA methylation pattern in people with obesity and we wondered if the very-low-calorie ketogenic diet would be able to reverse that methylome.

“We conducted a study in which we collected blood samples from patients on the very-low-calorie ketogenic diet (600 to 800 kcal/day) drawn before treatment, at peak ketosis, and at the end of treatment. After determining the global pattern of DNA in all patients with obesity targeted with this strategy and through bioinformatic analysis, we were able to obtain a methylation pattern. The results showed that after weight loss on the very-low-calorie ketogenic diet, the methylome that obese people initially had [was] reversed and matched that of normal-weight people.

“Continuing with this bioinformatic analysis more comprehensively, we wanted to see what kind of genes were differentially methylated, especially by the action of the ketosis itself. We found that most of the genes that exhibited differential methylation (in total, 292 identified) belonged to pathways that were involved in the regulation of metabolism, adipose tissue function, CNS function, and also carcinogenesis,” she continued.
 

Immunomodulatory effect

Dr. Crujeiras said that her research group also observed the modulatory role of the very-low-calorie ketogenic diet in the functioning of the immune system, “something that was not seen after similar weight loss induced by bariatric surgery. We analyzed this data in the context of the situation created by COVID-19, taking into account the evidence that people with obesity, compared to those with normal weight, have a higher risk of becoming infected and of having a poor evolution of the infection.”

In this regard, Dr. Crujeiras’ team launched an investigation to study the ACE2 gene methylation pattern, comparing obesity with normal weight and the situation after following a very-low-calorie ketogenic diet or undergoing bariatric surgery. “We observed that the methylation pattern of this gene in obese people was increased, compared to normal-weight people,” she explained, “and this increase was observed mainly in visceral adipose tissue. However, we did not see this in subcutaneous adipose tissue, which is in agreement with the hypothesis that visceral adipose tissue is that mostly associated with obesity-related comorbidities.

“Likewise, the very-low-calorie ketogenic diet was associated with decreased ACE2 methylation, along with increased exposure of this gene. However, after bariatric surgery, no significant changes were observed, so we deduce that we are protecting the patient in some way from inflammation and, therefore, from the potential of serious illness if they become infected.

“In light of these results, we wanted to dig deeper into what was happening with the immune system of obese patients and that inflammation after a very-low-calorie ketogenic diet. We conducted a new study, currently under review in the journal Clinical Nutrition, with the same approach, comparing this diet with a standard hypocaloric balanced diet and bariatric surgery, in which we analyzed a wide battery of cytokines (32). We have observed a differential pattern between the very-low-calorie ketogenic diet and bariatric surgery.

“The results confirm our hypothesis that the very-low-calorie ketogenic diet remodels the inflammatory status of obese patients, and we were also able to verify that the increase in ketone bodies has immunomodulatory properties that were previously demonstrated in preclinical and animal models, which is associated with increased immune function in these patients,” added Dr. Crujeiras.
 

Personalization and weight regain

In regard to the next steps to take in the knowledge and clinical application of the benefits of this dietary strategy, Dr. Crujeiras said that despite the fact that this diet is known to be effective, it is currently prescribed in a standard manner to all patients, “but there is some variability in the response and also a high risk of regaining weight, as is the case with any nutritional intervention strategy, with that ‘regain’ of lost weight being the main challenge in the treatment of obesity. In this sense, the epigenomic and epigenetic markers that we have identified could help us optimize treatment.”

She added that the future lies in establishing an algorithm that encompasses the patient’s exposome data, along with their genetic and epigenetic profile, to properly classify patients and prescribe a personalized precision therapeutic strategy.

Luca Busetto, MD, cochair of the Obesity Management Task Force (OMTF) of the European Association for the Study of Obesity (EASO), also insisted on the challenge posed by the individualized application of the very-low-calorie ketogenic diet, emphasizing that this diet should always be prescribed by a doctor after an appropriate assessment of the patient. “Obesity is not a matter of willpower or motivation, and most people with obesity have struggled their entire lives and failed because their biology tends to cause weight regain. Therefore, we should try to offer them the options that we currently have, including the very-low-calorie ketogenic diet, adapting them as much as possible to the profile of each patient.”

During his speech, Dr. Busetto presented the recent European guidelines for the management of obesity in adults with a very-low-calorie ketogenic diet, endorsed by EASO, and analyzed the main strengths of these recommendations.

Dr. Busetto remarked that three important points clearly justify the use of the very-low-calorie ketogenic diet. The first is the speed with which the initial weight loss occurs. Recent studies have looked at the benefits of a significant loss of excess weight early in a weight-loss diet, and although this is an association rather than a cause, the results strongly suggest that rapid initial weight loss increases the chance of the result being maintained in the long term. This clashes with the traditional recommendation of losing weight little by little as a strategy to achieve long-term results, but it must be taken into account that there are many myths in the treatment of obesity that current evidence is dismantling with new data – and this is one of them.

Secondly, the effect of the very-low-calorie ketogenic diet can be added to other treatments. This has been demonstrated by studies carried out with liraglutide that showed that this dietary strategy optimizes results, compared with patients who had been treated only with this drug. The third point that justifies the use of the very-low-calorie ketogenic diet is the management of obesity comorbidities. Several investigations demonstrate the effectiveness of this diet in this regard, especially in the case of type 2 diabetes. Data suggest that the substantial weight reductions achieved with it also favor the remission of these comorbidities in many patients.
 

EASO ‘approval’

Dr. Busetto pointed out that, based on this evidence, the OMTF proposed the development of standards to be included in the EASO guidelines, since there had been no specific recommendation on the very-low-calorie ketogenic diet.

“The main objective of these European guidelines was to provide data referenced by scientific evidence and to suggest a common protocol for the use of this dietary strategy,” he added.

For this, a very exhaustive meta-analysis was carried out, researching all the publications that compared the very-low-calorie ketogenic diet with other diets. The results showed the superiority of the former method for the reduction of body mass index and weight and fat mass, with no difference in lean (muscle) mass, despite significant weight loss in these patients.

This evidence also demonstrates a reduction and an improvement in metabolic markers, specifically glucose metabolism and lipid metabolism.

“The final conclusions of the study corroborate that the very-low-calorie ketogenic diet can be recommended as an effective and safe tool for people with obesity, especially those with severe obesity or comorbidities (joint disease, preoperative period to bariatric surgery, metabolic and cardiovascular diseases) who need immediate, substantial weight loss. In addition, it can be prescribed to specific groups of patients with obesity after considering potential contraindications and under medical follow-up,” said Dr. Busetto.

In Dr. Busetto’s opinion, it would be convenient to refer to this approach as a method, instead of as a diet, “because, in reality, the state of ketosis is limited in time, and if the ketogenic phase is stopped without a continuity plan, obviously weight is regained. In addition, the method approach may increase adherence by patients.”

Finally, Dr. Busetto emphasized the importance of integrating this type of treatment into a long-term lifestyle strategy (including habits, exercise, and nutritional advice). “We must start from the basis that obesity is a chronic and relapsing disease, whose management should also be chronic and probably maintained throughout life.”

Dr. Crujeiras and Dr. Busetto have disclosed no relevant financial relationships. PronoKal Group has recently become part of Nestlé Health Science.

A version of this article appeared on Medscape.com. It was translated from Medscape Spanish Edition.

THE CASE

A 43-year-old Black male presented to his primary care physician with an 8-month history of progressive fatigue, weakness, and unintentional weight loss. The patient’s history also included antiphospholipid antibody syndrome (APS) with prior deep venous thrombosis/­pulmonary embolism for which he was taking warfarin.

At the time of presentation, he reported profound dyspnea on exertion, lightheadedness, dry mouth, low back pain, and worsening nocturia. The remainder of the review of systems was negative. He denied tobacco, alcohol, or illicit drug use or recent travel. His personal and family histories were negative for cancer.

Laboratory data collected during the outpatient visit were notable for a white blood cell count of 2300/mcL (reference range, 4000-11,000/mcL); hemoglobin, 8.6 g/dL (13.5-17.5 g/dL); and platelets, 44,000/mcL (150,000-400,000/mcL). Proteinuria was indicated by a measurement > 500 mg/dL on urine dipstick.

The patient was admitted to the hospital for further work-up of new pancytopenia. His vital signs on admission were notable for tachycardia and a weight of 237 lbs, decreased from 283 lbs 8 months prior. His physical exam revealed dry mucous membranes, bruising of fingertips, and marked lower extremity weakness with preserved sensation. No lymphadenopathy was noted on the admission physical exam.

THE DIAGNOSIS

Inpatient laboratory studies showed elevated inflammatory markers and a positive Coombs test with low haptoglobin. There was no evidence of bacterial or viral infection. Computed tomography of the chest, abdomen, and pelvis revealed axillary, subpectoral, and pelvic lymphadenopathy (see FIGURE). A work-up for multiple myeloma was negative, and a bone marrow biopsy was nondiagnostic.

Autoimmune laboratory data included a positive antiphospholipid antibody (ANA) test (1:10,240, diffuse; reference < 1:160), an elevated dsDNA antibody level (800 IU/mL; reference range, 0-99 IU/mL), low complement levels, and antibody titers consistent with the patient’s known APS. Based on these findings, the patient was given a diagnosis of systemic lupus erythematosus (SLE).

DISCUSSION

Lymphadenopathy, revealed by exam or by imaging, in combination with systemic symptoms such as weight loss and fatigue, elicits an extensive differential diagnosis. In the absence of recent exposures, travel, or risk factors for infectious causes, our patient’s work-up was appropriately narrowed to noninfectious etiologies of pancytopenia and lymphadenopathy. At the top of this differential are malignancies—in particular, multiple myeloma and lymphoma—and rheumatologic processes, such as sarcoidosis, connective tissue disease, and SLE.^1,2 Ultimately, the combination of autoimmune markers with the pancytopenia and a negative work-up for malignancy confirmed a diagnosis of SLE.

Continue to: SLE classification and generalized lymphadenopathy

SLE classification and generalized lymphadenopathy. SLE is a multisystem inflammatory process with a wide spectrum of clinical presentations. The American College of Rheumatology (ACR) has established validated criteria to aid in the diagnosis of SLE,³ which were most recently updated in 2012 to improve clinical utility. For a diagnosis to be made, at least 1 clinical and 1 immunologic criterion must be present or a renal biopsy must show lupus nephritis.³

Notably, lymphadenopathy is not included in this validated model, despite its occurrence in 25% to 50% of patients with SLE.^1,3,4 With this in mind, SLE should be considered in the work-up of generalized lymphadenopathy.

ANA and SLE. Although it is estimated that 30% to 40% of patients with SLE test positive for ANA,⁵ the presence of ANA also is not part of the diagnostic criteria for SLE. Interestingly, the co-occurrence of the 2 has clinical implications for patients. In particular, patients with SLE and a positive ANA have higher prevalence of thrombosis, valvular disease, thrombocytopenia, and hemolytic anemia, among other complications.⁵ Although our patient’s presentation of thrombocytopenia and hemolysis clouded the initial work-up, such a combination is consistent with co-presentation of SLE and APS.

Differences in sex, age, and race. SLE is more common in women than in men, with a prevalence ratio of 7:1.⁶ It is estimated that 65% of patients with SLE experience disease onset between the ages of 16 and 55 years.⁷

The median age of diagnosis also differs based on sex and race: According to Rus et al,⁸ the typical age ranges are 37 to 50 years for White women; 50 to 59 for White men; 15 to 44 for Black women; and 45 to 64 for Black men. These estimates of incidence stratified by race, sex, and age can be helpful when evaluating patients with confusing clinical presentations. Our patient’s age was consistent with the median for his sex and race.

Continue to: Our patient

Our patient was started on oral prednisone 60 mg/d with plans for a prolonged taper over 6 months under the close supervision of Rheumatology. His weakness and polyuria began to improve within a month, and lupus-­related symptoms resolved within 3 months. His cytopenia also significantly improved, with the exception of refractory thrombocytopenia.

THE TAKEAWAY

SLE is a common diagnosis with multiple presentations. Although lymphadenopathy is not part of the clinical criteria for the diagnosis of SLE, multiple case studies have highlighted its prevalence among affected patients.^1,2,4,9-17 APS and antiphospholipid antibodies are also absent in the diagnostic criteria despite being highly associated with SLE. Thus, co-­presentation (as well as age and sex) can be helpful with both disease stratification and risk assessment once a diagnosis is made.

CORRESPONDENCE
Isabella Buzzo Bellon Brout, MD, 409 West Broadway, Boston, MA 02127; [email protected]

THE CASE

A 43-year-old Black male presented to his primary care physician with an 8-month history of progressive fatigue, weakness, and unintentional weight loss. The patient’s history also included antiphospholipid antibody syndrome (APS) with prior deep venous thrombosis/­pulmonary embolism for which he was taking warfarin.

At the time of presentation, he reported profound dyspnea on exertion, lightheadedness, dry mouth, low back pain, and worsening nocturia. The remainder of the review of systems was negative. He denied tobacco, alcohol, or illicit drug use or recent travel. His personal and family histories were negative for cancer.

Laboratory data collected during the outpatient visit were notable for a white blood cell count of 2300/mcL (reference range, 4000-11,000/mcL); hemoglobin, 8.6 g/dL (13.5-17.5 g/dL); and platelets, 44,000/mcL (150,000-400,000/mcL). Proteinuria was indicated by a measurement > 500 mg/dL on urine dipstick.

The patient was admitted to the hospital for further work-up of new pancytopenia. His vital signs on admission were notable for tachycardia and a weight of 237 lbs, decreased from 283 lbs 8 months prior. His physical exam revealed dry mucous membranes, bruising of fingertips, and marked lower extremity weakness with preserved sensation. No lymphadenopathy was noted on the admission physical exam.

THE DIAGNOSIS

Inpatient laboratory studies showed elevated inflammatory markers and a positive Coombs test with low haptoglobin. There was no evidence of bacterial or viral infection. Computed tomography of the chest, abdomen, and pelvis revealed axillary, subpectoral, and pelvic lymphadenopathy (see FIGURE). A work-up for multiple myeloma was negative, and a bone marrow biopsy was nondiagnostic.

Autoimmune laboratory data included a positive antiphospholipid antibody (ANA) test (1:10,240, diffuse; reference < 1:160), an elevated dsDNA antibody level (800 IU/mL; reference range, 0-99 IU/mL), low complement levels, and antibody titers consistent with the patient’s known APS. Based on these findings, the patient was given a diagnosis of systemic lupus erythematosus (SLE).

DISCUSSION

Lymphadenopathy, revealed by exam or by imaging, in combination with systemic symptoms such as weight loss and fatigue, elicits an extensive differential diagnosis. In the absence of recent exposures, travel, or risk factors for infectious causes, our patient’s work-up was appropriately narrowed to noninfectious etiologies of pancytopenia and lymphadenopathy. At the top of this differential are malignancies—in particular, multiple myeloma and lymphoma—and rheumatologic processes, such as sarcoidosis, connective tissue disease, and SLE.^1,2 Ultimately, the combination of autoimmune markers with the pancytopenia and a negative work-up for malignancy confirmed a diagnosis of SLE.

Continue to: SLE classification and generalized lymphadenopathy

SLE classification and generalized lymphadenopathy. SLE is a multisystem inflammatory process with a wide spectrum of clinical presentations. The American College of Rheumatology (ACR) has established validated criteria to aid in the diagnosis of SLE,³ which were most recently updated in 2012 to improve clinical utility. For a diagnosis to be made, at least 1 clinical and 1 immunologic criterion must be present or a renal biopsy must show lupus nephritis.³

Notably, lymphadenopathy is not included in this validated model, despite its occurrence in 25% to 50% of patients with SLE.^1,3,4 With this in mind, SLE should be considered in the work-up of generalized lymphadenopathy.

ANA and SLE. Although it is estimated that 30% to 40% of patients with SLE test positive for ANA,⁵ the presence of ANA also is not part of the diagnostic criteria for SLE. Interestingly, the co-occurrence of the 2 has clinical implications for patients. In particular, patients with SLE and a positive ANA have higher prevalence of thrombosis, valvular disease, thrombocytopenia, and hemolytic anemia, among other complications.⁵ Although our patient’s presentation of thrombocytopenia and hemolysis clouded the initial work-up, such a combination is consistent with co-presentation of SLE and APS.

Differences in sex, age, and race. SLE is more common in women than in men, with a prevalence ratio of 7:1.⁶ It is estimated that 65% of patients with SLE experience disease onset between the ages of 16 and 55 years.⁷

The median age of diagnosis also differs based on sex and race: According to Rus et al,⁸ the typical age ranges are 37 to 50 years for White women; 50 to 59 for White men; 15 to 44 for Black women; and 45 to 64 for Black men. These estimates of incidence stratified by race, sex, and age can be helpful when evaluating patients with confusing clinical presentations. Our patient’s age was consistent with the median for his sex and race.

Continue to: Our patient

Our patient was started on oral prednisone 60 mg/d with plans for a prolonged taper over 6 months under the close supervision of Rheumatology. His weakness and polyuria began to improve within a month, and lupus-­related symptoms resolved within 3 months. His cytopenia also significantly improved, with the exception of refractory thrombocytopenia.

THE TAKEAWAY

SLE is a common diagnosis with multiple presentations. Although lymphadenopathy is not part of the clinical criteria for the diagnosis of SLE, multiple case studies have highlighted its prevalence among affected patients.^1,2,4,9-17 APS and antiphospholipid antibodies are also absent in the diagnostic criteria despite being highly associated with SLE. Thus, co-­presentation (as well as age and sex) can be helpful with both disease stratification and risk assessment once a diagnosis is made.

CORRESPONDENCE
Isabella Buzzo Bellon Brout, MD, 409 West Broadway, Boston, MA 02127; [email protected]

THE CASE

A 43-year-old Black male presented to his primary care physician with an 8-month history of progressive fatigue, weakness, and unintentional weight loss. The patient’s history also included antiphospholipid antibody syndrome (APS) with prior deep venous thrombosis/­pulmonary embolism for which he was taking warfarin.

At the time of presentation, he reported profound dyspnea on exertion, lightheadedness, dry mouth, low back pain, and worsening nocturia. The remainder of the review of systems was negative. He denied tobacco, alcohol, or illicit drug use or recent travel. His personal and family histories were negative for cancer.

Laboratory data collected during the outpatient visit were notable for a white blood cell count of 2300/mcL (reference range, 4000-11,000/mcL); hemoglobin, 8.6 g/dL (13.5-17.5 g/dL); and platelets, 44,000/mcL (150,000-400,000/mcL). Proteinuria was indicated by a measurement > 500 mg/dL on urine dipstick.

The patient was admitted to the hospital for further work-up of new pancytopenia. His vital signs on admission were notable for tachycardia and a weight of 237 lbs, decreased from 283 lbs 8 months prior. His physical exam revealed dry mucous membranes, bruising of fingertips, and marked lower extremity weakness with preserved sensation. No lymphadenopathy was noted on the admission physical exam.

THE DIAGNOSIS

Inpatient laboratory studies showed elevated inflammatory markers and a positive Coombs test with low haptoglobin. There was no evidence of bacterial or viral infection. Computed tomography of the chest, abdomen, and pelvis revealed axillary, subpectoral, and pelvic lymphadenopathy (see FIGURE). A work-up for multiple myeloma was negative, and a bone marrow biopsy was nondiagnostic.

Autoimmune laboratory data included a positive antiphospholipid antibody (ANA) test (1:10,240, diffuse; reference < 1:160), an elevated dsDNA antibody level (800 IU/mL; reference range, 0-99 IU/mL), low complement levels, and antibody titers consistent with the patient’s known APS. Based on these findings, the patient was given a diagnosis of systemic lupus erythematosus (SLE).

DISCUSSION

Lymphadenopathy, revealed by exam or by imaging, in combination with systemic symptoms such as weight loss and fatigue, elicits an extensive differential diagnosis. In the absence of recent exposures, travel, or risk factors for infectious causes, our patient’s work-up was appropriately narrowed to noninfectious etiologies of pancytopenia and lymphadenopathy. At the top of this differential are malignancies—in particular, multiple myeloma and lymphoma—and rheumatologic processes, such as sarcoidosis, connective tissue disease, and SLE.^1,2 Ultimately, the combination of autoimmune markers with the pancytopenia and a negative work-up for malignancy confirmed a diagnosis of SLE.

Continue to: SLE classification and generalized lymphadenopathy

SLE classification and generalized lymphadenopathy. SLE is a multisystem inflammatory process with a wide spectrum of clinical presentations. The American College of Rheumatology (ACR) has established validated criteria to aid in the diagnosis of SLE,³ which were most recently updated in 2012 to improve clinical utility. For a diagnosis to be made, at least 1 clinical and 1 immunologic criterion must be present or a renal biopsy must show lupus nephritis.³

Notably, lymphadenopathy is not included in this validated model, despite its occurrence in 25% to 50% of patients with SLE.^1,3,4 With this in mind, SLE should be considered in the work-up of generalized lymphadenopathy.

ANA and SLE. Although it is estimated that 30% to 40% of patients with SLE test positive for ANA,⁵ the presence of ANA also is not part of the diagnostic criteria for SLE. Interestingly, the co-occurrence of the 2 has clinical implications for patients. In particular, patients with SLE and a positive ANA have higher prevalence of thrombosis, valvular disease, thrombocytopenia, and hemolytic anemia, among other complications.⁵ Although our patient’s presentation of thrombocytopenia and hemolysis clouded the initial work-up, such a combination is consistent with co-presentation of SLE and APS.

Differences in sex, age, and race. SLE is more common in women than in men, with a prevalence ratio of 7:1.⁶ It is estimated that 65% of patients with SLE experience disease onset between the ages of 16 and 55 years.⁷

The median age of diagnosis also differs based on sex and race: According to Rus et al,⁸ the typical age ranges are 37 to 50 years for White women; 50 to 59 for White men; 15 to 44 for Black women; and 45 to 64 for Black men. These estimates of incidence stratified by race, sex, and age can be helpful when evaluating patients with confusing clinical presentations. Our patient’s age was consistent with the median for his sex and race.

Continue to: Our patient

Our patient was started on oral prednisone 60 mg/d with plans for a prolonged taper over 6 months under the close supervision of Rheumatology. His weakness and polyuria began to improve within a month, and lupus-­related symptoms resolved within 3 months. His cytopenia also significantly improved, with the exception of refractory thrombocytopenia.

THE TAKEAWAY

SLE is a common diagnosis with multiple presentations. Although lymphadenopathy is not part of the clinical criteria for the diagnosis of SLE, multiple case studies have highlighted its prevalence among affected patients.^1,2,4,9-17 APS and antiphospholipid antibodies are also absent in the diagnostic criteria despite being highly associated with SLE. Thus, co-­presentation (as well as age and sex) can be helpful with both disease stratification and risk assessment once a diagnosis is made.

CORRESPONDENCE
Isabella Buzzo Bellon Brout, MD, 409 West Broadway, Boston, MA 02127; [email protected]

CHICAGO – Many physicians still hold beliefs despite the existence of clear evidence that they are incorrect, said a presenter at the annual meeting of the American College of Physicians.

These long-held pieces of dogma – or “medical myths” – were engraved during training or early in the careers of many physicians, and are difficult to overcome, noted Douglas Paauw, MD, professor of medicine at the University of Washington, Seattle.

“I think that myths persist because medical professionals get taught one way in training, given a ‘truth’ or ‘This is the way we do it,’ and then do not ever rethink, ‘Is it true?’ ” he said in an interview. “Studies pop up to question conventional wisdom, but unless the studies get highly publicized, they aren’t noticed.”

During his presentation, Dr. Paauw discussed three of what he considers to be some of the some of the medical myths that are in greatest need of being dispelled.
 

Shellfish allergy and radiocontrast

A myth persists that people with a shellfish allergy could have an allergic reaction when a contrast agent is used for a scan, he said.

This belief arose, because fish and shellfish contain iodine, and allergic reactions to seafood are fairly common, and contrast agents contain iodine, too, Dr. Paauw said.

The belief is widespread, with 65% of radiologists and 88.9% of interventional cardiologists saying they ask about seafood or shellfish allergies before administering contrast. And a third of radiologists and 50% of cardiologists said they would withhold contrast media or recommend a premedication for patients with such an allergy.

But the belief makes no sense, Dr. Pauuw said. Iodine is present in many other foods, including milk and bread, and allergies to shellfish are because of parvalbumin protein and tropomyosins, not iodine.
 

Colonoscopy dogma

It’s been long believed that people need to be on a clear, liquid diet for 1 or 2 days and need to drink a bowel-prep liquid before a colonoscopy, noted Dr. Paauw.

But the evidence shows this isn’t necessary, he said.

A 2020 study found that a low-residual diet, allowing foods such as meat, eggs, dairy, and bread, were comparable to the clear liquid diet in terms of bowel prep and detection of polyps during the exam. The patients on the low-residual diet had less nausea, less vomiting, and less hunger, and expressed more willingness to have a repeat colonoscopy.

“Let them eat,” Dr. Paauw said in his presentation.
 

Metronidazole and alcohol

There is a belief that patients shouldn’t drink alcohol if they are taking metronidazole, because of concerns about nausea, vomiting, flushing and other symptoms – also known as a disulfiramlike reaction, Dr. Paauw explained.

Case reports have been published, but the cases were presented as though a metronidazole-ethanol reaction was an established fact, and the authors didn’t provide evidence to justify this, Dr. Paauw said.

But it’s been shown in rat models that metronidazole can increase levels of acetaldehyde, the trigger of symptoms, in the colon, but not in the blood. And in a small placebo-controlled, randomized trial, six people were given metronidazole and ethanol and, after regular blood testing, no difference was seen in acetaldehyde blood levels, vital signs, or symptoms.

The Centers for Disease Control and Prevention has said that avoiding alcohol while taking metronidazole is unnecessary, said Dr. Paauw.
 

Sinus headaches

Contrary to common belief, headaches thought to be “sinus headaches” are usually migraine headaches, Dr. Paauw said.

In one study, 2,991 patients with six headaches in the previous 6 months were self-diagnosed or were physician-diagnosed with sinus headaches. But 88% of these headaches met the International Headache Society criteria for migraine headache.

Dr. Paauw said he hopes that clinicians reconsider the evidence regularly when deciding how to treat their patients, and not rely on bits of dogma.

“They stay with us,” he said, “and sometimes there are other ways to do it.”

Shien Tze, MD, an internist in Fargo, N,D,, said that patients sometimes also hold misconceptions, based on outdated dogma, that he needs to dispel.

“I try to convince them that this is a myth that is not based on evidence, not based on science,” he said. “I think it depends on the way you say it. If you say it in a calm, firm, not wishy-washy way, the patients believe you.”

Dr. Paauw reported no relevant financial disclosures. He serves on the editorial advisory board of Internal Medicine News, and he contributes “Myth of the Month” and “Pearl of the Month” columns to this publication.

CHICAGO – Many physicians still hold beliefs despite the existence of clear evidence that they are incorrect, said a presenter at the annual meeting of the American College of Physicians.

These long-held pieces of dogma – or “medical myths” – were engraved during training or early in the careers of many physicians, and are difficult to overcome, noted Douglas Paauw, MD, professor of medicine at the University of Washington, Seattle.

“I think that myths persist because medical professionals get taught one way in training, given a ‘truth’ or ‘This is the way we do it,’ and then do not ever rethink, ‘Is it true?’ ” he said in an interview. “Studies pop up to question conventional wisdom, but unless the studies get highly publicized, they aren’t noticed.”

During his presentation, Dr. Paauw discussed three of what he considers to be some of the some of the medical myths that are in greatest need of being dispelled.
 

Shellfish allergy and radiocontrast

A myth persists that people with a shellfish allergy could have an allergic reaction when a contrast agent is used for a scan, he said.

This belief arose, because fish and shellfish contain iodine, and allergic reactions to seafood are fairly common, and contrast agents contain iodine, too, Dr. Paauw said.

The belief is widespread, with 65% of radiologists and 88.9% of interventional cardiologists saying they ask about seafood or shellfish allergies before administering contrast. And a third of radiologists and 50% of cardiologists said they would withhold contrast media or recommend a premedication for patients with such an allergy.

But the belief makes no sense, Dr. Pauuw said. Iodine is present in many other foods, including milk and bread, and allergies to shellfish are because of parvalbumin protein and tropomyosins, not iodine.
 

Colonoscopy dogma

It’s been long believed that people need to be on a clear, liquid diet for 1 or 2 days and need to drink a bowel-prep liquid before a colonoscopy, noted Dr. Paauw.

But the evidence shows this isn’t necessary, he said.

A 2020 study found that a low-residual diet, allowing foods such as meat, eggs, dairy, and bread, were comparable to the clear liquid diet in terms of bowel prep and detection of polyps during the exam. The patients on the low-residual diet had less nausea, less vomiting, and less hunger, and expressed more willingness to have a repeat colonoscopy.

“Let them eat,” Dr. Paauw said in his presentation.
 

Metronidazole and alcohol

There is a belief that patients shouldn’t drink alcohol if they are taking metronidazole, because of concerns about nausea, vomiting, flushing and other symptoms – also known as a disulfiramlike reaction, Dr. Paauw explained.

Case reports have been published, but the cases were presented as though a metronidazole-ethanol reaction was an established fact, and the authors didn’t provide evidence to justify this, Dr. Paauw said.

But it’s been shown in rat models that metronidazole can increase levels of acetaldehyde, the trigger of symptoms, in the colon, but not in the blood. And in a small placebo-controlled, randomized trial, six people were given metronidazole and ethanol and, after regular blood testing, no difference was seen in acetaldehyde blood levels, vital signs, or symptoms.

The Centers for Disease Control and Prevention has said that avoiding alcohol while taking metronidazole is unnecessary, said Dr. Paauw.
 

Sinus headaches

Contrary to common belief, headaches thought to be “sinus headaches” are usually migraine headaches, Dr. Paauw said.

In one study, 2,991 patients with six headaches in the previous 6 months were self-diagnosed or were physician-diagnosed with sinus headaches. But 88% of these headaches met the International Headache Society criteria for migraine headache.

Dr. Paauw said he hopes that clinicians reconsider the evidence regularly when deciding how to treat their patients, and not rely on bits of dogma.

“They stay with us,” he said, “and sometimes there are other ways to do it.”

Shien Tze, MD, an internist in Fargo, N,D,, said that patients sometimes also hold misconceptions, based on outdated dogma, that he needs to dispel.

“I try to convince them that this is a myth that is not based on evidence, not based on science,” he said. “I think it depends on the way you say it. If you say it in a calm, firm, not wishy-washy way, the patients believe you.”

Dr. Paauw reported no relevant financial disclosures. He serves on the editorial advisory board of Internal Medicine News, and he contributes “Myth of the Month” and “Pearl of the Month” columns to this publication.

CHICAGO – Many physicians still hold beliefs despite the existence of clear evidence that they are incorrect, said a presenter at the annual meeting of the American College of Physicians.

These long-held pieces of dogma – or “medical myths” – were engraved during training or early in the careers of many physicians, and are difficult to overcome, noted Douglas Paauw, MD, professor of medicine at the University of Washington, Seattle.

“I think that myths persist because medical professionals get taught one way in training, given a ‘truth’ or ‘This is the way we do it,’ and then do not ever rethink, ‘Is it true?’ ” he said in an interview. “Studies pop up to question conventional wisdom, but unless the studies get highly publicized, they aren’t noticed.”

During his presentation, Dr. Paauw discussed three of what he considers to be some of the some of the medical myths that are in greatest need of being dispelled.
 

Shellfish allergy and radiocontrast

A myth persists that people with a shellfish allergy could have an allergic reaction when a contrast agent is used for a scan, he said.

This belief arose, because fish and shellfish contain iodine, and allergic reactions to seafood are fairly common, and contrast agents contain iodine, too, Dr. Paauw said.

The belief is widespread, with 65% of radiologists and 88.9% of interventional cardiologists saying they ask about seafood or shellfish allergies before administering contrast. And a third of radiologists and 50% of cardiologists said they would withhold contrast media or recommend a premedication for patients with such an allergy.

But the belief makes no sense, Dr. Pauuw said. Iodine is present in many other foods, including milk and bread, and allergies to shellfish are because of parvalbumin protein and tropomyosins, not iodine.
 

Colonoscopy dogma

It’s been long believed that people need to be on a clear, liquid diet for 1 or 2 days and need to drink a bowel-prep liquid before a colonoscopy, noted Dr. Paauw.

But the evidence shows this isn’t necessary, he said.

A 2020 study found that a low-residual diet, allowing foods such as meat, eggs, dairy, and bread, were comparable to the clear liquid diet in terms of bowel prep and detection of polyps during the exam. The patients on the low-residual diet had less nausea, less vomiting, and less hunger, and expressed more willingness to have a repeat colonoscopy.

“Let them eat,” Dr. Paauw said in his presentation.
 

Metronidazole and alcohol

There is a belief that patients shouldn’t drink alcohol if they are taking metronidazole, because of concerns about nausea, vomiting, flushing and other symptoms – also known as a disulfiramlike reaction, Dr. Paauw explained.

Case reports have been published, but the cases were presented as though a metronidazole-ethanol reaction was an established fact, and the authors didn’t provide evidence to justify this, Dr. Paauw said.

But it’s been shown in rat models that metronidazole can increase levels of acetaldehyde, the trigger of symptoms, in the colon, but not in the blood. And in a small placebo-controlled, randomized trial, six people were given metronidazole and ethanol and, after regular blood testing, no difference was seen in acetaldehyde blood levels, vital signs, or symptoms.

The Centers for Disease Control and Prevention has said that avoiding alcohol while taking metronidazole is unnecessary, said Dr. Paauw.
 

Sinus headaches

Contrary to common belief, headaches thought to be “sinus headaches” are usually migraine headaches, Dr. Paauw said.

In one study, 2,991 patients with six headaches in the previous 6 months were self-diagnosed or were physician-diagnosed with sinus headaches. But 88% of these headaches met the International Headache Society criteria for migraine headache.

Dr. Paauw said he hopes that clinicians reconsider the evidence regularly when deciding how to treat their patients, and not rely on bits of dogma.

“They stay with us,” he said, “and sometimes there are other ways to do it.”

Shien Tze, MD, an internist in Fargo, N,D,, said that patients sometimes also hold misconceptions, based on outdated dogma, that he needs to dispel.

“I try to convince them that this is a myth that is not based on evidence, not based on science,” he said. “I think it depends on the way you say it. If you say it in a calm, firm, not wishy-washy way, the patients believe you.”

Dr. Paauw reported no relevant financial disclosures. He serves on the editorial advisory board of Internal Medicine News, and he contributes “Myth of the Month” and “Pearl of the Month” columns to this publication.

Mental disorders were significantly more likely in children whose mothers had one of five common autoimmune diseases, a new study found.

Previous research has linked both maternal and paternal autoimmune diseases and specific mental disorders, such as attention-deficit/hyperactivity disorder (ADHD), but most of these studies focused on specific conditions in relatively small populations. The new study included data on more than 2 million births, making it one of the largest efforts to date to examine the association, according to the researchers, whose findings were published in JAMA Network Open.

Previous evidence of the possible association between certain maternal autoimmune diseases and mental disorders in offspring has been “scattered and limited,” which “hampered an overall understanding” of the link, Fei Li, MD, the corresponding author of the study, told this news organization.

Dr. Li, of Shanghai Jiao Tong University China, and colleagues reviewed data from a Danish registry cohort of singleton births with up to 38 years of follow-up. They explored associations between a range of maternal autoimmune diseases diagnosed before childbirth and the risks of mental disorders in children in early childhood through young adulthood.

The study population included 2,254,234 births and 38,916,359 person-years. Data on mental health were collected from the Psychiatric Central Research Register and the country’s National Patient Register. The median age of the children at the time of assessment was 16.7 years; approximately half were male.

A total of 50,863 children (2.26%) were born to mothers who had been diagnosed with autoimmune diseases before childbirth. During the follow-up period, 5,460 children of mothers with autoimmune diseases and 303,092 children of mothers without autoimmune diseases were diagnosed with a mental disorder (10.73% vs. 13.76%), according to the researchers.

The risk of being diagnosed with a mental disorder was significantly higher among children of mothers with any autoimmune disease (hazard ratio [HR,], 1.16), with an incidence of 9.38 vs. 7.91 per 1,000 person-years, the researchers reported.

The increased risk persisted when the results were classified by organ system, including connective tissue (HR, 1.11), endocrine (HR, 1.19), gastrointestinal (HR, 1.11), blood (HR, 1.10), nervous (HR, 1.17), and skin (HR, 1.19).

The five autoimmune diseases in mothers that were most commonly associated mental health disorders in children were type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and psoriasis vulgaris.

The greatest risk for children of mothers with any autoimmune disease was observed for organic conditions such as delirium, (HR, 1.54), followed by obsessive-compulsive disorder (HR, 1.42), schizophrenia (HR, 1.54), and mood problems (HR, 1.12).

Children of mothers with any autoimmune disorder also had a significantly increased risk of autism (HR, 1.21), intellectual disability (HR, 1.19), and ADHD (HR, 1.19).

The results add to evidence that activation of the maternal immune system may drive changes in the brain and behavioral problems, which has been observed in animal studies, the researchers wrote.

Potential underlying mechanisms in need of more exploration include genetic risk factors, maternal transmission of autoantibodies to the fetus during pregnancy, and the increased risk of obstetric complications, such as preterm birth, for women with autoimmune disorders that could affect mental development in children, they added.

The study findings were limited by several factors, including the lack of data on potential exacerbation of autoimmune disease activity during pregnancy and its effect on the fetus, the researchers noted. Other limitations included potential detection bias, lack of data on mental disorders in adulthood, and potential changes in diagnostic criteria over the long study period.

The results were strengthened by the use of a population-based registry, the large sample size, and ability to consider a range of confounders, the researchers said.

“This study could help acquire a comprehensive compilation of the associations between maternal autoimmune disorders diagnosed before childbirth and offspring’s mental disorders from childhood through early adulthood,” Dr. Li said in an interview.

For clinicians, Dr. Li said, the findings suggest that the offspring of mothers with autoimmune diseases may benefit from long-term surveillance for mental health disorders.

“Further studies should provide more evidence on the detailed associations of specific maternal autoimmune diseases with a full spectrum of mental disorders in offspring, and more research on underlying mechanisms is needed as well,” she said.
 

Pay early attention

M. Susan Jay, MD, an adjunct professor of pediatrics at the Medical College of Wisconsin, Milwaukee, said previous efforts to examine the association between maternal autoimmunity were hampered by study design, small samples, and self-report of disease history – problems the new research avoids.

The large patient population allowed for detailed subgroup analysis of different conditions and outcomes. Another advantage was the availability of sociodemographic and clinical information, which allowed for the elimination of confounding factors, said Dr. Jay, who was not involved in the research.

“It would be prudent to follow children of mothers with autoimmune disorders before or during pregnancy for mental health issues, and if identified clinically, to offer psychological and developmental behavioral support options,” Dr. Jay added.

The authors have reported no relevant financial relationships.

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

Mental disorders were significantly more likely in children whose mothers had one of five common autoimmune diseases, a new study found.

Previous research has linked both maternal and paternal autoimmune diseases and specific mental disorders, such as attention-deficit/hyperactivity disorder (ADHD), but most of these studies focused on specific conditions in relatively small populations. The new study included data on more than 2 million births, making it one of the largest efforts to date to examine the association, according to the researchers, whose findings were published in JAMA Network Open.

Previous evidence of the possible association between certain maternal autoimmune diseases and mental disorders in offspring has been “scattered and limited,” which “hampered an overall understanding” of the link, Fei Li, MD, the corresponding author of the study, told this news organization.

Dr. Li, of Shanghai Jiao Tong University China, and colleagues reviewed data from a Danish registry cohort of singleton births with up to 38 years of follow-up. They explored associations between a range of maternal autoimmune diseases diagnosed before childbirth and the risks of mental disorders in children in early childhood through young adulthood.

The study population included 2,254,234 births and 38,916,359 person-years. Data on mental health were collected from the Psychiatric Central Research Register and the country’s National Patient Register. The median age of the children at the time of assessment was 16.7 years; approximately half were male.

A total of 50,863 children (2.26%) were born to mothers who had been diagnosed with autoimmune diseases before childbirth. During the follow-up period, 5,460 children of mothers with autoimmune diseases and 303,092 children of mothers without autoimmune diseases were diagnosed with a mental disorder (10.73% vs. 13.76%), according to the researchers.

The risk of being diagnosed with a mental disorder was significantly higher among children of mothers with any autoimmune disease (hazard ratio [HR,], 1.16), with an incidence of 9.38 vs. 7.91 per 1,000 person-years, the researchers reported.

The increased risk persisted when the results were classified by organ system, including connective tissue (HR, 1.11), endocrine (HR, 1.19), gastrointestinal (HR, 1.11), blood (HR, 1.10), nervous (HR, 1.17), and skin (HR, 1.19).

The five autoimmune diseases in mothers that were most commonly associated mental health disorders in children were type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and psoriasis vulgaris.

The greatest risk for children of mothers with any autoimmune disease was observed for organic conditions such as delirium, (HR, 1.54), followed by obsessive-compulsive disorder (HR, 1.42), schizophrenia (HR, 1.54), and mood problems (HR, 1.12).

Children of mothers with any autoimmune disorder also had a significantly increased risk of autism (HR, 1.21), intellectual disability (HR, 1.19), and ADHD (HR, 1.19).

The results add to evidence that activation of the maternal immune system may drive changes in the brain and behavioral problems, which has been observed in animal studies, the researchers wrote.

Potential underlying mechanisms in need of more exploration include genetic risk factors, maternal transmission of autoantibodies to the fetus during pregnancy, and the increased risk of obstetric complications, such as preterm birth, for women with autoimmune disorders that could affect mental development in children, they added.

The study findings were limited by several factors, including the lack of data on potential exacerbation of autoimmune disease activity during pregnancy and its effect on the fetus, the researchers noted. Other limitations included potential detection bias, lack of data on mental disorders in adulthood, and potential changes in diagnostic criteria over the long study period.

The results were strengthened by the use of a population-based registry, the large sample size, and ability to consider a range of confounders, the researchers said.

“This study could help acquire a comprehensive compilation of the associations between maternal autoimmune disorders diagnosed before childbirth and offspring’s mental disorders from childhood through early adulthood,” Dr. Li said in an interview.

For clinicians, Dr. Li said, the findings suggest that the offspring of mothers with autoimmune diseases may benefit from long-term surveillance for mental health disorders.

“Further studies should provide more evidence on the detailed associations of specific maternal autoimmune diseases with a full spectrum of mental disorders in offspring, and more research on underlying mechanisms is needed as well,” she said.
 

Pay early attention

M. Susan Jay, MD, an adjunct professor of pediatrics at the Medical College of Wisconsin, Milwaukee, said previous efforts to examine the association between maternal autoimmunity were hampered by study design, small samples, and self-report of disease history – problems the new research avoids.

The large patient population allowed for detailed subgroup analysis of different conditions and outcomes. Another advantage was the availability of sociodemographic and clinical information, which allowed for the elimination of confounding factors, said Dr. Jay, who was not involved in the research.

“It would be prudent to follow children of mothers with autoimmune disorders before or during pregnancy for mental health issues, and if identified clinically, to offer psychological and developmental behavioral support options,” Dr. Jay added.

The authors have reported no relevant financial relationships.

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

Mental disorders were significantly more likely in children whose mothers had one of five common autoimmune diseases, a new study found.

Previous research has linked both maternal and paternal autoimmune diseases and specific mental disorders, such as attention-deficit/hyperactivity disorder (ADHD), but most of these studies focused on specific conditions in relatively small populations. The new study included data on more than 2 million births, making it one of the largest efforts to date to examine the association, according to the researchers, whose findings were published in JAMA Network Open.

Previous evidence of the possible association between certain maternal autoimmune diseases and mental disorders in offspring has been “scattered and limited,” which “hampered an overall understanding” of the link, Fei Li, MD, the corresponding author of the study, told this news organization.

Dr. Li, of Shanghai Jiao Tong University China, and colleagues reviewed data from a Danish registry cohort of singleton births with up to 38 years of follow-up. They explored associations between a range of maternal autoimmune diseases diagnosed before childbirth and the risks of mental disorders in children in early childhood through young adulthood.

The study population included 2,254,234 births and 38,916,359 person-years. Data on mental health were collected from the Psychiatric Central Research Register and the country’s National Patient Register. The median age of the children at the time of assessment was 16.7 years; approximately half were male.

A total of 50,863 children (2.26%) were born to mothers who had been diagnosed with autoimmune diseases before childbirth. During the follow-up period, 5,460 children of mothers with autoimmune diseases and 303,092 children of mothers without autoimmune diseases were diagnosed with a mental disorder (10.73% vs. 13.76%), according to the researchers.

The risk of being diagnosed with a mental disorder was significantly higher among children of mothers with any autoimmune disease (hazard ratio [HR,], 1.16), with an incidence of 9.38 vs. 7.91 per 1,000 person-years, the researchers reported.

The increased risk persisted when the results were classified by organ system, including connective tissue (HR, 1.11), endocrine (HR, 1.19), gastrointestinal (HR, 1.11), blood (HR, 1.10), nervous (HR, 1.17), and skin (HR, 1.19).

The five autoimmune diseases in mothers that were most commonly associated mental health disorders in children were type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and psoriasis vulgaris.

The greatest risk for children of mothers with any autoimmune disease was observed for organic conditions such as delirium, (HR, 1.54), followed by obsessive-compulsive disorder (HR, 1.42), schizophrenia (HR, 1.54), and mood problems (HR, 1.12).

Children of mothers with any autoimmune disorder also had a significantly increased risk of autism (HR, 1.21), intellectual disability (HR, 1.19), and ADHD (HR, 1.19).

The results add to evidence that activation of the maternal immune system may drive changes in the brain and behavioral problems, which has been observed in animal studies, the researchers wrote.

Potential underlying mechanisms in need of more exploration include genetic risk factors, maternal transmission of autoantibodies to the fetus during pregnancy, and the increased risk of obstetric complications, such as preterm birth, for women with autoimmune disorders that could affect mental development in children, they added.

The study findings were limited by several factors, including the lack of data on potential exacerbation of autoimmune disease activity during pregnancy and its effect on the fetus, the researchers noted. Other limitations included potential detection bias, lack of data on mental disorders in adulthood, and potential changes in diagnostic criteria over the long study period.

The results were strengthened by the use of a population-based registry, the large sample size, and ability to consider a range of confounders, the researchers said.

“This study could help acquire a comprehensive compilation of the associations between maternal autoimmune disorders diagnosed before childbirth and offspring’s mental disorders from childhood through early adulthood,” Dr. Li said in an interview.

For clinicians, Dr. Li said, the findings suggest that the offspring of mothers with autoimmune diseases may benefit from long-term surveillance for mental health disorders.

“Further studies should provide more evidence on the detailed associations of specific maternal autoimmune diseases with a full spectrum of mental disorders in offspring, and more research on underlying mechanisms is needed as well,” she said.
 

Pay early attention

M. Susan Jay, MD, an adjunct professor of pediatrics at the Medical College of Wisconsin, Milwaukee, said previous efforts to examine the association between maternal autoimmunity were hampered by study design, small samples, and self-report of disease history – problems the new research avoids.

The large patient population allowed for detailed subgroup analysis of different conditions and outcomes. Another advantage was the availability of sociodemographic and clinical information, which allowed for the elimination of confounding factors, said Dr. Jay, who was not involved in the research.

“It would be prudent to follow children of mothers with autoimmune disorders before or during pregnancy for mental health issues, and if identified clinically, to offer psychological and developmental behavioral support options,” Dr. Jay added.

The authors have reported no relevant financial relationships.

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

In this column I have previously discussed the microbiome and its importance to health, especially as it relates to infections in children. Given the appreciated connection between microbiome and immunity, my group in Rochester, N.Y., recently undertook a study of the effect of antibiotic usage on the immune response to routine early childhood vaccines. In mouse models, it was previously shown that antibiotic exposure induced a reduction in the abundance and diversity of gut microbiota that in turn negatively affected the generation and maintenance of vaccine-induced immunity.^1,2 A study from Stanford University was the first experimental human trial of antibiotic effects on vaccine responses. Adult volunteers were given an antibiotic or not before seasonal influenza vaccination and the researchers identified specific bacteria in the gut that were reduced by the antibiotics given. Those normal bacteria in the gut microbiome were shown to provide positive immunity signals to the systemic immune system that potentiated vaccine responses.³

My group conducted the first-ever study in children to explore whether an association existed between antibiotic use and vaccine-induced antibody levels. In the May issue of Pediatrics we report results from 560 children studied.⁴ From these children, 11,888 serum antibody levels to vaccine antigens were measured. Vaccine-induced antibody levels were determined at various time points after primary vaccination at child age 2, 4, and 6 months and boosters at age 12-18 months for 10 antigens included in four vaccines: DTaP, Hib, IPV, and PCV. The antibody levels to vaccine components were measured to DTaP (diphtheria toxoid, pertussis toxoid, tetanus toxoid, pertactin, and filamentous hemagglutinin), Hib conjugate (polyribosylribitol phosphate), IPV (polio 2), and PCV (serotypes 6B, 14, and 23F). A total of 342 children with 1,678 antibiotic courses prescribed were compared with 218 children with no antibiotic exposures. The predominant antibiotics prescribed were amoxicillin, cefdinir, amoxicillin/clavulanate, and ceftriaxone, since most treatments were for acute otitis media.

Of possible high clinical relevance, we found that from 9 to 24 months of age, children with antibiotic exposure had a higher frequency of vaccine-induced antibody levels below protection compared with children with no antibiotic use, placing them at risk of contracting a vaccine-preventable infection for DTaP antigens DT, TT, and PT and for PCV serotype 14.

For time points where antibody levels were determined within 30 days of completion of a course of antibiotics (recent antibiotic use), individual antibiotics were analyzed for effect on antibody levels below protective levels. Across all vaccine antigens measured, we found that all antibiotics had a negative effect on antibody levels and percentage of children achieving the protective antibody level threshold. Amoxicillin use had a lower association with lower antibody levels than the broader spectrum antibiotics, amoxicillin clavulanate (Augmentin), cefdinir, and ceftriaxone. For children receiving amoxicillin/clavulanate prescriptions, it was possible to compare the effect of shorter versus longer courses and we found that a 5-day course was associated with subprotective antibody levels similar to 10 days of amoxicillin, whereas 10-day amoxicillin/clavulanate was associated with higher frequency of children having subprotective antibody levels (Figure).

We examined whether accumulation of antibiotic courses in the first year of life had an association with subsequent vaccine-induced antibody levels and found that each antibiotic prescription was associated with a reduction in the median antibody level. For DTaP, each prescription was associated with 5.8% drop in antibody level to the vaccine components. For Hib the drop was 6.8%, IPV was 11.3%, and PCV was 10.4% – all statistically significant. To determine if booster vaccination influenced this association, a second analysis was performed using antibiotic prescriptions up to 15 months of age. We found each antibiotic prescription was associated with a reduction in median vaccine-induced antibody levels for DTaP by 18%, Hib by 21%, IPV by 19%, and PCV by 12% – all statistically significant.

Our study is the first in young children during the early age window where vaccine-induced immunity is established. Antibiotic use was associated with increased frequency of subprotective antibody levels for several vaccines used in children up to 2 years of age. The lower antibody levels could leave children vulnerable to vaccine preventable diseases. Perhaps outbreaks of vaccine-preventable diseases, such as pertussis, may be a consequence of multiple courses of antibiotics suppressing vaccine-induced immunity.

A goal of this study was to explore potential acute and long-term effects of antibiotic exposure on vaccine-induced antibody levels. Accumulated antibiotic courses up to booster immunization was associated with decreased vaccine antibody levels both before and after booster, suggesting that booster immunization was not sufficient to change the negative association with antibiotic exposure. The results were similar for all vaccines tested, suggesting that the specific vaccine formulation was not a factor.

The study has several limitations. The antibiotic prescription data and measurements of vaccine-induced antibody levels were recorded and measured prospectively; however, our analysis was done retrospectively. The group of study children was derived from my private practice in Rochester, N.Y., and may not be broadly representative of all children. The number of vaccine antibody measurements was limited by serum availability at some sampling time points in some children; and sometimes, the serum samples were collected far apart, which weakened our ability to perform longitudinal analyses. We did not collect stool samples from the children so we could not directly study the effect of antibiotic courses on the gut microbiome.

Our study adds new reasons to be cautious about overprescribing antibiotics on an individual child basis because an adverse effect extends to reduction in vaccine responses. This should be explained to parents requesting unnecessary antibiotics for colds and coughs. When antibiotics are necessary, the judicious choice of a narrow-spectrum antibiotic or a shorter duration of a broader spectrum antibiotic may reduce adverse effects on vaccine-induced immunity.

References

1. Valdez Y et al. Influence of the microbiota on vaccine effectiveness. Trends Immunol. 2014;35(11):526-37.

2. Lynn MA et al. Early-life antibiotic-driven dysbiosis leads to dysregulated vaccine immune responses in mice. Cell Host Microbe. 2018;23(5):653-60.e5.

3. Hagan T et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019;178(6):1313-28.e13.

4. Chapman T et al. Antibiotic use and vaccine antibody levels. Pediatrics. 2022;149(5);1-17. doi: 10.1542/peds.2021-052061.

In this column I have previously discussed the microbiome and its importance to health, especially as it relates to infections in children. Given the appreciated connection between microbiome and immunity, my group in Rochester, N.Y., recently undertook a study of the effect of antibiotic usage on the immune response to routine early childhood vaccines. In mouse models, it was previously shown that antibiotic exposure induced a reduction in the abundance and diversity of gut microbiota that in turn negatively affected the generation and maintenance of vaccine-induced immunity.^1,2 A study from Stanford University was the first experimental human trial of antibiotic effects on vaccine responses. Adult volunteers were given an antibiotic or not before seasonal influenza vaccination and the researchers identified specific bacteria in the gut that were reduced by the antibiotics given. Those normal bacteria in the gut microbiome were shown to provide positive immunity signals to the systemic immune system that potentiated vaccine responses.³

My group conducted the first-ever study in children to explore whether an association existed between antibiotic use and vaccine-induced antibody levels. In the May issue of Pediatrics we report results from 560 children studied.⁴ From these children, 11,888 serum antibody levels to vaccine antigens were measured. Vaccine-induced antibody levels were determined at various time points after primary vaccination at child age 2, 4, and 6 months and boosters at age 12-18 months for 10 antigens included in four vaccines: DTaP, Hib, IPV, and PCV. The antibody levels to vaccine components were measured to DTaP (diphtheria toxoid, pertussis toxoid, tetanus toxoid, pertactin, and filamentous hemagglutinin), Hib conjugate (polyribosylribitol phosphate), IPV (polio 2), and PCV (serotypes 6B, 14, and 23F). A total of 342 children with 1,678 antibiotic courses prescribed were compared with 218 children with no antibiotic exposures. The predominant antibiotics prescribed were amoxicillin, cefdinir, amoxicillin/clavulanate, and ceftriaxone, since most treatments were for acute otitis media.

Of possible high clinical relevance, we found that from 9 to 24 months of age, children with antibiotic exposure had a higher frequency of vaccine-induced antibody levels below protection compared with children with no antibiotic use, placing them at risk of contracting a vaccine-preventable infection for DTaP antigens DT, TT, and PT and for PCV serotype 14.

For time points where antibody levels were determined within 30 days of completion of a course of antibiotics (recent antibiotic use), individual antibiotics were analyzed for effect on antibody levels below protective levels. Across all vaccine antigens measured, we found that all antibiotics had a negative effect on antibody levels and percentage of children achieving the protective antibody level threshold. Amoxicillin use had a lower association with lower antibody levels than the broader spectrum antibiotics, amoxicillin clavulanate (Augmentin), cefdinir, and ceftriaxone. For children receiving amoxicillin/clavulanate prescriptions, it was possible to compare the effect of shorter versus longer courses and we found that a 5-day course was associated with subprotective antibody levels similar to 10 days of amoxicillin, whereas 10-day amoxicillin/clavulanate was associated with higher frequency of children having subprotective antibody levels (Figure).

We examined whether accumulation of antibiotic courses in the first year of life had an association with subsequent vaccine-induced antibody levels and found that each antibiotic prescription was associated with a reduction in the median antibody level. For DTaP, each prescription was associated with 5.8% drop in antibody level to the vaccine components. For Hib the drop was 6.8%, IPV was 11.3%, and PCV was 10.4% – all statistically significant. To determine if booster vaccination influenced this association, a second analysis was performed using antibiotic prescriptions up to 15 months of age. We found each antibiotic prescription was associated with a reduction in median vaccine-induced antibody levels for DTaP by 18%, Hib by 21%, IPV by 19%, and PCV by 12% – all statistically significant.

Our study is the first in young children during the early age window where vaccine-induced immunity is established. Antibiotic use was associated with increased frequency of subprotective antibody levels for several vaccines used in children up to 2 years of age. The lower antibody levels could leave children vulnerable to vaccine preventable diseases. Perhaps outbreaks of vaccine-preventable diseases, such as pertussis, may be a consequence of multiple courses of antibiotics suppressing vaccine-induced immunity.

A goal of this study was to explore potential acute and long-term effects of antibiotic exposure on vaccine-induced antibody levels. Accumulated antibiotic courses up to booster immunization was associated with decreased vaccine antibody levels both before and after booster, suggesting that booster immunization was not sufficient to change the negative association with antibiotic exposure. The results were similar for all vaccines tested, suggesting that the specific vaccine formulation was not a factor.

The study has several limitations. The antibiotic prescription data and measurements of vaccine-induced antibody levels were recorded and measured prospectively; however, our analysis was done retrospectively. The group of study children was derived from my private practice in Rochester, N.Y., and may not be broadly representative of all children. The number of vaccine antibody measurements was limited by serum availability at some sampling time points in some children; and sometimes, the serum samples were collected far apart, which weakened our ability to perform longitudinal analyses. We did not collect stool samples from the children so we could not directly study the effect of antibiotic courses on the gut microbiome.

Our study adds new reasons to be cautious about overprescribing antibiotics on an individual child basis because an adverse effect extends to reduction in vaccine responses. This should be explained to parents requesting unnecessary antibiotics for colds and coughs. When antibiotics are necessary, the judicious choice of a narrow-spectrum antibiotic or a shorter duration of a broader spectrum antibiotic may reduce adverse effects on vaccine-induced immunity.

References

1. Valdez Y et al. Influence of the microbiota on vaccine effectiveness. Trends Immunol. 2014;35(11):526-37.

2. Lynn MA et al. Early-life antibiotic-driven dysbiosis leads to dysregulated vaccine immune responses in mice. Cell Host Microbe. 2018;23(5):653-60.e5.

3. Hagan T et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019;178(6):1313-28.e13.

4. Chapman T et al. Antibiotic use and vaccine antibody levels. Pediatrics. 2022;149(5);1-17. doi: 10.1542/peds.2021-052061.

In this column I have previously discussed the microbiome and its importance to health, especially as it relates to infections in children. Given the appreciated connection between microbiome and immunity, my group in Rochester, N.Y., recently undertook a study of the effect of antibiotic usage on the immune response to routine early childhood vaccines. In mouse models, it was previously shown that antibiotic exposure induced a reduction in the abundance and diversity of gut microbiota that in turn negatively affected the generation and maintenance of vaccine-induced immunity.^1,2 A study from Stanford University was the first experimental human trial of antibiotic effects on vaccine responses. Adult volunteers were given an antibiotic or not before seasonal influenza vaccination and the researchers identified specific bacteria in the gut that were reduced by the antibiotics given. Those normal bacteria in the gut microbiome were shown to provide positive immunity signals to the systemic immune system that potentiated vaccine responses.³

My group conducted the first-ever study in children to explore whether an association existed between antibiotic use and vaccine-induced antibody levels. In the May issue of Pediatrics we report results from 560 children studied.⁴ From these children, 11,888 serum antibody levels to vaccine antigens were measured. Vaccine-induced antibody levels were determined at various time points after primary vaccination at child age 2, 4, and 6 months and boosters at age 12-18 months for 10 antigens included in four vaccines: DTaP, Hib, IPV, and PCV. The antibody levels to vaccine components were measured to DTaP (diphtheria toxoid, pertussis toxoid, tetanus toxoid, pertactin, and filamentous hemagglutinin), Hib conjugate (polyribosylribitol phosphate), IPV (polio 2), and PCV (serotypes 6B, 14, and 23F). A total of 342 children with 1,678 antibiotic courses prescribed were compared with 218 children with no antibiotic exposures. The predominant antibiotics prescribed were amoxicillin, cefdinir, amoxicillin/clavulanate, and ceftriaxone, since most treatments were for acute otitis media.

Of possible high clinical relevance, we found that from 9 to 24 months of age, children with antibiotic exposure had a higher frequency of vaccine-induced antibody levels below protection compared with children with no antibiotic use, placing them at risk of contracting a vaccine-preventable infection for DTaP antigens DT, TT, and PT and for PCV serotype 14.

For time points where antibody levels were determined within 30 days of completion of a course of antibiotics (recent antibiotic use), individual antibiotics were analyzed for effect on antibody levels below protective levels. Across all vaccine antigens measured, we found that all antibiotics had a negative effect on antibody levels and percentage of children achieving the protective antibody level threshold. Amoxicillin use had a lower association with lower antibody levels than the broader spectrum antibiotics, amoxicillin clavulanate (Augmentin), cefdinir, and ceftriaxone. For children receiving amoxicillin/clavulanate prescriptions, it was possible to compare the effect of shorter versus longer courses and we found that a 5-day course was associated with subprotective antibody levels similar to 10 days of amoxicillin, whereas 10-day amoxicillin/clavulanate was associated with higher frequency of children having subprotective antibody levels (Figure).

We examined whether accumulation of antibiotic courses in the first year of life had an association with subsequent vaccine-induced antibody levels and found that each antibiotic prescription was associated with a reduction in the median antibody level. For DTaP, each prescription was associated with 5.8% drop in antibody level to the vaccine components. For Hib the drop was 6.8%, IPV was 11.3%, and PCV was 10.4% – all statistically significant. To determine if booster vaccination influenced this association, a second analysis was performed using antibiotic prescriptions up to 15 months of age. We found each antibiotic prescription was associated with a reduction in median vaccine-induced antibody levels for DTaP by 18%, Hib by 21%, IPV by 19%, and PCV by 12% – all statistically significant.

Our study is the first in young children during the early age window where vaccine-induced immunity is established. Antibiotic use was associated with increased frequency of subprotective antibody levels for several vaccines used in children up to 2 years of age. The lower antibody levels could leave children vulnerable to vaccine preventable diseases. Perhaps outbreaks of vaccine-preventable diseases, such as pertussis, may be a consequence of multiple courses of antibiotics suppressing vaccine-induced immunity.

A goal of this study was to explore potential acute and long-term effects of antibiotic exposure on vaccine-induced antibody levels. Accumulated antibiotic courses up to booster immunization was associated with decreased vaccine antibody levels both before and after booster, suggesting that booster immunization was not sufficient to change the negative association with antibiotic exposure. The results were similar for all vaccines tested, suggesting that the specific vaccine formulation was not a factor.

The study has several limitations. The antibiotic prescription data and measurements of vaccine-induced antibody levels were recorded and measured prospectively; however, our analysis was done retrospectively. The group of study children was derived from my private practice in Rochester, N.Y., and may not be broadly representative of all children. The number of vaccine antibody measurements was limited by serum availability at some sampling time points in some children; and sometimes, the serum samples were collected far apart, which weakened our ability to perform longitudinal analyses. We did not collect stool samples from the children so we could not directly study the effect of antibiotic courses on the gut microbiome.

Our study adds new reasons to be cautious about overprescribing antibiotics on an individual child basis because an adverse effect extends to reduction in vaccine responses. This should be explained to parents requesting unnecessary antibiotics for colds and coughs. When antibiotics are necessary, the judicious choice of a narrow-spectrum antibiotic or a shorter duration of a broader spectrum antibiotic may reduce adverse effects on vaccine-induced immunity.

References

1. Valdez Y et al. Influence of the microbiota on vaccine effectiveness. Trends Immunol. 2014;35(11):526-37.

2. Lynn MA et al. Early-life antibiotic-driven dysbiosis leads to dysregulated vaccine immune responses in mice. Cell Host Microbe. 2018;23(5):653-60.e5.

3. Hagan T et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019;178(6):1313-28.e13.

4. Chapman T et al. Antibiotic use and vaccine antibody levels. Pediatrics. 2022;149(5);1-17. doi: 10.1542/peds.2021-052061.