TOPLINE:

The estimated number of US adults who consumed at least one of the six most frequently reported hepatotoxic botanicals in the last 30 days is similar to the number of patients prescribed potentially hepatotoxic drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs) and simvastatin.

METHODOLOGY:

• Herbal and dietary supplements (HDS) are an increasingly common source of drug hepatotoxicity cases, but their prevalence and the reasons for their use among the general population are uncertain.
• This survey study evaluated nationally representative data from 9685 adults (mean age, 47.5 years; 51.8% women) enrolled in the National Health and Nutrition Examination Survey (NHANES) between January 2017 and March 2020.
• Participants reported their use of HDS and prescription drugs through personal interviews for a 30-day period prior to the survey date.
• Researchers compared the clinical features and baseline demographic characteristics of users of six potentially hepatotoxic botanicals (ie, turmeric, green tea, Garcinia cambogia, black cohosh, red yeast rice, and ashwagandha) with those of nonusers.
• The prevalence of use of these at-risk botanicals was compared with that of widely prescribed potentially hepatotoxic medications, including NSAIDs, simvastatin, and sertraline.

TAKEAWAY:

• In the cohort of 9685 participants, 4.7% of individuals reported consumption of at least one of the six potentially hepatotoxic botanicals in the past 30 days, with turmeric being the most common, followed by green tea.
• Extrapolating the survey data, researchers estimated that 15.6 million US adults use at least one of these six botanicals, which is comparable to the number of those prescribed potentially hepatotoxic drugs, including NSAIDs (14.8 million) and simvastatin (14.0 million). Sertraline use was lower (7.7 million).
• Most individuals used these botanicals without the recommendation of their healthcare provider.
• Those using botanicals were more likely to be older (adjusted odds ratio [aOR], 2.36; P = .04 for 40-59 years; aOR, 3.96; P = .001 for ≥ 60 years), to have some college education (aOR, 4.78; P < .001), and to have arthritis (aOR, 2.27; P < .001) than nonusers.
• The most common reasons for using any of these six potential hepatotoxic botanicals were to improve or maintain health or to prevent health problems or boost immunity.

IN PRACTICE:

“In light of the lack of regulatory oversight on the manufacturing and testing of botanical products, it is recommended that clinicians obtain a full medication and HDS use history when evaluating patients with unexplained symptoms or liver test abnormalities,” the authors wrote.

SOURCE:

The study, led by Alisa Likhitsup, MD, MPH, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, was published online in JAMA Network Open. 

LIMITATIONS:

The survey response rate was low at 43.9% for adults aged ≥ 20 years. As NHANES is a cross-sectional study, the causal relationship between consumption of the six botanicals of interest and the development of liver injury could not be determined. The use of HDS products and medications was self-reported in NHANES and not independently verified using source documents. 

DISCLOSURES:

This study did not report any source of funding. Two authors declared receiving grants from pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

The estimated number of US adults who consumed at least one of the six most frequently reported hepatotoxic botanicals in the last 30 days is similar to the number of patients prescribed potentially hepatotoxic drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs) and simvastatin.

METHODOLOGY:

• Herbal and dietary supplements (HDS) are an increasingly common source of drug hepatotoxicity cases, but their prevalence and the reasons for their use among the general population are uncertain.
• This survey study evaluated nationally representative data from 9685 adults (mean age, 47.5 years; 51.8% women) enrolled in the National Health and Nutrition Examination Survey (NHANES) between January 2017 and March 2020.
• Participants reported their use of HDS and prescription drugs through personal interviews for a 30-day period prior to the survey date.
• Researchers compared the clinical features and baseline demographic characteristics of users of six potentially hepatotoxic botanicals (ie, turmeric, green tea, Garcinia cambogia, black cohosh, red yeast rice, and ashwagandha) with those of nonusers.
• The prevalence of use of these at-risk botanicals was compared with that of widely prescribed potentially hepatotoxic medications, including NSAIDs, simvastatin, and sertraline.

TAKEAWAY:

• In the cohort of 9685 participants, 4.7% of individuals reported consumption of at least one of the six potentially hepatotoxic botanicals in the past 30 days, with turmeric being the most common, followed by green tea.
• Extrapolating the survey data, researchers estimated that 15.6 million US adults use at least one of these six botanicals, which is comparable to the number of those prescribed potentially hepatotoxic drugs, including NSAIDs (14.8 million) and simvastatin (14.0 million). Sertraline use was lower (7.7 million).
• Most individuals used these botanicals without the recommendation of their healthcare provider.
• Those using botanicals were more likely to be older (adjusted odds ratio [aOR], 2.36; P = .04 for 40-59 years; aOR, 3.96; P = .001 for ≥ 60 years), to have some college education (aOR, 4.78; P < .001), and to have arthritis (aOR, 2.27; P < .001) than nonusers.
• The most common reasons for using any of these six potential hepatotoxic botanicals were to improve or maintain health or to prevent health problems or boost immunity.

IN PRACTICE:

“In light of the lack of regulatory oversight on the manufacturing and testing of botanical products, it is recommended that clinicians obtain a full medication and HDS use history when evaluating patients with unexplained symptoms or liver test abnormalities,” the authors wrote.

SOURCE:

The study, led by Alisa Likhitsup, MD, MPH, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, was published online in JAMA Network Open. 

LIMITATIONS:

The survey response rate was low at 43.9% for adults aged ≥ 20 years. As NHANES is a cross-sectional study, the causal relationship between consumption of the six botanicals of interest and the development of liver injury could not be determined. The use of HDS products and medications was self-reported in NHANES and not independently verified using source documents. 

DISCLOSURES:

This study did not report any source of funding. Two authors declared receiving grants from pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

The estimated number of US adults who consumed at least one of the six most frequently reported hepatotoxic botanicals in the last 30 days is similar to the number of patients prescribed potentially hepatotoxic drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs) and simvastatin.

METHODOLOGY:

• Herbal and dietary supplements (HDS) are an increasingly common source of drug hepatotoxicity cases, but their prevalence and the reasons for their use among the general population are uncertain.
• This survey study evaluated nationally representative data from 9685 adults (mean age, 47.5 years; 51.8% women) enrolled in the National Health and Nutrition Examination Survey (NHANES) between January 2017 and March 2020.
• Participants reported their use of HDS and prescription drugs through personal interviews for a 30-day period prior to the survey date.
• Researchers compared the clinical features and baseline demographic characteristics of users of six potentially hepatotoxic botanicals (ie, turmeric, green tea, Garcinia cambogia, black cohosh, red yeast rice, and ashwagandha) with those of nonusers.
• The prevalence of use of these at-risk botanicals was compared with that of widely prescribed potentially hepatotoxic medications, including NSAIDs, simvastatin, and sertraline.

TAKEAWAY:

• In the cohort of 9685 participants, 4.7% of individuals reported consumption of at least one of the six potentially hepatotoxic botanicals in the past 30 days, with turmeric being the most common, followed by green tea.
• Extrapolating the survey data, researchers estimated that 15.6 million US adults use at least one of these six botanicals, which is comparable to the number of those prescribed potentially hepatotoxic drugs, including NSAIDs (14.8 million) and simvastatin (14.0 million). Sertraline use was lower (7.7 million).
• Most individuals used these botanicals without the recommendation of their healthcare provider.
• Those using botanicals were more likely to be older (adjusted odds ratio [aOR], 2.36; P = .04 for 40-59 years; aOR, 3.96; P = .001 for ≥ 60 years), to have some college education (aOR, 4.78; P < .001), and to have arthritis (aOR, 2.27; P < .001) than nonusers.
• The most common reasons for using any of these six potential hepatotoxic botanicals were to improve or maintain health or to prevent health problems or boost immunity.

IN PRACTICE:

“In light of the lack of regulatory oversight on the manufacturing and testing of botanical products, it is recommended that clinicians obtain a full medication and HDS use history when evaluating patients with unexplained symptoms or liver test abnormalities,” the authors wrote.

SOURCE:

The study, led by Alisa Likhitsup, MD, MPH, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, was published online in JAMA Network Open. 

LIMITATIONS:

The survey response rate was low at 43.9% for adults aged ≥ 20 years. As NHANES is a cross-sectional study, the causal relationship between consumption of the six botanicals of interest and the development of liver injury could not be determined. The use of HDS products and medications was self-reported in NHANES and not independently verified using source documents. 

DISCLOSURES:

This study did not report any source of funding. Two authors declared receiving grants from pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

Is going sugar free really good advice for patients with cardiometabolic risk factors? 

That’s the question raised by new Cleveland Clinic research, which suggests that consuming erythritol, a sweetener widely found in sugar-free and keto food products, could spur a prothrombotic response. 

In the study, published in Arteriosclerosis, Thrombosis, and Vascular Biology, 10 healthy participants ate 30 grams of erythritol. Thirty minutes later, their blood showed enhanced platelet aggregation and increased markers of platelet responsiveness and activation. 

Specifically, the researchers saw enhanced stimulus-dependent release of serotonin (a marker of platelet dense granules) and CXCL4 (a platelet alpha-granule marker). 

“ With every single person, you see a prothrombotic effect with every single test that we did,” said study author Stanley Hazen, MD, PhD, chair of the Department of Cardiovascular & Metabolic Sciences at Cleveland Clinic in Ohio. By contrast, participants who ate 30 grams of glucose saw no such effect. 

The erythritol itself does not activate the platelets, Dr. Hazen said, rather it lowers the threshold for triggering a response. This could make someone more prone to clotting, raising heart attack and stroke risk over time.

Though the mechanism is unknown, Dr. Hazen has an idea. 

“There appears to be a receptor on platelets that is recognizing and sensing these sugar alcohols,” Dr. Hazen said, “much in the same way your taste bud for sweet is a receptor for recognizing a glucose or sugar molecule.” 

“We’re very interested in trying to figure out what the receptor is,” Dr. Hazen said, “because I think that then becomes a very interesting potential target for further investigation and study into how this is linked to causing heart disease.”
 

The Past and Future of Erythritol Research

In 2001, the Food and Drug Administration classified erythritol as a “generally recognized as safe” food additive. A sugar alcohol that occurs naturally in foods like melon and grapes, erythritol is also manufactured by fermenting sugars. It’s about 70% as sweet as table sugar. Humans also produce small amounts of erythritol naturally: Our blood cells make it from glucose via the pentose phosphate pathway. 

Previous research from Dr. Hazen’s group linked erythritol to a risk for major adverse cardiovascular events and clotting. 

“Based on their previous study, I think this was a really important study to do in healthy individuals,” said Martha Field, PhD, assistant professor in the Division of Nutritional Sciences at Cornell University, Ithaca, New York, who was not involved in the study.

The earlier paper analyzed blood samples from participants with unknown erythritol intake, including some taken before the sweetener, and it was as widespread as it is today. That made disentangling the effects of eating erythritol vs naturally producing it more difficult. 

By showing that eating erythritol raises markers associated with thrombosis, the new paper reinforces the importance of thinking about and developing a deeper understanding of what we put into our bodies. 

“This paper was conducted in healthy individuals — might this be particularly dangerous for individuals who are at increased risk of clotting?” asked Dr. Field. “There are lots of genetic polymorphisms that increase your risk for clotting disorders or your propensity to form thrombosis.” 

Field would like to see similar analyses of xylitol and sorbitol, other sugar alcohols found in sugar-free foods. And she called for more studies on erythritol that look at lower erythritol consumption over longer time periods. 

Registered dietitian nutritionist Valisa E. Hedrick, PhD, agreed: Much more work is needed in this area, particularly in higher-risk groups, such as those with prediabetes and diabetes, said Dr. Hedrick, an associate professor in the Department of Human Nutrition, Foods, and Exercise at Virginia Tech, Blacksburg, who was not involved in the study. 

“Because this study was conducted in healthy individuals, the impact of a small dose of glucose was negligible, as their body can effectively regulate blood glucose levels,” she said. “Because high blood glucose concentrations have also been shown to increase platelet reactivity, and consequently increase thrombosis potential, individuals who are not able to regulate their blood glucose levels, such as those with prediabetes and diabetes, could potentially see a similar effect on the body as erythritol when consuming large amounts of sugar.” 

At the same time, “individuals with diabetes or prediabetes may be more inclined to consume erythritol as an alternative to sugar,” Dr. Hedrick added. “It will be important to design studies that include these individuals to determine if erythritol has an additive adverse effect on cardiac event risk.”
 

Criticism and Impact 

Critics have suggested the 30-gram dose of erythritol ingested by study participants is unrealistic. Dr. Hazen said that it’s not. 

Erythritol is often recommended as a one-to-one sugar replacement. And you could top 30 grams with a few servings of erythritol-sweetened ice cream or soda, Dr. Hazen said. 

“The dose that we used, it’s on the high end, but it’s well within a physiologically relevant level,” he said. 

Still others say the results are only relevant for people with preexisting heart trouble. But Dr. Hazen said they matter for the masses. 

“I think there’s a significant health concern at a population level that this work is underscoring,” he said. 

After all, heart disease risk factors like obesity, hypertension, diabetes, and smoking are common and quickly add up. 

“If you look at middle-aged America, most people who experience a heart attack or stroke do not know that they have coronary artery disease, and the first recognition of it is that event,” Dr. Hazen said. 

For now, Dr. Hazen recommends eating real sugar in moderation. He hopes future research will reveal a nonnutritive sweetener that doesn’t activate platelets. 
 

The Bigger Picture

The new research adds yet another piece to the puzzle of whether nonnutritive sweeteners are better than sugar. 

“I think these results are concerning,” said JoAnn E. Manson, MD, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts. They “ may help explain the surprising results in some observational studies that artificial sweeteners are linked to an increased risk of cardiovascular disease.”

Dr. Manson, who was not involved in the new study, has conducted other research linking artificial sweetener use with stroke risk.

In an upcoming randomized clinical study, her team is comparing head-to-head sugar-sweetened beverages, drinks sweetened with calorie-free substitutes, and water to determine which is best for a range of cardiometabolic outcomes. 

“We need more research on this question,” she said, “because these artificial sweeteners are commonly used, and many people are assuming that their health outcomes will be better with the artificial sweeteners than with sugar-sweetened products.”

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

Is going sugar free really good advice for patients with cardiometabolic risk factors? 

That’s the question raised by new Cleveland Clinic research, which suggests that consuming erythritol, a sweetener widely found in sugar-free and keto food products, could spur a prothrombotic response. 

In the study, published in Arteriosclerosis, Thrombosis, and Vascular Biology, 10 healthy participants ate 30 grams of erythritol. Thirty minutes later, their blood showed enhanced platelet aggregation and increased markers of platelet responsiveness and activation. 

Specifically, the researchers saw enhanced stimulus-dependent release of serotonin (a marker of platelet dense granules) and CXCL4 (a platelet alpha-granule marker). 

“ With every single person, you see a prothrombotic effect with every single test that we did,” said study author Stanley Hazen, MD, PhD, chair of the Department of Cardiovascular & Metabolic Sciences at Cleveland Clinic in Ohio. By contrast, participants who ate 30 grams of glucose saw no such effect. 

The erythritol itself does not activate the platelets, Dr. Hazen said, rather it lowers the threshold for triggering a response. This could make someone more prone to clotting, raising heart attack and stroke risk over time.

Though the mechanism is unknown, Dr. Hazen has an idea. 

“There appears to be a receptor on platelets that is recognizing and sensing these sugar alcohols,” Dr. Hazen said, “much in the same way your taste bud for sweet is a receptor for recognizing a glucose or sugar molecule.” 

“We’re very interested in trying to figure out what the receptor is,” Dr. Hazen said, “because I think that then becomes a very interesting potential target for further investigation and study into how this is linked to causing heart disease.”
 

The Past and Future of Erythritol Research

In 2001, the Food and Drug Administration classified erythritol as a “generally recognized as safe” food additive. A sugar alcohol that occurs naturally in foods like melon and grapes, erythritol is also manufactured by fermenting sugars. It’s about 70% as sweet as table sugar. Humans also produce small amounts of erythritol naturally: Our blood cells make it from glucose via the pentose phosphate pathway. 

Previous research from Dr. Hazen’s group linked erythritol to a risk for major adverse cardiovascular events and clotting. 

“Based on their previous study, I think this was a really important study to do in healthy individuals,” said Martha Field, PhD, assistant professor in the Division of Nutritional Sciences at Cornell University, Ithaca, New York, who was not involved in the study.

The earlier paper analyzed blood samples from participants with unknown erythritol intake, including some taken before the sweetener, and it was as widespread as it is today. That made disentangling the effects of eating erythritol vs naturally producing it more difficult. 

By showing that eating erythritol raises markers associated with thrombosis, the new paper reinforces the importance of thinking about and developing a deeper understanding of what we put into our bodies. 

“This paper was conducted in healthy individuals — might this be particularly dangerous for individuals who are at increased risk of clotting?” asked Dr. Field. “There are lots of genetic polymorphisms that increase your risk for clotting disorders or your propensity to form thrombosis.” 

Field would like to see similar analyses of xylitol and sorbitol, other sugar alcohols found in sugar-free foods. And she called for more studies on erythritol that look at lower erythritol consumption over longer time periods. 

Registered dietitian nutritionist Valisa E. Hedrick, PhD, agreed: Much more work is needed in this area, particularly in higher-risk groups, such as those with prediabetes and diabetes, said Dr. Hedrick, an associate professor in the Department of Human Nutrition, Foods, and Exercise at Virginia Tech, Blacksburg, who was not involved in the study. 

“Because this study was conducted in healthy individuals, the impact of a small dose of glucose was negligible, as their body can effectively regulate blood glucose levels,” she said. “Because high blood glucose concentrations have also been shown to increase platelet reactivity, and consequently increase thrombosis potential, individuals who are not able to regulate their blood glucose levels, such as those with prediabetes and diabetes, could potentially see a similar effect on the body as erythritol when consuming large amounts of sugar.” 

At the same time, “individuals with diabetes or prediabetes may be more inclined to consume erythritol as an alternative to sugar,” Dr. Hedrick added. “It will be important to design studies that include these individuals to determine if erythritol has an additive adverse effect on cardiac event risk.”
 

Criticism and Impact 

Critics have suggested the 30-gram dose of erythritol ingested by study participants is unrealistic. Dr. Hazen said that it’s not. 

Erythritol is often recommended as a one-to-one sugar replacement. And you could top 30 grams with a few servings of erythritol-sweetened ice cream or soda, Dr. Hazen said. 

“The dose that we used, it’s on the high end, but it’s well within a physiologically relevant level,” he said. 

Still others say the results are only relevant for people with preexisting heart trouble. But Dr. Hazen said they matter for the masses. 

“I think there’s a significant health concern at a population level that this work is underscoring,” he said. 

After all, heart disease risk factors like obesity, hypertension, diabetes, and smoking are common and quickly add up. 

“If you look at middle-aged America, most people who experience a heart attack or stroke do not know that they have coronary artery disease, and the first recognition of it is that event,” Dr. Hazen said. 

For now, Dr. Hazen recommends eating real sugar in moderation. He hopes future research will reveal a nonnutritive sweetener that doesn’t activate platelets. 
 

The Bigger Picture

The new research adds yet another piece to the puzzle of whether nonnutritive sweeteners are better than sugar. 

“I think these results are concerning,” said JoAnn E. Manson, MD, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts. They “ may help explain the surprising results in some observational studies that artificial sweeteners are linked to an increased risk of cardiovascular disease.”

Dr. Manson, who was not involved in the new study, has conducted other research linking artificial sweetener use with stroke risk.

In an upcoming randomized clinical study, her team is comparing head-to-head sugar-sweetened beverages, drinks sweetened with calorie-free substitutes, and water to determine which is best for a range of cardiometabolic outcomes. 

“We need more research on this question,” she said, “because these artificial sweeteners are commonly used, and many people are assuming that their health outcomes will be better with the artificial sweeteners than with sugar-sweetened products.”

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

Is going sugar free really good advice for patients with cardiometabolic risk factors? 

That’s the question raised by new Cleveland Clinic research, which suggests that consuming erythritol, a sweetener widely found in sugar-free and keto food products, could spur a prothrombotic response. 

In the study, published in Arteriosclerosis, Thrombosis, and Vascular Biology, 10 healthy participants ate 30 grams of erythritol. Thirty minutes later, their blood showed enhanced platelet aggregation and increased markers of platelet responsiveness and activation. 

Specifically, the researchers saw enhanced stimulus-dependent release of serotonin (a marker of platelet dense granules) and CXCL4 (a platelet alpha-granule marker). 

“ With every single person, you see a prothrombotic effect with every single test that we did,” said study author Stanley Hazen, MD, PhD, chair of the Department of Cardiovascular & Metabolic Sciences at Cleveland Clinic in Ohio. By contrast, participants who ate 30 grams of glucose saw no such effect. 

The erythritol itself does not activate the platelets, Dr. Hazen said, rather it lowers the threshold for triggering a response. This could make someone more prone to clotting, raising heart attack and stroke risk over time.

Though the mechanism is unknown, Dr. Hazen has an idea. 

“There appears to be a receptor on platelets that is recognizing and sensing these sugar alcohols,” Dr. Hazen said, “much in the same way your taste bud for sweet is a receptor for recognizing a glucose or sugar molecule.” 

“We’re very interested in trying to figure out what the receptor is,” Dr. Hazen said, “because I think that then becomes a very interesting potential target for further investigation and study into how this is linked to causing heart disease.”
 

The Past and Future of Erythritol Research

In 2001, the Food and Drug Administration classified erythritol as a “generally recognized as safe” food additive. A sugar alcohol that occurs naturally in foods like melon and grapes, erythritol is also manufactured by fermenting sugars. It’s about 70% as sweet as table sugar. Humans also produce small amounts of erythritol naturally: Our blood cells make it from glucose via the pentose phosphate pathway. 

Previous research from Dr. Hazen’s group linked erythritol to a risk for major adverse cardiovascular events and clotting. 

“Based on their previous study, I think this was a really important study to do in healthy individuals,” said Martha Field, PhD, assistant professor in the Division of Nutritional Sciences at Cornell University, Ithaca, New York, who was not involved in the study.

The earlier paper analyzed blood samples from participants with unknown erythritol intake, including some taken before the sweetener, and it was as widespread as it is today. That made disentangling the effects of eating erythritol vs naturally producing it more difficult. 

By showing that eating erythritol raises markers associated with thrombosis, the new paper reinforces the importance of thinking about and developing a deeper understanding of what we put into our bodies. 

“This paper was conducted in healthy individuals — might this be particularly dangerous for individuals who are at increased risk of clotting?” asked Dr. Field. “There are lots of genetic polymorphisms that increase your risk for clotting disorders or your propensity to form thrombosis.” 

Field would like to see similar analyses of xylitol and sorbitol, other sugar alcohols found in sugar-free foods. And she called for more studies on erythritol that look at lower erythritol consumption over longer time periods. 

Registered dietitian nutritionist Valisa E. Hedrick, PhD, agreed: Much more work is needed in this area, particularly in higher-risk groups, such as those with prediabetes and diabetes, said Dr. Hedrick, an associate professor in the Department of Human Nutrition, Foods, and Exercise at Virginia Tech, Blacksburg, who was not involved in the study. 

“Because this study was conducted in healthy individuals, the impact of a small dose of glucose was negligible, as their body can effectively regulate blood glucose levels,” she said. “Because high blood glucose concentrations have also been shown to increase platelet reactivity, and consequently increase thrombosis potential, individuals who are not able to regulate their blood glucose levels, such as those with prediabetes and diabetes, could potentially see a similar effect on the body as erythritol when consuming large amounts of sugar.” 

At the same time, “individuals with diabetes or prediabetes may be more inclined to consume erythritol as an alternative to sugar,” Dr. Hedrick added. “It will be important to design studies that include these individuals to determine if erythritol has an additive adverse effect on cardiac event risk.”
 

Criticism and Impact 

Critics have suggested the 30-gram dose of erythritol ingested by study participants is unrealistic. Dr. Hazen said that it’s not. 

Erythritol is often recommended as a one-to-one sugar replacement. And you could top 30 grams with a few servings of erythritol-sweetened ice cream or soda, Dr. Hazen said. 

“The dose that we used, it’s on the high end, but it’s well within a physiologically relevant level,” he said. 

Still others say the results are only relevant for people with preexisting heart trouble. But Dr. Hazen said they matter for the masses. 

“I think there’s a significant health concern at a population level that this work is underscoring,” he said. 

After all, heart disease risk factors like obesity, hypertension, diabetes, and smoking are common and quickly add up. 

“If you look at middle-aged America, most people who experience a heart attack or stroke do not know that they have coronary artery disease, and the first recognition of it is that event,” Dr. Hazen said. 

For now, Dr. Hazen recommends eating real sugar in moderation. He hopes future research will reveal a nonnutritive sweetener that doesn’t activate platelets. 
 

The Bigger Picture

The new research adds yet another piece to the puzzle of whether nonnutritive sweeteners are better than sugar. 

“I think these results are concerning,” said JoAnn E. Manson, MD, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts. They “ may help explain the surprising results in some observational studies that artificial sweeteners are linked to an increased risk of cardiovascular disease.”

Dr. Manson, who was not involved in the new study, has conducted other research linking artificial sweetener use with stroke risk.

In an upcoming randomized clinical study, her team is comparing head-to-head sugar-sweetened beverages, drinks sweetened with calorie-free substitutes, and water to determine which is best for a range of cardiometabolic outcomes. 

“We need more research on this question,” she said, “because these artificial sweeteners are commonly used, and many people are assuming that their health outcomes will be better with the artificial sweeteners than with sugar-sweetened products.”

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

The Diagnosis: Mycobacterium marinum Infection

A repeat excisional biopsy showed suppurative granulomatous dermatitis with negative stains for infectious organisms; however, tissue culture grew Mycobacterium marinum. The patient had a history of exposure to fish tanks, which are a potential habitat for nontuberculous mycobacteria. These bacteria can enter the body through a minor laceration or cut in the skin, which was likely due to her occupation and pet care activities.¹ Her fish tank exposure combined with the cutaneous findings of a long-standing indurated plaque with proximal nodular lymphangitis made M marinum infection the most likely diagnosis.²

Due to the limited specificity and sensitivity of patient symptoms, histologic staining, and direct microscopy, the gold standard for diagnosing acid-fast bacilli is tissue culture. ³ Tissue polymerase chain reaction testing is most useful in identifying the species of mycobacteria when histologic stains identify acid-fast bacilli but repeated tissue cultures are negative.⁴ With M marinum, a high clinical suspicion is needed to acquire a positive tissue culture because it needs to be grown for several weeks and at a temperature of 30 °C.⁵ Therefore, the physician should inform the laboratory if there is any suspicion for M marinum to increase the likelihood of obtaining a positive culture.

The differential diagnosis for M marinum infection includes other skin diseases that can cause nodular lymphangitis (also known as sporotrichoid spread) such as sporotrichosis, leishmaniasis, and certain bacterial and fungal infections. Although cat scratch disease, which is caused by Bartonella henselae, can appear similar to M marinum on histopathology, it clinically manifests with a single papulovesicular lesion at the site of inoculation that then forms a central eschar and resolves within a few weeks. Cat scratch disease typically causes painful lymphadenopathy, but it does not cause nodular lymphangitis or sporotrichoid spread.⁶ Sporotrichosis can have a similar clinical and histologic manifestation to M marinum infection, but the patient history typically includes exposure to Sporothrix schenckii through gardening or other contact with thorns, plants, or soil.² Cutaneous sarcoidosis can have a similar clinical appearance to M marinum infection, but nodular lymphangitis does not occur and histopathology would demonstrate noncaseating epithelioid cell granulomas.⁷ Lastly, although vegetative pyoderma gangrenosum can have some of the same histologic findings as M marinum, it typically also demonstrates sinus tract formation, which was not present in our case. Additionally, vegetative pyoderma gangrenosum manifests with a verrucous and pustular plaque that would not have lymphocutaneous spread.⁸

Treatment of cutaneous M marinum infection is guided by antibiotic susceptibility testing. One regimen is clarithromycin (500 mg twice daily⁹) plus ethambutol. ¹⁰ Treatment often entails a multidrug combination due to the high rates of antibiotic resistance. Other antibiotics that potentially can be used include rifampin, trimethoprim-sulfamethoxazole, minocycline, and quinolones. The treatment duration typically is more than 3 months, and therapy is continued for 4 to 6 weeks after the skin lesions resolve.¹¹ Excision of the lesion is reserved for patients with M marinum infection that fails to respond to antibiotic therapy.⁵

The Diagnosis: Mycobacterium marinum Infection

A repeat excisional biopsy showed suppurative granulomatous dermatitis with negative stains for infectious organisms; however, tissue culture grew Mycobacterium marinum. The patient had a history of exposure to fish tanks, which are a potential habitat for nontuberculous mycobacteria. These bacteria can enter the body through a minor laceration or cut in the skin, which was likely due to her occupation and pet care activities.¹ Her fish tank exposure combined with the cutaneous findings of a long-standing indurated plaque with proximal nodular lymphangitis made M marinum infection the most likely diagnosis.²

Due to the limited specificity and sensitivity of patient symptoms, histologic staining, and direct microscopy, the gold standard for diagnosing acid-fast bacilli is tissue culture. ³ Tissue polymerase chain reaction testing is most useful in identifying the species of mycobacteria when histologic stains identify acid-fast bacilli but repeated tissue cultures are negative.⁴ With M marinum, a high clinical suspicion is needed to acquire a positive tissue culture because it needs to be grown for several weeks and at a temperature of 30 °C.⁵ Therefore, the physician should inform the laboratory if there is any suspicion for M marinum to increase the likelihood of obtaining a positive culture.

The differential diagnosis for M marinum infection includes other skin diseases that can cause nodular lymphangitis (also known as sporotrichoid spread) such as sporotrichosis, leishmaniasis, and certain bacterial and fungal infections. Although cat scratch disease, which is caused by Bartonella henselae, can appear similar to M marinum on histopathology, it clinically manifests with a single papulovesicular lesion at the site of inoculation that then forms a central eschar and resolves within a few weeks. Cat scratch disease typically causes painful lymphadenopathy, but it does not cause nodular lymphangitis or sporotrichoid spread.⁶ Sporotrichosis can have a similar clinical and histologic manifestation to M marinum infection, but the patient history typically includes exposure to Sporothrix schenckii through gardening or other contact with thorns, plants, or soil.² Cutaneous sarcoidosis can have a similar clinical appearance to M marinum infection, but nodular lymphangitis does not occur and histopathology would demonstrate noncaseating epithelioid cell granulomas.⁷ Lastly, although vegetative pyoderma gangrenosum can have some of the same histologic findings as M marinum, it typically also demonstrates sinus tract formation, which was not present in our case. Additionally, vegetative pyoderma gangrenosum manifests with a verrucous and pustular plaque that would not have lymphocutaneous spread.⁸

Treatment of cutaneous M marinum infection is guided by antibiotic susceptibility testing. One regimen is clarithromycin (500 mg twice daily⁹) plus ethambutol. ¹⁰ Treatment often entails a multidrug combination due to the high rates of antibiotic resistance. Other antibiotics that potentially can be used include rifampin, trimethoprim-sulfamethoxazole, minocycline, and quinolones. The treatment duration typically is more than 3 months, and therapy is continued for 4 to 6 weeks after the skin lesions resolve.¹¹ Excision of the lesion is reserved for patients with M marinum infection that fails to respond to antibiotic therapy.⁵

The Diagnosis: Mycobacterium marinum Infection

A repeat excisional biopsy showed suppurative granulomatous dermatitis with negative stains for infectious organisms; however, tissue culture grew Mycobacterium marinum. The patient had a history of exposure to fish tanks, which are a potential habitat for nontuberculous mycobacteria. These bacteria can enter the body through a minor laceration or cut in the skin, which was likely due to her occupation and pet care activities.¹ Her fish tank exposure combined with the cutaneous findings of a long-standing indurated plaque with proximal nodular lymphangitis made M marinum infection the most likely diagnosis.²

Due to the limited specificity and sensitivity of patient symptoms, histologic staining, and direct microscopy, the gold standard for diagnosing acid-fast bacilli is tissue culture. ³ Tissue polymerase chain reaction testing is most useful in identifying the species of mycobacteria when histologic stains identify acid-fast bacilli but repeated tissue cultures are negative.⁴ With M marinum, a high clinical suspicion is needed to acquire a positive tissue culture because it needs to be grown for several weeks and at a temperature of 30 °C.⁵ Therefore, the physician should inform the laboratory if there is any suspicion for M marinum to increase the likelihood of obtaining a positive culture.

The differential diagnosis for M marinum infection includes other skin diseases that can cause nodular lymphangitis (also known as sporotrichoid spread) such as sporotrichosis, leishmaniasis, and certain bacterial and fungal infections. Although cat scratch disease, which is caused by Bartonella henselae, can appear similar to M marinum on histopathology, it clinically manifests with a single papulovesicular lesion at the site of inoculation that then forms a central eschar and resolves within a few weeks. Cat scratch disease typically causes painful lymphadenopathy, but it does not cause nodular lymphangitis or sporotrichoid spread.⁶ Sporotrichosis can have a similar clinical and histologic manifestation to M marinum infection, but the patient history typically includes exposure to Sporothrix schenckii through gardening or other contact with thorns, plants, or soil.² Cutaneous sarcoidosis can have a similar clinical appearance to M marinum infection, but nodular lymphangitis does not occur and histopathology would demonstrate noncaseating epithelioid cell granulomas.⁷ Lastly, although vegetative pyoderma gangrenosum can have some of the same histologic findings as M marinum, it typically also demonstrates sinus tract formation, which was not present in our case. Additionally, vegetative pyoderma gangrenosum manifests with a verrucous and pustular plaque that would not have lymphocutaneous spread.⁸

Treatment of cutaneous M marinum infection is guided by antibiotic susceptibility testing. One regimen is clarithromycin (500 mg twice daily⁹) plus ethambutol. ¹⁰ Treatment often entails a multidrug combination due to the high rates of antibiotic resistance. Other antibiotics that potentially can be used include rifampin, trimethoprim-sulfamethoxazole, minocycline, and quinolones. The treatment duration typically is more than 3 months, and therapy is continued for 4 to 6 weeks after the skin lesions resolve.¹¹ Excision of the lesion is reserved for patients with M marinum infection that fails to respond to antibiotic therapy.⁵

TOPLINE:

Cannabis-related disorders are associated with a more than a threefold increased risk for head and neck cancer. The study analyzed data from over four million patients, highlighting the potential carcinogenic effects of the substance.

METHODOLOGY:

• Researchers analyzed data from a globally federated health research network TriNetX, which included over 90 million men and women from 64 health care organizations in the United States.
• More than 4.1 million patients were included in the analysis, including 116,076 individuals diagnosed with cannabis-related disorder and 3.9 million without the disorder. Cannabis-related disorders involve the excessive use of cannabis with associated psychosocial symptoms, such as impaired social and/or occupational functioning.
• Patients with cannabis-related disorder were matched with those without the disorder based on demographic characteristics, alcohol-related disorders, and tobacco use.
• The primary outcome was the diagnosis of head and neck cancer, including subsites such as oral, oropharyngeal, nasopharyngeal, laryngeal, hypopharyngeal, and salivary gland malignancies.
• Propensity score matching and Poisson regression analysis were used to compare the incidence of head and neck cancers between the groups.

TAKEAWAY:

• According to the researchers, patients with a cannabis-related disorder had a higher risk for any head and neck cancer (relative risk [RR], 3.49; 95% CI, 2.78-4.39) than those without the disorder.
• The risk for specific cancers was also higher in the group with cannabis-related disorders, including oral (RR, 2.51; 95% CI, 1.81-3.47) and oropharyngeal malignancies (RR, 4.90; 95% CI, 2.99-8.02).
• The RR for laryngeal cancer was significantly higher in the patients with a cannabis-related disorder (RR, 8.39; 95% CI, 4.72-14.90).
• The findings suggest that cannabis use disorder is associated with an increased risk for head and neck cancers, highlighting the need for further research to understand the mechanisms involved.

IN PRACTICE:

“In this cohort study, cannabis disorder diagnosis was independently associated with greater risk of subsequent development of any [head or neck cancer] as well as cancers in various subsites of the head and neck among US adults. When limited to cases of [such cancers] occurring greater than 1 year after cannabis use disorder diagnosis, many of the associations increased, demonstrating additional strength in the association,” the authors of the study wrote. 

“The association of cannabis and head and neck cancer in this study spanned 2 decades during a rapid growth in use. If this association is causative, the burden of [head and neck cancers] attributable to cannabis will continue to increase, and perhaps dramatically,” said the authors of an editorial accompanying the journal article. “Given that cannabis is now a $20 billion industry in the US alone with expanding availability, use, and popularity, this may be “déjà vu, all over again” without appropriate research to understand the potential carcinogenic and salutatory effects of cannabis. Or, in the words of Yogi Berra, “If you don’t know where you are going, you might wind up someplace else.”
 

SOURCE:

The study was led by Tyler J. Gallagher and Niels C. Kokot, MD, at the Keck School of Medicine of the University of Southern California in Los Angeles. It was published online in JAMA Otolaryngology–Head & Neck Surgery.

LIMITATIONS:

The study had limited information about cohort composition and length of follow-up, which may affect the generalizability of the findings. The lack of direct exposure duration, intensity, and dosage information limits the ability to analyze dose-response relationships. Potential inconsistency of diagnosis and reliance on medical record codes may introduce bias. Cannabis use is likely underreported, which could decrease the relative risks discovered. The study was further limited by the lack of information on dosage and frequency of cannabis use, as well as some controls, including alcohol and tobacco use.

DISCLOSURES:

Gallagher disclosed receiving grants from the Keck School of Medicine of the University of Southern California, Los Angeles. Additional disclosures are noted in the original article.

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

TOPLINE:

Cannabis-related disorders are associated with a more than a threefold increased risk for head and neck cancer. The study analyzed data from over four million patients, highlighting the potential carcinogenic effects of the substance.

METHODOLOGY:

• Researchers analyzed data from a globally federated health research network TriNetX, which included over 90 million men and women from 64 health care organizations in the United States.
• More than 4.1 million patients were included in the analysis, including 116,076 individuals diagnosed with cannabis-related disorder and 3.9 million without the disorder. Cannabis-related disorders involve the excessive use of cannabis with associated psychosocial symptoms, such as impaired social and/or occupational functioning.
• Patients with cannabis-related disorder were matched with those without the disorder based on demographic characteristics, alcohol-related disorders, and tobacco use.
• The primary outcome was the diagnosis of head and neck cancer, including subsites such as oral, oropharyngeal, nasopharyngeal, laryngeal, hypopharyngeal, and salivary gland malignancies.
• Propensity score matching and Poisson regression analysis were used to compare the incidence of head and neck cancers between the groups.

TAKEAWAY:

• According to the researchers, patients with a cannabis-related disorder had a higher risk for any head and neck cancer (relative risk [RR], 3.49; 95% CI, 2.78-4.39) than those without the disorder.
• The risk for specific cancers was also higher in the group with cannabis-related disorders, including oral (RR, 2.51; 95% CI, 1.81-3.47) and oropharyngeal malignancies (RR, 4.90; 95% CI, 2.99-8.02).
• The RR for laryngeal cancer was significantly higher in the patients with a cannabis-related disorder (RR, 8.39; 95% CI, 4.72-14.90).
• The findings suggest that cannabis use disorder is associated with an increased risk for head and neck cancers, highlighting the need for further research to understand the mechanisms involved.

IN PRACTICE:

“In this cohort study, cannabis disorder diagnosis was independently associated with greater risk of subsequent development of any [head or neck cancer] as well as cancers in various subsites of the head and neck among US adults. When limited to cases of [such cancers] occurring greater than 1 year after cannabis use disorder diagnosis, many of the associations increased, demonstrating additional strength in the association,” the authors of the study wrote. 

“The association of cannabis and head and neck cancer in this study spanned 2 decades during a rapid growth in use. If this association is causative, the burden of [head and neck cancers] attributable to cannabis will continue to increase, and perhaps dramatically,” said the authors of an editorial accompanying the journal article. “Given that cannabis is now a $20 billion industry in the US alone with expanding availability, use, and popularity, this may be “déjà vu, all over again” without appropriate research to understand the potential carcinogenic and salutatory effects of cannabis. Or, in the words of Yogi Berra, “If you don’t know where you are going, you might wind up someplace else.”
 

SOURCE:

The study was led by Tyler J. Gallagher and Niels C. Kokot, MD, at the Keck School of Medicine of the University of Southern California in Los Angeles. It was published online in JAMA Otolaryngology–Head & Neck Surgery.

LIMITATIONS:

The study had limited information about cohort composition and length of follow-up, which may affect the generalizability of the findings. The lack of direct exposure duration, intensity, and dosage information limits the ability to analyze dose-response relationships. Potential inconsistency of diagnosis and reliance on medical record codes may introduce bias. Cannabis use is likely underreported, which could decrease the relative risks discovered. The study was further limited by the lack of information on dosage and frequency of cannabis use, as well as some controls, including alcohol and tobacco use.

DISCLOSURES:

Gallagher disclosed receiving grants from the Keck School of Medicine of the University of Southern California, Los Angeles. Additional disclosures are noted in the original article.

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

TOPLINE:

Cannabis-related disorders are associated with a more than a threefold increased risk for head and neck cancer. The study analyzed data from over four million patients, highlighting the potential carcinogenic effects of the substance.

METHODOLOGY:

• Researchers analyzed data from a globally federated health research network TriNetX, which included over 90 million men and women from 64 health care organizations in the United States.
• More than 4.1 million patients were included in the analysis, including 116,076 individuals diagnosed with cannabis-related disorder and 3.9 million without the disorder. Cannabis-related disorders involve the excessive use of cannabis with associated psychosocial symptoms, such as impaired social and/or occupational functioning.
• Patients with cannabis-related disorder were matched with those without the disorder based on demographic characteristics, alcohol-related disorders, and tobacco use.
• The primary outcome was the diagnosis of head and neck cancer, including subsites such as oral, oropharyngeal, nasopharyngeal, laryngeal, hypopharyngeal, and salivary gland malignancies.
• Propensity score matching and Poisson regression analysis were used to compare the incidence of head and neck cancers between the groups.

TAKEAWAY:

• According to the researchers, patients with a cannabis-related disorder had a higher risk for any head and neck cancer (relative risk [RR], 3.49; 95% CI, 2.78-4.39) than those without the disorder.
• The risk for specific cancers was also higher in the group with cannabis-related disorders, including oral (RR, 2.51; 95% CI, 1.81-3.47) and oropharyngeal malignancies (RR, 4.90; 95% CI, 2.99-8.02).
• The RR for laryngeal cancer was significantly higher in the patients with a cannabis-related disorder (RR, 8.39; 95% CI, 4.72-14.90).
• The findings suggest that cannabis use disorder is associated with an increased risk for head and neck cancers, highlighting the need for further research to understand the mechanisms involved.

IN PRACTICE:

“In this cohort study, cannabis disorder diagnosis was independently associated with greater risk of subsequent development of any [head or neck cancer] as well as cancers in various subsites of the head and neck among US adults. When limited to cases of [such cancers] occurring greater than 1 year after cannabis use disorder diagnosis, many of the associations increased, demonstrating additional strength in the association,” the authors of the study wrote. 

“The association of cannabis and head and neck cancer in this study spanned 2 decades during a rapid growth in use. If this association is causative, the burden of [head and neck cancers] attributable to cannabis will continue to increase, and perhaps dramatically,” said the authors of an editorial accompanying the journal article. “Given that cannabis is now a $20 billion industry in the US alone with expanding availability, use, and popularity, this may be “déjà vu, all over again” without appropriate research to understand the potential carcinogenic and salutatory effects of cannabis. Or, in the words of Yogi Berra, “If you don’t know where you are going, you might wind up someplace else.”
 

SOURCE:

The study was led by Tyler J. Gallagher and Niels C. Kokot, MD, at the Keck School of Medicine of the University of Southern California in Los Angeles. It was published online in JAMA Otolaryngology–Head & Neck Surgery.

LIMITATIONS:

The study had limited information about cohort composition and length of follow-up, which may affect the generalizability of the findings. The lack of direct exposure duration, intensity, and dosage information limits the ability to analyze dose-response relationships. Potential inconsistency of diagnosis and reliance on medical record codes may introduce bias. Cannabis use is likely underreported, which could decrease the relative risks discovered. The study was further limited by the lack of information on dosage and frequency of cannabis use, as well as some controls, including alcohol and tobacco use.

DISCLOSURES:

Gallagher disclosed receiving grants from the Keck School of Medicine of the University of Southern California, Los Angeles. Additional disclosures are noted in the original article.

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

After endoscopic mucosal resection (EMR), both snare tip soft coagulation (STSC) and argon plasma coagulation (APC) appear superior to no thermal margin treatment, according to a recent study.

Since STSC was faster to apply than APC and results in lower cost and plastic waste (because of APC requiring an additional catheter), STSC was the preferred option.

“The reduction in recurrence rate with thermal margin treatment is arguably the most important development in endoscopic mucosal resection in the past 2 decades,” said lead author Douglas Rex, MD, AGAF, a distinguished professor emeritus at the Indiana University School of Medicine and director of endoscopy at Indiana University Hospitals, both in Indianapolis.

“Margin thermal therapy with STSC should now be standard treatment after piecemeal EMR in the colorectum,” he said. “Before applying STSC, the endoscopist must ensure that the entire lesion is resected down to the submucosa. Then STSC should be aggressively applied to 100% of the margin.”

The study was published in Clinical Gastroenterology and Hepatology .
 

Comparing Treatments

Dr. Rex and colleagues performed a randomized three-arm trial in nine U.S. centers, comparing STSC with APC and no margin treatment in patients undergoing colorectal EMR of nonpedunculated lesions of 15 mm or greater.

All lesions underwent conventional injection and snare resection EMR using electrocautery, but the endoscopist chose the injection fluid and snare type and size. Areas with residual polyp that weren’t removable by snare resection because of flat shape or fibrosis were removed by hot or cold avulsion. After that, patients were randomized to one of the three arms.

Patients were scheduled for a follow-up appointment six months after the initial EMR. Any visible recurrence was resected using methods at the discretion of the endoscopist, and if no visible recurrence was present, EMR site biopsies were recommended.

Among 384 patients with 414 lesions, 308 patients with 328 lesions completed at least one follow-up appointment. The median interval to the first follow-up was 6.4 months, ranging from 2 to 37 months. The primary endpoint was the presence of recurrent or residual polyp at first follow-up.

The median polyp size was 25 mm, and 65 of the 414 polyps (15.7%) were 15-19 mm in size. Overall, 14.8% of lesions were resected en bloc, with no difference between the study arms.

The proportion of lesions with residual polyp at first follow-up was 4.6% with STSC, 9.3% with APC, and 21.4% among control subjects with no margin treatment.

The odds of having a residual polyp at first follow-up were lower for STSC and APC when compared with control subjects (odds ratio [OR] of 0.182 and 0.341, or P = .001 and P = .01, respectively). There wasn’t a significant difference in the odds of recurrence between STSC and APC (OR, 1.874).

In 259 lesions in 248 patients that were 20 mm or greater, the recurrence rates at first follow-up were 5.9% for STSC, 10.1% for APC, and 25.9% for the control group. In these lesions, STSC and APC remained associated with a lower risk of recurrence versus the control (OR, 0.18 and 0.323, respectively). The difference in recurrence rates between STSC and APC wasn’t significant.

Even still, STSC took less time to apply than APC, with a median time of 3.35 minutes vs 4.08 minutes.

The rates of adverse events were low, with no difference between the three arms. There were no immediate or delayed perforations in any arm, and the overall occurrence of delayed bleeding was low at 3.6%.

“I think STSC won the trial because it was numerically (though not statistically) superior to APC, was faster to apply, and using STSC results in lower cost and less plastic compared to APC,” Dr. Rex said.
 

Additional Considerations

Based on charges at the nine U.S. centers and a survey of two manufacturers, APC catheters typically cost $175-$275 each, the study authors wrote, noting that APC results in increased cost, plastic waste because of the catheter, and carbon emissions associated with its manufacture.

“What we’re seeing — now over several trials — is STSC appears to be the most effective method of treating the edges, and it’s inexpensive because it uses the same device used for snare resection, so there’s no incremental cost for the device,” said Michael Wallace, MD, professor of medicine and director of the digestive diseases research program at Mayo Clinic, Jacksonville, Florida.

Dr. Wallace, who wasn’t involved with this study, has researched thermal ablation after EMR, including both the margins and the base.

“The single most important message now is that patients shouldn’t be getting surgical resections for endoscopically treatable polyps,” he said. “We see many patients who are told they need to get surgery, but overwhelmingly, the data shows we can remove polyps without surgery.”

Dr. Rex and several authors declared fees and grants from numerous companies outside of this study. Dr. Wallace reported no relevant disclosures.

After endoscopic mucosal resection (EMR), both snare tip soft coagulation (STSC) and argon plasma coagulation (APC) appear superior to no thermal margin treatment, according to a recent study.

Since STSC was faster to apply than APC and results in lower cost and plastic waste (because of APC requiring an additional catheter), STSC was the preferred option.

“The reduction in recurrence rate with thermal margin treatment is arguably the most important development in endoscopic mucosal resection in the past 2 decades,” said lead author Douglas Rex, MD, AGAF, a distinguished professor emeritus at the Indiana University School of Medicine and director of endoscopy at Indiana University Hospitals, both in Indianapolis.

“Margin thermal therapy with STSC should now be standard treatment after piecemeal EMR in the colorectum,” he said. “Before applying STSC, the endoscopist must ensure that the entire lesion is resected down to the submucosa. Then STSC should be aggressively applied to 100% of the margin.”

The study was published in Clinical Gastroenterology and Hepatology .
 

Comparing Treatments

Dr. Rex and colleagues performed a randomized three-arm trial in nine U.S. centers, comparing STSC with APC and no margin treatment in patients undergoing colorectal EMR of nonpedunculated lesions of 15 mm or greater.

All lesions underwent conventional injection and snare resection EMR using electrocautery, but the endoscopist chose the injection fluid and snare type and size. Areas with residual polyp that weren’t removable by snare resection because of flat shape or fibrosis were removed by hot or cold avulsion. After that, patients were randomized to one of the three arms.

Patients were scheduled for a follow-up appointment six months after the initial EMR. Any visible recurrence was resected using methods at the discretion of the endoscopist, and if no visible recurrence was present, EMR site biopsies were recommended.

Among 384 patients with 414 lesions, 308 patients with 328 lesions completed at least one follow-up appointment. The median interval to the first follow-up was 6.4 months, ranging from 2 to 37 months. The primary endpoint was the presence of recurrent or residual polyp at first follow-up.

The median polyp size was 25 mm, and 65 of the 414 polyps (15.7%) were 15-19 mm in size. Overall, 14.8% of lesions were resected en bloc, with no difference between the study arms.

The proportion of lesions with residual polyp at first follow-up was 4.6% with STSC, 9.3% with APC, and 21.4% among control subjects with no margin treatment.

The odds of having a residual polyp at first follow-up were lower for STSC and APC when compared with control subjects (odds ratio [OR] of 0.182 and 0.341, or P = .001 and P = .01, respectively). There wasn’t a significant difference in the odds of recurrence between STSC and APC (OR, 1.874).

In 259 lesions in 248 patients that were 20 mm or greater, the recurrence rates at first follow-up were 5.9% for STSC, 10.1% for APC, and 25.9% for the control group. In these lesions, STSC and APC remained associated with a lower risk of recurrence versus the control (OR, 0.18 and 0.323, respectively). The difference in recurrence rates between STSC and APC wasn’t significant.

Even still, STSC took less time to apply than APC, with a median time of 3.35 minutes vs 4.08 minutes.

The rates of adverse events were low, with no difference between the three arms. There were no immediate or delayed perforations in any arm, and the overall occurrence of delayed bleeding was low at 3.6%.

“I think STSC won the trial because it was numerically (though not statistically) superior to APC, was faster to apply, and using STSC results in lower cost and less plastic compared to APC,” Dr. Rex said.
 

Additional Considerations

Based on charges at the nine U.S. centers and a survey of two manufacturers, APC catheters typically cost $175-$275 each, the study authors wrote, noting that APC results in increased cost, plastic waste because of the catheter, and carbon emissions associated with its manufacture.

“What we’re seeing — now over several trials — is STSC appears to be the most effective method of treating the edges, and it’s inexpensive because it uses the same device used for snare resection, so there’s no incremental cost for the device,” said Michael Wallace, MD, professor of medicine and director of the digestive diseases research program at Mayo Clinic, Jacksonville, Florida.

Dr. Wallace, who wasn’t involved with this study, has researched thermal ablation after EMR, including both the margins and the base.

“The single most important message now is that patients shouldn’t be getting surgical resections for endoscopically treatable polyps,” he said. “We see many patients who are told they need to get surgery, but overwhelmingly, the data shows we can remove polyps without surgery.”

Dr. Rex and several authors declared fees and grants from numerous companies outside of this study. Dr. Wallace reported no relevant disclosures.

After endoscopic mucosal resection (EMR), both snare tip soft coagulation (STSC) and argon plasma coagulation (APC) appear superior to no thermal margin treatment, according to a recent study.

Since STSC was faster to apply than APC and results in lower cost and plastic waste (because of APC requiring an additional catheter), STSC was the preferred option.

“The reduction in recurrence rate with thermal margin treatment is arguably the most important development in endoscopic mucosal resection in the past 2 decades,” said lead author Douglas Rex, MD, AGAF, a distinguished professor emeritus at the Indiana University School of Medicine and director of endoscopy at Indiana University Hospitals, both in Indianapolis.

“Margin thermal therapy with STSC should now be standard treatment after piecemeal EMR in the colorectum,” he said. “Before applying STSC, the endoscopist must ensure that the entire lesion is resected down to the submucosa. Then STSC should be aggressively applied to 100% of the margin.”

The study was published in Clinical Gastroenterology and Hepatology .
 

Comparing Treatments

Dr. Rex and colleagues performed a randomized three-arm trial in nine U.S. centers, comparing STSC with APC and no margin treatment in patients undergoing colorectal EMR of nonpedunculated lesions of 15 mm or greater.

All lesions underwent conventional injection and snare resection EMR using electrocautery, but the endoscopist chose the injection fluid and snare type and size. Areas with residual polyp that weren’t removable by snare resection because of flat shape or fibrosis were removed by hot or cold avulsion. After that, patients were randomized to one of the three arms.

Patients were scheduled for a follow-up appointment six months after the initial EMR. Any visible recurrence was resected using methods at the discretion of the endoscopist, and if no visible recurrence was present, EMR site biopsies were recommended.

Among 384 patients with 414 lesions, 308 patients with 328 lesions completed at least one follow-up appointment. The median interval to the first follow-up was 6.4 months, ranging from 2 to 37 months. The primary endpoint was the presence of recurrent or residual polyp at first follow-up.

The median polyp size was 25 mm, and 65 of the 414 polyps (15.7%) were 15-19 mm in size. Overall, 14.8% of lesions were resected en bloc, with no difference between the study arms.

The proportion of lesions with residual polyp at first follow-up was 4.6% with STSC, 9.3% with APC, and 21.4% among control subjects with no margin treatment.

The odds of having a residual polyp at first follow-up were lower for STSC and APC when compared with control subjects (odds ratio [OR] of 0.182 and 0.341, or P = .001 and P = .01, respectively). There wasn’t a significant difference in the odds of recurrence between STSC and APC (OR, 1.874).

In 259 lesions in 248 patients that were 20 mm or greater, the recurrence rates at first follow-up were 5.9% for STSC, 10.1% for APC, and 25.9% for the control group. In these lesions, STSC and APC remained associated with a lower risk of recurrence versus the control (OR, 0.18 and 0.323, respectively). The difference in recurrence rates between STSC and APC wasn’t significant.

Even still, STSC took less time to apply than APC, with a median time of 3.35 minutes vs 4.08 minutes.

The rates of adverse events were low, with no difference between the three arms. There were no immediate or delayed perforations in any arm, and the overall occurrence of delayed bleeding was low at 3.6%.

“I think STSC won the trial because it was numerically (though not statistically) superior to APC, was faster to apply, and using STSC results in lower cost and less plastic compared to APC,” Dr. Rex said.
 

Additional Considerations

Based on charges at the nine U.S. centers and a survey of two manufacturers, APC catheters typically cost $175-$275 each, the study authors wrote, noting that APC results in increased cost, plastic waste because of the catheter, and carbon emissions associated with its manufacture.

“What we’re seeing — now over several trials — is STSC appears to be the most effective method of treating the edges, and it’s inexpensive because it uses the same device used for snare resection, so there’s no incremental cost for the device,” said Michael Wallace, MD, professor of medicine and director of the digestive diseases research program at Mayo Clinic, Jacksonville, Florida.

Dr. Wallace, who wasn’t involved with this study, has researched thermal ablation after EMR, including both the margins and the base.

“The single most important message now is that patients shouldn’t be getting surgical resections for endoscopically treatable polyps,” he said. “We see many patients who are told they need to get surgery, but overwhelmingly, the data shows we can remove polyps without surgery.”

Dr. Rex and several authors declared fees and grants from numerous companies outside of this study. Dr. Wallace reported no relevant disclosures.

As the prevalence of obesity grows in the United States and worldwide, more solutions are needed at more levels of care to help patients, according to a series of presentations during the American Gastroenterological Association (AGA) Postgraduate Course held at Digestive Disease Week® (DDW) in May.

Gastroenterologists can step up as part of a multidisciplinary response to provide treatment — with a range of lifestyle interventions, pharmacological options, and bariatric endoscopic possibilities — based on a patient’s needs and preferences.

“Obesity is in our clinics. We’re usually the first line of obesity, and that’s why we need to know it, learn how to manage it, and understand the complications,” said Andres Acosta, MD, an associate professor of medicine and gastroenterologist at Mayo Clinic, Rochester, Minnesota, and principal investigator of Mayo’s Precision Medicine for Obesity Laboratory.

Obesity tops the charts as the most significant chronic disease in the world, affecting 130 million patients in the United States and 1 billion globally, he said, and those numbers will only climb higher in coming years. By 2030, the United States is projected to have an obesity prevalence of 50% and overweight prevalence of 80%, with every state having a prevalence greater than 35%.

The alarming prevalence rates matter not because of aesthetics or personal preference, he noted, but because of the major associations with premature death, cardiovascular disease, stroke, type 2 diabetes, numerous cancers, and 280 other diseases.

“Choose the organ you like, and obesity is a major contributor to its most important disease,” Dr. Acosta said. “Obesity affects every single disease and every single organ in the gastrointestinal system, so it’s essential that we actually manage this.”

Based on current recommendations focused on body mass index (BMI), diet, exercise, and behavioral therapy are suggested for a BMI of 25 or higher, followed by pharmacotherapy for a BMI greater than 27 with comorbidities, endoscopic procedures for a BMI greater than 30, and surgical options for a BMI greater than 40 or BMI greater than 30 with comorbidities. At each step, clinicians can start shared decision-making conversations with patients about the best options for them.

“We’re moving from a pyramid approach where we tell patients to choose one intervention toward multidisciplinary programs where we offer interventions in combination,” Dr. Acosta said, recommending AGA’s POWER - Practice Guide on Obesity and Weight Management Education and Resources . Other AGA resources for physicians treating patients with obesity include the AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity , and the Obesity Resource Center on the AGA website .
 

Progress in Pharmacotherapy

In recent years, developments focused on glucagon-like peptide 1 (GLP-1) receptor agonists, such as semaglutide and tirzepatide, have “changed the conversation about obesity,” Dr. Acosta said. For the first time, medications not only reduce weight but also cardiovascular disease risks, which were previously only observed with bariatric surgery.

Additional GLP-1 options are in research pipelines. During the next 3 years, for instance, more medications will focus on how the gut signals to the brain through intestinal hormones, targeting GLP-1, glucose-dependent insulinotropic polypeptide, and other receptors. Leading the pipeline, Eli Lilly’s retatrutide shows promise, with weight loss and comorbidity improvement reported similar to or better than tirzepatide. Additional data from phase 3 trials are forthcoming.

In clinical practice, major conversations remain about gastrointestinal side effects, particularly gastroparesis, that may pose a risk for aspiration in upper endoscopy. Gastroenterologists should feel comfortable about managing these types of side effects when starting patients on these medications, Dr. Acosta said, but also continue to ask questions about side effects and the latest research developments.

Of course, major obstacles remain regarding patient access, insurance coverage, cost-effective options, and heterogeneous patient responses. At the Mayo Clinic, Dr. Acosta and colleagues are researching and targeting obesity phenotypes — such as the “hungry gut” or “hungry brain” — to improve weight loss outcomes and patient adherence.

Ultimately, he said, the most important obstacle is our healthcare system. “We cannot afford to manage obesity with expensive procedures or expensive medications.”
 

Efficacy of Endobariatrics

For patients with a BMI of 30 or higher, minimally invasive bariatric endoscopic procedures can lead to weight loss, improvement in metabolic outcomes, and fewer adverse events compared to bariatric surgery, said Violeta Popov, MD, director of bariatric endoscopy at the New York Veterans Affairs Harbor Healthcare System in New York City.

For example, intragastric balloons — marketed under the names Orbera and Spatz — work by altering the rate of gastric emptying. They’re placed temporarily and removed after several months, and Spatz can be adjusted while in place, either by removing or adding volume if needed. Data show that associated weight loss can lead to improvements in insulin resistance, visceral obesity, dyslipidemia, high blood pressure, liver enzymes, metabolic dysfunction–associated steatotic liver disease (MASLD), and metabolic dysfunction–associated steatohepatitis (MASH).

Although the majority of patients undergoing minimally invasive procedures do experience adverse events such as nausea and vomiting, symptoms tend to subside in the first few weeks, Dr. Popov said. At the same time, gastroesophageal reflux disease (GERD) can worsen in patients who have experienced it, so proton pump inhibitors are recommended for as long as the balloon is inserted.

Endoscopic sleeve gastroplasty has become the most prevalent endobariatric method in Dr. Popov’s practice during the past few years. The procedure uses full thickness sutures placed with an endoscopic suturing device called OverStitch, to decrease the size of the opening into the stomach. In previous trials, patients lost up to 40 pounds, and more than 80% maintained the lost weight up to 5 years. The procedure, which showed no worsening of GERD, works by preserving gastric contractility while delaying gastric emptying.

Dr. Popov noted one of the main challenges is training and credentialing, with many patients not having access to those who can perform these procedures. As a diplomate of the American Board of Obesity Medicine, Dr. Popov highlighted the need for bariatric endoscopy fellowships or training during GI fellowships, post-fellowship hands-on courses, and competency training with simulators.

“It’s not just technical competency in performing a procedure — it’s also the administrative work of setting up a multidisciplinary program,” she said. “It’s very important to understand obesity as a disease and learn how to manage it.”
 

Monitoring MASLD

Linked strongly to insulin resistance, MASLD prevalence is increasing worldwide as obesity increases, reaching 30% in the United States and even higher among certain patient populations, said Sonali Paul, MD, an assistant professor of medicine and hepatologist at the Center for Liver Diseases at the University of Chicago Medicine in Illinois.

University of Chicago

The good news is that the associations between MASLD and obesity also move the other way — if patients lose weight and improve cardiovascular risk factors, MASLD can improve as well. Notably, steatosis can disappear at 3% weight loss, inflammation decreases at 5% weight loss, MASH resolution occurs at 7% weight loss, and fibrosis improves at 10% weight loss.

Primarily, Dr. Paul and colleagues have focused on lifestyle interventions, especially diet, by working carefully with dietitians. A modified Mediterranean diet with olive oil and monounsaturated fats can decrease steatosis on MRI, as compared with a high-fat/low-carb diet, and it also appears to decrease mortality, cardiovascular disease, and obesity. As part of the modified diet, carbohydrates are limited to 30 grams per meal per day.

“We really want to tailor the diet to cultural and personal preferences,” she said. “I’m South Asian, and when I tell my South Asian patients not to eat rice, they don’t love that, so we work with them to meet them where they are.”

Dr. Paul recommends physical activity interventions, proper sleep hygiene, treatment of obstructive sleep apnea, pharmacological options, and bariatric solutions to reduce weight, improve insulin resistance, and target MASLD risk factors. For instance, recent phase 2b studies indicate semaglutide can lead to MASH resolution, with phase 3 trial data expected by the end of 2024.

In addition, resmetirom, a liver-directed thyroid hormone receptor beta selective agonist — the first Food and Drug Administration–approved drug for MASH — achieved both primary endpoints of MASH resolution and fibrosis improvement. American Association for the Study of Liver Diseases guidelines are forthcoming about who should use the drug, Dr. Paul said.

“In terms of the paradigm that I think about with MASLD, we want to target other causes and diagnose advanced fibrosis, treat risk factors, and target MASH through treatment,” she said.
 

Considering the Community Perspective

Community-based clinicians face a unique set of challenges when addressing obesity through a multidisciplinary approach and longitudinal care, but it remains vital as more practices see increased patient loads with obesity-related GI comorbidities, said Pooja Singhal, MD, assistant professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and founder/president of Oklahoma Gastro Health and Wellness.

Oklahoma Gastro Health and Wellness

Dr. Singhal noted obesity-related associations with earlier presentations of GERD, elevated liver enzymes, MASLD, MASH, IBS, IBD, gallbladder disease, colon polyps, and GI cancers.

“Gastroenterologists, as most of us are board-certified internists, are in a unique position to offer both pharmacotherapy and endoscopic treatment,” she said. “The GI comorbidities provide an opportunity for early intervention, and we’re seeing a lot of side effects of antiobesity medications, so whether we like it or not, we are involved.”

The best practices at the community level start with a patient-centric approach, Dr. Singhal said. Although clinicians are already time constrained and focused on addressing GI-related comorbidities, using the 5A’s framework can help:

• Asking if the patient is ready to talk
• Assessing for factors contributing to obesity
• Advising them of treatment options
• Agreeing on goals based on shared decision-making
• Assisting or Arranging the agreed-on plan.

During the assessment phase, Dr. Singhal suggested not only looking at medical and physical values but also secondary causes of weight gain, including the patient’s relationship with food, micronutrient deficiencies, psychosocial concerns, body image disorders, and triggers for eating.

During the advising phase, clinicians should consider multiple targets — such as diet, physical activity, and behavior — with a supervised and structured approach. Dr. Singhal and colleagues include a meal plan, aerobic activity, resistance training, behavior modification of eating habits, sleep hygiene, and patient self-monitoring through smartphone apps and wearables. Pharmacotherapy may be relevant and effective for some patients but less accessible for many, she noted.

Above all, Dr. Singhal recommended training through the American Board of Obesity Medicine, major GI society guidelines and conferences, American Society for Gastrointestinal Endoscopy STAR courses, and connecting with a multidisciplinary team of dietitians, coaches, physical therapists, and other GI specialists when possible.

“Most importantly, we’re dealing with decades of stigma and bias around this disease, where ‘you are what you eat,’ ” she said. “This mentality of ‘I can lose weight without help’ is a real challenge.”

As the prevalence of obesity grows in the United States and worldwide, more solutions are needed at more levels of care to help patients, according to a series of presentations during the American Gastroenterological Association (AGA) Postgraduate Course held at Digestive Disease Week® (DDW) in May.

Gastroenterologists can step up as part of a multidisciplinary response to provide treatment — with a range of lifestyle interventions, pharmacological options, and bariatric endoscopic possibilities — based on a patient’s needs and preferences.

“Obesity is in our clinics. We’re usually the first line of obesity, and that’s why we need to know it, learn how to manage it, and understand the complications,” said Andres Acosta, MD, an associate professor of medicine and gastroenterologist at Mayo Clinic, Rochester, Minnesota, and principal investigator of Mayo’s Precision Medicine for Obesity Laboratory.

Obesity tops the charts as the most significant chronic disease in the world, affecting 130 million patients in the United States and 1 billion globally, he said, and those numbers will only climb higher in coming years. By 2030, the United States is projected to have an obesity prevalence of 50% and overweight prevalence of 80%, with every state having a prevalence greater than 35%.

The alarming prevalence rates matter not because of aesthetics or personal preference, he noted, but because of the major associations with premature death, cardiovascular disease, stroke, type 2 diabetes, numerous cancers, and 280 other diseases.

“Choose the organ you like, and obesity is a major contributor to its most important disease,” Dr. Acosta said. “Obesity affects every single disease and every single organ in the gastrointestinal system, so it’s essential that we actually manage this.”

Based on current recommendations focused on body mass index (BMI), diet, exercise, and behavioral therapy are suggested for a BMI of 25 or higher, followed by pharmacotherapy for a BMI greater than 27 with comorbidities, endoscopic procedures for a BMI greater than 30, and surgical options for a BMI greater than 40 or BMI greater than 30 with comorbidities. At each step, clinicians can start shared decision-making conversations with patients about the best options for them.

“We’re moving from a pyramid approach where we tell patients to choose one intervention toward multidisciplinary programs where we offer interventions in combination,” Dr. Acosta said, recommending AGA’s POWER - Practice Guide on Obesity and Weight Management Education and Resources . Other AGA resources for physicians treating patients with obesity include the AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity , and the Obesity Resource Center on the AGA website .
 

Progress in Pharmacotherapy

In recent years, developments focused on glucagon-like peptide 1 (GLP-1) receptor agonists, such as semaglutide and tirzepatide, have “changed the conversation about obesity,” Dr. Acosta said. For the first time, medications not only reduce weight but also cardiovascular disease risks, which were previously only observed with bariatric surgery.

Additional GLP-1 options are in research pipelines. During the next 3 years, for instance, more medications will focus on how the gut signals to the brain through intestinal hormones, targeting GLP-1, glucose-dependent insulinotropic polypeptide, and other receptors. Leading the pipeline, Eli Lilly’s retatrutide shows promise, with weight loss and comorbidity improvement reported similar to or better than tirzepatide. Additional data from phase 3 trials are forthcoming.

In clinical practice, major conversations remain about gastrointestinal side effects, particularly gastroparesis, that may pose a risk for aspiration in upper endoscopy. Gastroenterologists should feel comfortable about managing these types of side effects when starting patients on these medications, Dr. Acosta said, but also continue to ask questions about side effects and the latest research developments.

Of course, major obstacles remain regarding patient access, insurance coverage, cost-effective options, and heterogeneous patient responses. At the Mayo Clinic, Dr. Acosta and colleagues are researching and targeting obesity phenotypes — such as the “hungry gut” or “hungry brain” — to improve weight loss outcomes and patient adherence.

Ultimately, he said, the most important obstacle is our healthcare system. “We cannot afford to manage obesity with expensive procedures or expensive medications.”
 

Efficacy of Endobariatrics

For patients with a BMI of 30 or higher, minimally invasive bariatric endoscopic procedures can lead to weight loss, improvement in metabolic outcomes, and fewer adverse events compared to bariatric surgery, said Violeta Popov, MD, director of bariatric endoscopy at the New York Veterans Affairs Harbor Healthcare System in New York City.

For example, intragastric balloons — marketed under the names Orbera and Spatz — work by altering the rate of gastric emptying. They’re placed temporarily and removed after several months, and Spatz can be adjusted while in place, either by removing or adding volume if needed. Data show that associated weight loss can lead to improvements in insulin resistance, visceral obesity, dyslipidemia, high blood pressure, liver enzymes, metabolic dysfunction–associated steatotic liver disease (MASLD), and metabolic dysfunction–associated steatohepatitis (MASH).

Although the majority of patients undergoing minimally invasive procedures do experience adverse events such as nausea and vomiting, symptoms tend to subside in the first few weeks, Dr. Popov said. At the same time, gastroesophageal reflux disease (GERD) can worsen in patients who have experienced it, so proton pump inhibitors are recommended for as long as the balloon is inserted.

Endoscopic sleeve gastroplasty has become the most prevalent endobariatric method in Dr. Popov’s practice during the past few years. The procedure uses full thickness sutures placed with an endoscopic suturing device called OverStitch, to decrease the size of the opening into the stomach. In previous trials, patients lost up to 40 pounds, and more than 80% maintained the lost weight up to 5 years. The procedure, which showed no worsening of GERD, works by preserving gastric contractility while delaying gastric emptying.

Dr. Popov noted one of the main challenges is training and credentialing, with many patients not having access to those who can perform these procedures. As a diplomate of the American Board of Obesity Medicine, Dr. Popov highlighted the need for bariatric endoscopy fellowships or training during GI fellowships, post-fellowship hands-on courses, and competency training with simulators.

“It’s not just technical competency in performing a procedure — it’s also the administrative work of setting up a multidisciplinary program,” she said. “It’s very important to understand obesity as a disease and learn how to manage it.”
 

Monitoring MASLD

Linked strongly to insulin resistance, MASLD prevalence is increasing worldwide as obesity increases, reaching 30% in the United States and even higher among certain patient populations, said Sonali Paul, MD, an assistant professor of medicine and hepatologist at the Center for Liver Diseases at the University of Chicago Medicine in Illinois.

University of Chicago

The good news is that the associations between MASLD and obesity also move the other way — if patients lose weight and improve cardiovascular risk factors, MASLD can improve as well. Notably, steatosis can disappear at 3% weight loss, inflammation decreases at 5% weight loss, MASH resolution occurs at 7% weight loss, and fibrosis improves at 10% weight loss.

Primarily, Dr. Paul and colleagues have focused on lifestyle interventions, especially diet, by working carefully with dietitians. A modified Mediterranean diet with olive oil and monounsaturated fats can decrease steatosis on MRI, as compared with a high-fat/low-carb diet, and it also appears to decrease mortality, cardiovascular disease, and obesity. As part of the modified diet, carbohydrates are limited to 30 grams per meal per day.

“We really want to tailor the diet to cultural and personal preferences,” she said. “I’m South Asian, and when I tell my South Asian patients not to eat rice, they don’t love that, so we work with them to meet them where they are.”

Dr. Paul recommends physical activity interventions, proper sleep hygiene, treatment of obstructive sleep apnea, pharmacological options, and bariatric solutions to reduce weight, improve insulin resistance, and target MASLD risk factors. For instance, recent phase 2b studies indicate semaglutide can lead to MASH resolution, with phase 3 trial data expected by the end of 2024.

In addition, resmetirom, a liver-directed thyroid hormone receptor beta selective agonist — the first Food and Drug Administration–approved drug for MASH — achieved both primary endpoints of MASH resolution and fibrosis improvement. American Association for the Study of Liver Diseases guidelines are forthcoming about who should use the drug, Dr. Paul said.

“In terms of the paradigm that I think about with MASLD, we want to target other causes and diagnose advanced fibrosis, treat risk factors, and target MASH through treatment,” she said.
 

Considering the Community Perspective

Community-based clinicians face a unique set of challenges when addressing obesity through a multidisciplinary approach and longitudinal care, but it remains vital as more practices see increased patient loads with obesity-related GI comorbidities, said Pooja Singhal, MD, assistant professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and founder/president of Oklahoma Gastro Health and Wellness.

Oklahoma Gastro Health and Wellness

Dr. Singhal noted obesity-related associations with earlier presentations of GERD, elevated liver enzymes, MASLD, MASH, IBS, IBD, gallbladder disease, colon polyps, and GI cancers.

“Gastroenterologists, as most of us are board-certified internists, are in a unique position to offer both pharmacotherapy and endoscopic treatment,” she said. “The GI comorbidities provide an opportunity for early intervention, and we’re seeing a lot of side effects of antiobesity medications, so whether we like it or not, we are involved.”

The best practices at the community level start with a patient-centric approach, Dr. Singhal said. Although clinicians are already time constrained and focused on addressing GI-related comorbidities, using the 5A’s framework can help:

• Asking if the patient is ready to talk
• Assessing for factors contributing to obesity
• Advising them of treatment options
• Agreeing on goals based on shared decision-making
• Assisting or Arranging the agreed-on plan.

During the assessment phase, Dr. Singhal suggested not only looking at medical and physical values but also secondary causes of weight gain, including the patient’s relationship with food, micronutrient deficiencies, psychosocial concerns, body image disorders, and triggers for eating.

During the advising phase, clinicians should consider multiple targets — such as diet, physical activity, and behavior — with a supervised and structured approach. Dr. Singhal and colleagues include a meal plan, aerobic activity, resistance training, behavior modification of eating habits, sleep hygiene, and patient self-monitoring through smartphone apps and wearables. Pharmacotherapy may be relevant and effective for some patients but less accessible for many, she noted.

Above all, Dr. Singhal recommended training through the American Board of Obesity Medicine, major GI society guidelines and conferences, American Society for Gastrointestinal Endoscopy STAR courses, and connecting with a multidisciplinary team of dietitians, coaches, physical therapists, and other GI specialists when possible.

“Most importantly, we’re dealing with decades of stigma and bias around this disease, where ‘you are what you eat,’ ” she said. “This mentality of ‘I can lose weight without help’ is a real challenge.”

As the prevalence of obesity grows in the United States and worldwide, more solutions are needed at more levels of care to help patients, according to a series of presentations during the American Gastroenterological Association (AGA) Postgraduate Course held at Digestive Disease Week® (DDW) in May.

Gastroenterologists can step up as part of a multidisciplinary response to provide treatment — with a range of lifestyle interventions, pharmacological options, and bariatric endoscopic possibilities — based on a patient’s needs and preferences.

“Obesity is in our clinics. We’re usually the first line of obesity, and that’s why we need to know it, learn how to manage it, and understand the complications,” said Andres Acosta, MD, an associate professor of medicine and gastroenterologist at Mayo Clinic, Rochester, Minnesota, and principal investigator of Mayo’s Precision Medicine for Obesity Laboratory.

Obesity tops the charts as the most significant chronic disease in the world, affecting 130 million patients in the United States and 1 billion globally, he said, and those numbers will only climb higher in coming years. By 2030, the United States is projected to have an obesity prevalence of 50% and overweight prevalence of 80%, with every state having a prevalence greater than 35%.

The alarming prevalence rates matter not because of aesthetics or personal preference, he noted, but because of the major associations with premature death, cardiovascular disease, stroke, type 2 diabetes, numerous cancers, and 280 other diseases.

“Choose the organ you like, and obesity is a major contributor to its most important disease,” Dr. Acosta said. “Obesity affects every single disease and every single organ in the gastrointestinal system, so it’s essential that we actually manage this.”

Based on current recommendations focused on body mass index (BMI), diet, exercise, and behavioral therapy are suggested for a BMI of 25 or higher, followed by pharmacotherapy for a BMI greater than 27 with comorbidities, endoscopic procedures for a BMI greater than 30, and surgical options for a BMI greater than 40 or BMI greater than 30 with comorbidities. At each step, clinicians can start shared decision-making conversations with patients about the best options for them.

“We’re moving from a pyramid approach where we tell patients to choose one intervention toward multidisciplinary programs where we offer interventions in combination,” Dr. Acosta said, recommending AGA’s POWER - Practice Guide on Obesity and Weight Management Education and Resources . Other AGA resources for physicians treating patients with obesity include the AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity , and the Obesity Resource Center on the AGA website .
 

Progress in Pharmacotherapy

In recent years, developments focused on glucagon-like peptide 1 (GLP-1) receptor agonists, such as semaglutide and tirzepatide, have “changed the conversation about obesity,” Dr. Acosta said. For the first time, medications not only reduce weight but also cardiovascular disease risks, which were previously only observed with bariatric surgery.

Additional GLP-1 options are in research pipelines. During the next 3 years, for instance, more medications will focus on how the gut signals to the brain through intestinal hormones, targeting GLP-1, glucose-dependent insulinotropic polypeptide, and other receptors. Leading the pipeline, Eli Lilly’s retatrutide shows promise, with weight loss and comorbidity improvement reported similar to or better than tirzepatide. Additional data from phase 3 trials are forthcoming.

In clinical practice, major conversations remain about gastrointestinal side effects, particularly gastroparesis, that may pose a risk for aspiration in upper endoscopy. Gastroenterologists should feel comfortable about managing these types of side effects when starting patients on these medications, Dr. Acosta said, but also continue to ask questions about side effects and the latest research developments.

Of course, major obstacles remain regarding patient access, insurance coverage, cost-effective options, and heterogeneous patient responses. At the Mayo Clinic, Dr. Acosta and colleagues are researching and targeting obesity phenotypes — such as the “hungry gut” or “hungry brain” — to improve weight loss outcomes and patient adherence.

Ultimately, he said, the most important obstacle is our healthcare system. “We cannot afford to manage obesity with expensive procedures or expensive medications.”
 

Efficacy of Endobariatrics

For patients with a BMI of 30 or higher, minimally invasive bariatric endoscopic procedures can lead to weight loss, improvement in metabolic outcomes, and fewer adverse events compared to bariatric surgery, said Violeta Popov, MD, director of bariatric endoscopy at the New York Veterans Affairs Harbor Healthcare System in New York City.

For example, intragastric balloons — marketed under the names Orbera and Spatz — work by altering the rate of gastric emptying. They’re placed temporarily and removed after several months, and Spatz can be adjusted while in place, either by removing or adding volume if needed. Data show that associated weight loss can lead to improvements in insulin resistance, visceral obesity, dyslipidemia, high blood pressure, liver enzymes, metabolic dysfunction–associated steatotic liver disease (MASLD), and metabolic dysfunction–associated steatohepatitis (MASH).

Although the majority of patients undergoing minimally invasive procedures do experience adverse events such as nausea and vomiting, symptoms tend to subside in the first few weeks, Dr. Popov said. At the same time, gastroesophageal reflux disease (GERD) can worsen in patients who have experienced it, so proton pump inhibitors are recommended for as long as the balloon is inserted.

Endoscopic sleeve gastroplasty has become the most prevalent endobariatric method in Dr. Popov’s practice during the past few years. The procedure uses full thickness sutures placed with an endoscopic suturing device called OverStitch, to decrease the size of the opening into the stomach. In previous trials, patients lost up to 40 pounds, and more than 80% maintained the lost weight up to 5 years. The procedure, which showed no worsening of GERD, works by preserving gastric contractility while delaying gastric emptying.

Dr. Popov noted one of the main challenges is training and credentialing, with many patients not having access to those who can perform these procedures. As a diplomate of the American Board of Obesity Medicine, Dr. Popov highlighted the need for bariatric endoscopy fellowships or training during GI fellowships, post-fellowship hands-on courses, and competency training with simulators.

“It’s not just technical competency in performing a procedure — it’s also the administrative work of setting up a multidisciplinary program,” she said. “It’s very important to understand obesity as a disease and learn how to manage it.”
 

Monitoring MASLD

Linked strongly to insulin resistance, MASLD prevalence is increasing worldwide as obesity increases, reaching 30% in the United States and even higher among certain patient populations, said Sonali Paul, MD, an assistant professor of medicine and hepatologist at the Center for Liver Diseases at the University of Chicago Medicine in Illinois.

University of Chicago

The good news is that the associations between MASLD and obesity also move the other way — if patients lose weight and improve cardiovascular risk factors, MASLD can improve as well. Notably, steatosis can disappear at 3% weight loss, inflammation decreases at 5% weight loss, MASH resolution occurs at 7% weight loss, and fibrosis improves at 10% weight loss.

Primarily, Dr. Paul and colleagues have focused on lifestyle interventions, especially diet, by working carefully with dietitians. A modified Mediterranean diet with olive oil and monounsaturated fats can decrease steatosis on MRI, as compared with a high-fat/low-carb diet, and it also appears to decrease mortality, cardiovascular disease, and obesity. As part of the modified diet, carbohydrates are limited to 30 grams per meal per day.

“We really want to tailor the diet to cultural and personal preferences,” she said. “I’m South Asian, and when I tell my South Asian patients not to eat rice, they don’t love that, so we work with them to meet them where they are.”

Dr. Paul recommends physical activity interventions, proper sleep hygiene, treatment of obstructive sleep apnea, pharmacological options, and bariatric solutions to reduce weight, improve insulin resistance, and target MASLD risk factors. For instance, recent phase 2b studies indicate semaglutide can lead to MASH resolution, with phase 3 trial data expected by the end of 2024.

In addition, resmetirom, a liver-directed thyroid hormone receptor beta selective agonist — the first Food and Drug Administration–approved drug for MASH — achieved both primary endpoints of MASH resolution and fibrosis improvement. American Association for the Study of Liver Diseases guidelines are forthcoming about who should use the drug, Dr. Paul said.

“In terms of the paradigm that I think about with MASLD, we want to target other causes and diagnose advanced fibrosis, treat risk factors, and target MASH through treatment,” she said.
 

Considering the Community Perspective

Community-based clinicians face a unique set of challenges when addressing obesity through a multidisciplinary approach and longitudinal care, but it remains vital as more practices see increased patient loads with obesity-related GI comorbidities, said Pooja Singhal, MD, assistant professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and founder/president of Oklahoma Gastro Health and Wellness.

Oklahoma Gastro Health and Wellness

Dr. Singhal noted obesity-related associations with earlier presentations of GERD, elevated liver enzymes, MASLD, MASH, IBS, IBD, gallbladder disease, colon polyps, and GI cancers.

“Gastroenterologists, as most of us are board-certified internists, are in a unique position to offer both pharmacotherapy and endoscopic treatment,” she said. “The GI comorbidities provide an opportunity for early intervention, and we’re seeing a lot of side effects of antiobesity medications, so whether we like it or not, we are involved.”

The best practices at the community level start with a patient-centric approach, Dr. Singhal said. Although clinicians are already time constrained and focused on addressing GI-related comorbidities, using the 5A’s framework can help:

• Asking if the patient is ready to talk
• Assessing for factors contributing to obesity
• Advising them of treatment options
• Agreeing on goals based on shared decision-making
• Assisting or Arranging the agreed-on plan.

During the assessment phase, Dr. Singhal suggested not only looking at medical and physical values but also secondary causes of weight gain, including the patient’s relationship with food, micronutrient deficiencies, psychosocial concerns, body image disorders, and triggers for eating.

During the advising phase, clinicians should consider multiple targets — such as diet, physical activity, and behavior — with a supervised and structured approach. Dr. Singhal and colleagues include a meal plan, aerobic activity, resistance training, behavior modification of eating habits, sleep hygiene, and patient self-monitoring through smartphone apps and wearables. Pharmacotherapy may be relevant and effective for some patients but less accessible for many, she noted.

Above all, Dr. Singhal recommended training through the American Board of Obesity Medicine, major GI society guidelines and conferences, American Society for Gastrointestinal Endoscopy STAR courses, and connecting with a multidisciplinary team of dietitians, coaches, physical therapists, and other GI specialists when possible.

“Most importantly, we’re dealing with decades of stigma and bias around this disease, where ‘you are what you eat,’ ” she said. “This mentality of ‘I can lose weight without help’ is a real challenge.”

The clinical manifestations of snakebites vary based on the species of snake, bite location, and amount and strength of the venom injected. Locally acting toxins in snake venom predominantly consist of enzymes, such as phospholipase A₂, that cause local tissue destruction and can result in pain, swelling, blistering, ecchymosis, and tissue necrosis at the site of the bite within hours to days after the bite.¹ Systemically acting toxins can target a wide variety of tissues and cause severe systemic complications including paralysis, rhabdomyolysis secondary to muscle damage, coagulopathy, sepsis, and cardiorespiratory failure.²

Although pain and swelling following snakebites typically resolve by 1 month after envenomation, copperhead snakes—a type of pit viper—may cause residual symptoms of pain and swelling lasting for a year or more.³ Additional cutaneous manifestations of copperhead snakebites include wound infections at the bite site, such as cellulitis and necrotizing fasciitis. More devastating complications that have been described following snake envenomation include tissue injury of an entire extremity and development of compartment syndrome, which requires urgent fasciotomy to prevent potential loss of the affected limb.⁴

Physicians should be aware of the potential complications of snakebites to properly manage and counsel their patients. We describe a 42-year-old woman with tender, erythematous, subcutaneous nodules persisting for 4 months following a copperhead snakebite. A biopsy confirmed the diagnosis of snakebite-associated erythema nodosum (EN).

Case Report

A 42-year-old woman presented to our clinic with progressive tender, pruritic, deep-seated, erythematous nodules in multiple locations on the legs after sustaining a bite by a copperhead snake on the left foot 4 months prior. The lesions tended to fluctuate in intensity. In the days following the bite, she initially developed painful red bumps on the left foot just proximal to the bite site with associated pain and swelling extending up to just below the left knee. She reported no other notable symptoms such as fever, arthralgia, fatigue, or gastrointestinal tract symptoms. Physical examination revealed bilateral pitting edema, which was worse in the left leg, along with multiple deep, palpable, tender subcutaneous nodules with erythematous surface change (Figure 1).

Workup performed by an outside provider over the previous month included 2 venous duplex ultrasounds of the left leg, which showed no signs of deep vein thrombosis. Additionally, the patient underwent lateral and anteroposterior radiographs of the left foot, tibia, and fibula, which showed no evidence of fracture.

Given the morphology and distribution of the lesions (Figure 2), EN was strongly favored as the cause of the symptoms, and a biopsy confirmed the diagnosis. All immunohistochemical stains including auramine-­rhodamine for acid-fast bacilli, Grocott-Gomori methenamine silver for fungal organisms, and Brown and Brenn were negative. Given the waxing and waning course of the lesions, which suggested an active neutrophilic rather than purely chronic granulomatous phase of EN, the patient was treated with colchicine 0.6 mg twice daily for 1 month.

Causes of EN and Clinical Manifestations

Erythema nodosum is a common form of septal panniculitis that can be precipitated by inflammatory conditions, infection, or medications (commonly oral contraceptive pills) but often is idiopathic.⁵ The acute phase is neutrophilic, with evolution over time to a granulomatous phase. Common etiologies include sarcoidosis; inflammatory bowel disease; and bacterial or fungal infections such as Streptococcus (especially common in children), histoplasmosis, and coccidioidomycosis. The patient was otherwise healthy and was not taking any medications that are known triggers of EN. A PubMed search of articles indexed for MEDLINE in the English-language literature using the terms copperhead snake bite, erythema nodosum snake, and copperhead snake erythema nodosum revealed no reports of EN following a bite from a copperhead snake; however, in one case, an adder bite led to erysipelas, likely due to disturbed blood and lymphatic flow, which then triggered EN.⁶ Additionally, EN has been reported as a delayed reaction to jellyfish stings.⁷

Clinical features of EN include the development of tender, erythematous, subcutaneous nodules and plaques most frequently over the pretibial region. Lesions typically evolve from raised, deep-seated nodules into flat indurated plaques over a span of weeks. Occasionally, there is a slight prodromal phase marked by nonspecific symptoms such as fever and arthralgia lasting for 3 to 6 days. Erythema nodosum typically results in spontaneous resolution after 4 to 8 weeks, and management involves treatment of any underlying condition with symptomatic care. Interestingly, our patient experienced persistent symptoms over the course of 4 months, with development of new nodular lesions throughout this time period. The most frequently used drugs for the management of symptomatic EN include nonsteroidal anti-inflammatory drugs, colchicine, and potassium iodide.⁸ A characteristic histologic finding of the granulomatous phase is the Miescher radial granuloma, which is a septal collection of histiocytes surrounding a cleft.⁹

Snakebite Reactions

Snakebites can result in a wide range of local and systemic manifestations, as snake venom may contain 20 or more toxins.¹⁰ Local complications of pit viper bites include pain, swelling, and fang marks; when examining fang marks, the presence of 2 distinct puncture wounds often indicates envenomation with a poisonous snake, whereas nonvenomous snakebites often result in smaller puncture wounds arranged in an arc. Following bites, pain can develop immediately and spread proximally up the affected limb, which occurred in our patient in the days following the bite. Intense local reactions can occur, as bites often result in intense edema of the affected limb spreading to the trunk in the days to weeks after the bite, occasionally accompanied by regional lymphadenopathy. Some bites can result in local necrosis and secondary bacterial infection caused by organisms in the oral cavity of the culprit snake.

Although they were not present in our patient, snakebites can result in a wide range of systemic toxicities ranging from clotting defects and hemolysis to neurotoxicity, myotoxicity, and nephrotoxicity.¹⁰ In severe cases, snake venom can result in disseminated intravascular coagulation, sepsis, and cardiorespiratory collapse.

The eastern copperhead (Agkistrodon contortrix) is a species of venomous snake that is endemic to eastern North America. Copperheads are members of the subfamily Crotalinae in the family Viperidae.¹¹ Reported reactions to copperhead bites include cellulitis, necrotizing fasciitis, compartment syndrome, and tissue necrosis of an entire affected extremity.^12,13 Our patient displayed no systemic symptoms to suggest envenomation.

Management of Snakebites

Treatment of snakebites varies based on the constellation and severity of symptoms as well as how recently the envenomation occurred. In urgent cases, antivenom may be administered to prevent further toxicity. In cases of progressive compartment syndrome, emergent surgical procedures such as fasciotomy or amputation are required to prevent further complications. When a superimposed bacterial infection is suspected, broad-spectrum antibiotics are required. Because our patient presented 4 months following the initial bite with isolated cutaneous manifestations, she was treated symptomatically with colchicine for EN.^1,2

Final Thoughts

Our patient presented with EN following a bite from a copperhead snake. Physicians should be aware of possible etiologies of EN to evaluate patients who present with new-onset tender subcutaneous nodules. Additionally, physicians should be aware of venomous snakes endemic to their region and also understand the various complications that can result following a snakebite, with the potential for lingering cutaneous manifestations weeks to months following the initial bite.

The clinical manifestations of snakebites vary based on the species of snake, bite location, and amount and strength of the venom injected. Locally acting toxins in snake venom predominantly consist of enzymes, such as phospholipase A₂, that cause local tissue destruction and can result in pain, swelling, blistering, ecchymosis, and tissue necrosis at the site of the bite within hours to days after the bite.¹ Systemically acting toxins can target a wide variety of tissues and cause severe systemic complications including paralysis, rhabdomyolysis secondary to muscle damage, coagulopathy, sepsis, and cardiorespiratory failure.²

Although pain and swelling following snakebites typically resolve by 1 month after envenomation, copperhead snakes—a type of pit viper—may cause residual symptoms of pain and swelling lasting for a year or more.³ Additional cutaneous manifestations of copperhead snakebites include wound infections at the bite site, such as cellulitis and necrotizing fasciitis. More devastating complications that have been described following snake envenomation include tissue injury of an entire extremity and development of compartment syndrome, which requires urgent fasciotomy to prevent potential loss of the affected limb.⁴

Physicians should be aware of the potential complications of snakebites to properly manage and counsel their patients. We describe a 42-year-old woman with tender, erythematous, subcutaneous nodules persisting for 4 months following a copperhead snakebite. A biopsy confirmed the diagnosis of snakebite-associated erythema nodosum (EN).

Case Report

A 42-year-old woman presented to our clinic with progressive tender, pruritic, deep-seated, erythematous nodules in multiple locations on the legs after sustaining a bite by a copperhead snake on the left foot 4 months prior. The lesions tended to fluctuate in intensity. In the days following the bite, she initially developed painful red bumps on the left foot just proximal to the bite site with associated pain and swelling extending up to just below the left knee. She reported no other notable symptoms such as fever, arthralgia, fatigue, or gastrointestinal tract symptoms. Physical examination revealed bilateral pitting edema, which was worse in the left leg, along with multiple deep, palpable, tender subcutaneous nodules with erythematous surface change (Figure 1).

Workup performed by an outside provider over the previous month included 2 venous duplex ultrasounds of the left leg, which showed no signs of deep vein thrombosis. Additionally, the patient underwent lateral and anteroposterior radiographs of the left foot, tibia, and fibula, which showed no evidence of fracture.

Given the morphology and distribution of the lesions (Figure 2), EN was strongly favored as the cause of the symptoms, and a biopsy confirmed the diagnosis. All immunohistochemical stains including auramine-­rhodamine for acid-fast bacilli, Grocott-Gomori methenamine silver for fungal organisms, and Brown and Brenn were negative. Given the waxing and waning course of the lesions, which suggested an active neutrophilic rather than purely chronic granulomatous phase of EN, the patient was treated with colchicine 0.6 mg twice daily for 1 month.

Causes of EN and Clinical Manifestations

Erythema nodosum is a common form of septal panniculitis that can be precipitated by inflammatory conditions, infection, or medications (commonly oral contraceptive pills) but often is idiopathic.⁵ The acute phase is neutrophilic, with evolution over time to a granulomatous phase. Common etiologies include sarcoidosis; inflammatory bowel disease; and bacterial or fungal infections such as Streptococcus (especially common in children), histoplasmosis, and coccidioidomycosis. The patient was otherwise healthy and was not taking any medications that are known triggers of EN. A PubMed search of articles indexed for MEDLINE in the English-language literature using the terms copperhead snake bite, erythema nodosum snake, and copperhead snake erythema nodosum revealed no reports of EN following a bite from a copperhead snake; however, in one case, an adder bite led to erysipelas, likely due to disturbed blood and lymphatic flow, which then triggered EN.⁶ Additionally, EN has been reported as a delayed reaction to jellyfish stings.⁷

Clinical features of EN include the development of tender, erythematous, subcutaneous nodules and plaques most frequently over the pretibial region. Lesions typically evolve from raised, deep-seated nodules into flat indurated plaques over a span of weeks. Occasionally, there is a slight prodromal phase marked by nonspecific symptoms such as fever and arthralgia lasting for 3 to 6 days. Erythema nodosum typically results in spontaneous resolution after 4 to 8 weeks, and management involves treatment of any underlying condition with symptomatic care. Interestingly, our patient experienced persistent symptoms over the course of 4 months, with development of new nodular lesions throughout this time period. The most frequently used drugs for the management of symptomatic EN include nonsteroidal anti-inflammatory drugs, colchicine, and potassium iodide.⁸ A characteristic histologic finding of the granulomatous phase is the Miescher radial granuloma, which is a septal collection of histiocytes surrounding a cleft.⁹

Snakebite Reactions

Snakebites can result in a wide range of local and systemic manifestations, as snake venom may contain 20 or more toxins.¹⁰ Local complications of pit viper bites include pain, swelling, and fang marks; when examining fang marks, the presence of 2 distinct puncture wounds often indicates envenomation with a poisonous snake, whereas nonvenomous snakebites often result in smaller puncture wounds arranged in an arc. Following bites, pain can develop immediately and spread proximally up the affected limb, which occurred in our patient in the days following the bite. Intense local reactions can occur, as bites often result in intense edema of the affected limb spreading to the trunk in the days to weeks after the bite, occasionally accompanied by regional lymphadenopathy. Some bites can result in local necrosis and secondary bacterial infection caused by organisms in the oral cavity of the culprit snake.

Although they were not present in our patient, snakebites can result in a wide range of systemic toxicities ranging from clotting defects and hemolysis to neurotoxicity, myotoxicity, and nephrotoxicity.¹⁰ In severe cases, snake venom can result in disseminated intravascular coagulation, sepsis, and cardiorespiratory collapse.

The eastern copperhead (Agkistrodon contortrix) is a species of venomous snake that is endemic to eastern North America. Copperheads are members of the subfamily Crotalinae in the family Viperidae.¹¹ Reported reactions to copperhead bites include cellulitis, necrotizing fasciitis, compartment syndrome, and tissue necrosis of an entire affected extremity.^12,13 Our patient displayed no systemic symptoms to suggest envenomation.

Management of Snakebites

Treatment of snakebites varies based on the constellation and severity of symptoms as well as how recently the envenomation occurred. In urgent cases, antivenom may be administered to prevent further toxicity. In cases of progressive compartment syndrome, emergent surgical procedures such as fasciotomy or amputation are required to prevent further complications. When a superimposed bacterial infection is suspected, broad-spectrum antibiotics are required. Because our patient presented 4 months following the initial bite with isolated cutaneous manifestations, she was treated symptomatically with colchicine for EN.^1,2

Final Thoughts

Our patient presented with EN following a bite from a copperhead snake. Physicians should be aware of possible etiologies of EN to evaluate patients who present with new-onset tender subcutaneous nodules. Additionally, physicians should be aware of venomous snakes endemic to their region and also understand the various complications that can result following a snakebite, with the potential for lingering cutaneous manifestations weeks to months following the initial bite.

The clinical manifestations of snakebites vary based on the species of snake, bite location, and amount and strength of the venom injected. Locally acting toxins in snake venom predominantly consist of enzymes, such as phospholipase A₂, that cause local tissue destruction and can result in pain, swelling, blistering, ecchymosis, and tissue necrosis at the site of the bite within hours to days after the bite.¹ Systemically acting toxins can target a wide variety of tissues and cause severe systemic complications including paralysis, rhabdomyolysis secondary to muscle damage, coagulopathy, sepsis, and cardiorespiratory failure.²

Although pain and swelling following snakebites typically resolve by 1 month after envenomation, copperhead snakes—a type of pit viper—may cause residual symptoms of pain and swelling lasting for a year or more.³ Additional cutaneous manifestations of copperhead snakebites include wound infections at the bite site, such as cellulitis and necrotizing fasciitis. More devastating complications that have been described following snake envenomation include tissue injury of an entire extremity and development of compartment syndrome, which requires urgent fasciotomy to prevent potential loss of the affected limb.⁴

Physicians should be aware of the potential complications of snakebites to properly manage and counsel their patients. We describe a 42-year-old woman with tender, erythematous, subcutaneous nodules persisting for 4 months following a copperhead snakebite. A biopsy confirmed the diagnosis of snakebite-associated erythema nodosum (EN).

Case Report

A 42-year-old woman presented to our clinic with progressive tender, pruritic, deep-seated, erythematous nodules in multiple locations on the legs after sustaining a bite by a copperhead snake on the left foot 4 months prior. The lesions tended to fluctuate in intensity. In the days following the bite, she initially developed painful red bumps on the left foot just proximal to the bite site with associated pain and swelling extending up to just below the left knee. She reported no other notable symptoms such as fever, arthralgia, fatigue, or gastrointestinal tract symptoms. Physical examination revealed bilateral pitting edema, which was worse in the left leg, along with multiple deep, palpable, tender subcutaneous nodules with erythematous surface change (Figure 1).

Workup performed by an outside provider over the previous month included 2 venous duplex ultrasounds of the left leg, which showed no signs of deep vein thrombosis. Additionally, the patient underwent lateral and anteroposterior radiographs of the left foot, tibia, and fibula, which showed no evidence of fracture.

Given the morphology and distribution of the lesions (Figure 2), EN was strongly favored as the cause of the symptoms, and a biopsy confirmed the diagnosis. All immunohistochemical stains including auramine-­rhodamine for acid-fast bacilli, Grocott-Gomori methenamine silver for fungal organisms, and Brown and Brenn were negative. Given the waxing and waning course of the lesions, which suggested an active neutrophilic rather than purely chronic granulomatous phase of EN, the patient was treated with colchicine 0.6 mg twice daily for 1 month.

Causes of EN and Clinical Manifestations

Erythema nodosum is a common form of septal panniculitis that can be precipitated by inflammatory conditions, infection, or medications (commonly oral contraceptive pills) but often is idiopathic.⁵ The acute phase is neutrophilic, with evolution over time to a granulomatous phase. Common etiologies include sarcoidosis; inflammatory bowel disease; and bacterial or fungal infections such as Streptococcus (especially common in children), histoplasmosis, and coccidioidomycosis. The patient was otherwise healthy and was not taking any medications that are known triggers of EN. A PubMed search of articles indexed for MEDLINE in the English-language literature using the terms copperhead snake bite, erythema nodosum snake, and copperhead snake erythema nodosum revealed no reports of EN following a bite from a copperhead snake; however, in one case, an adder bite led to erysipelas, likely due to disturbed blood and lymphatic flow, which then triggered EN.⁶ Additionally, EN has been reported as a delayed reaction to jellyfish stings.⁷

Clinical features of EN include the development of tender, erythematous, subcutaneous nodules and plaques most frequently over the pretibial region. Lesions typically evolve from raised, deep-seated nodules into flat indurated plaques over a span of weeks. Occasionally, there is a slight prodromal phase marked by nonspecific symptoms such as fever and arthralgia lasting for 3 to 6 days. Erythema nodosum typically results in spontaneous resolution after 4 to 8 weeks, and management involves treatment of any underlying condition with symptomatic care. Interestingly, our patient experienced persistent symptoms over the course of 4 months, with development of new nodular lesions throughout this time period. The most frequently used drugs for the management of symptomatic EN include nonsteroidal anti-inflammatory drugs, colchicine, and potassium iodide.⁸ A characteristic histologic finding of the granulomatous phase is the Miescher radial granuloma, which is a septal collection of histiocytes surrounding a cleft.⁹

Snakebite Reactions

Snakebites can result in a wide range of local and systemic manifestations, as snake venom may contain 20 or more toxins.¹⁰ Local complications of pit viper bites include pain, swelling, and fang marks; when examining fang marks, the presence of 2 distinct puncture wounds often indicates envenomation with a poisonous snake, whereas nonvenomous snakebites often result in smaller puncture wounds arranged in an arc. Following bites, pain can develop immediately and spread proximally up the affected limb, which occurred in our patient in the days following the bite. Intense local reactions can occur, as bites often result in intense edema of the affected limb spreading to the trunk in the days to weeks after the bite, occasionally accompanied by regional lymphadenopathy. Some bites can result in local necrosis and secondary bacterial infection caused by organisms in the oral cavity of the culprit snake.

Although they were not present in our patient, snakebites can result in a wide range of systemic toxicities ranging from clotting defects and hemolysis to neurotoxicity, myotoxicity, and nephrotoxicity.¹⁰ In severe cases, snake venom can result in disseminated intravascular coagulation, sepsis, and cardiorespiratory collapse.

The eastern copperhead (Agkistrodon contortrix) is a species of venomous snake that is endemic to eastern North America. Copperheads are members of the subfamily Crotalinae in the family Viperidae.¹¹ Reported reactions to copperhead bites include cellulitis, necrotizing fasciitis, compartment syndrome, and tissue necrosis of an entire affected extremity.^12,13 Our patient displayed no systemic symptoms to suggest envenomation.

Management of Snakebites

Treatment of snakebites varies based on the constellation and severity of symptoms as well as how recently the envenomation occurred. In urgent cases, antivenom may be administered to prevent further toxicity. In cases of progressive compartment syndrome, emergent surgical procedures such as fasciotomy or amputation are required to prevent further complications. When a superimposed bacterial infection is suspected, broad-spectrum antibiotics are required. Because our patient presented 4 months following the initial bite with isolated cutaneous manifestations, she was treated symptomatically with colchicine for EN.^1,2

Final Thoughts

Our patient presented with EN following a bite from a copperhead snake. Physicians should be aware of possible etiologies of EN to evaluate patients who present with new-onset tender subcutaneous nodules. Additionally, physicians should be aware of venomous snakes endemic to their region and also understand the various complications that can result following a snakebite, with the potential for lingering cutaneous manifestations weeks to months following the initial bite.

To the Editor:

Generalized bullous fixed drug eruption (GBFDE) is a rare subtype of fixed drug eruption (FDE) that manifests as widespread blisters and erosions following exposure to a causative drug.¹ Diagnostic criteria include involvement of at least 3 to 6 anatomic sites—head and neck, anterior trunk, posterior trunk, upper extremities, lower extremities, or genitalia—and more than 10% of the body surface area. It can be challenging to differentiate GBFDE from severe drug rashes such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) due to extensive body surface area involvement of blisters and erosions. Specific features distinguishing GBFDE from SJS/TEN include primary lesions consisting of larger erythematous to dusky, circular plaques that progress to bullae and coalesce into widespread erosions; history of FDE; lack of severe mucosal involvement; and better overall prognosis.² Treatment typically involves discontinuation of the culprit medication and supportive care; evidence for systemic therapies is not well established.

Our study aimed to characterize the clinical and demographic features of GBFDE in our institution to highlight potential key differences between this diagnosis and SJS/TEN. An electronic medical record search was performed to identify patients who were clinically diagnosed with GBFDE at New York-Presbyterian/Weill Cornell Medical Center (New York, New York) in both outpatient and inpatient settings from January 2015 to December 2022. This retrospective study was approved by the Weill Cornell Medicine institutional review board (#22-05024777).

Ten patients were identified and included in the analysis (eTable). The mean age of the patients was 56 years (range, 39–76 years). Seven (70%) patients had skin of color (non-White) and 6 (60%) were female. The mean body mass index was 35 (range, 20–57), and 7 (70%) patients were clinically obese (body mass index >30). Only 2 (20%) patients had a history of a documented drug eruption (hives and erythema multiforme), and no patients had a history of FDE. Erythematous dusky patches followed by rapid development of blisters were noted within 3 days of drug initiation in 40% (4/10) and within 5 days in 80% (8/10) of patients. Antibiotics were identified as likely inciting agents in 8 (80%) patients. Biopsies were obtained in 3 (30%) patients and all 3 demonstrated cytotoxic CD8⁺ interface dermatitis with marked epithelial necrosis, neutrophilia, eosinophilia, and melanophage accumulation. Fever was present at initial presentation in only 4 (40%) patients, and only 1 (10%) patient had oral mucosal involvement. All 10 patients had intertriginous involvement (axillae, 90% [9/10]; gluteal cleft, 80% [8/10]; groin, 80% [8/10]; inframammary folds, 20% [2/10]), and there was considerable flank involvement in 9 (90%) patients. All 10 patients had initial erythematous to dusky, circular patches on the trunk and proximal extremities that then denuded most dramatically in the intertriginous areas (Figure). Six (60%) patients received systemic therapy, including 5 patients treated with a single dose of etanercept 50 mg. In patients with continued progression, 1 or 2 additional doses of etanercept 50 mg were administered at 48- to 72-hour intervals until blistering halted. Treatment with etanercept resulted in clinical improvement in all 5 patients, and there were no identifiable adverse events. The mean hospital stay was 19.7 days (range, 1–63 days).

This study highlights notable demographic and clinical features of GBFDE that have not been widely described in the literature. Large erythematous and dusky patches with broad zones of blistering with particular localization to the neck, intertriginous areas, and flanks typically are not described in SJS/TEN and may be helpful in distinguishing these conditions from GBFDE. Mild or complete lack of mucosal and facial involvement as well as more rapid time from drug initiation to rash (as rapid as 1 day) were key factors that aided in distinguishing GBFDE from SJS/TEN in our patients. Although a history of FDE is considered a key characteristic in the diagnosis of GBFDE, none of our patients had a known history of FDE, suggesting GBFDE may be the initial manifestation of FDE in some patients. Histopathology showed similar findings consistent with FDE in the 3 patients in whom a biopsy was performed. The remaining patients were diagnosed clinically based on the presence of distinctive, perfectly circular, dusky plaques present at the periphery of larger denuded areas, which are characteristic of GBFDE. Lower levels of serum granulysin³ have been shown to help distinguish GBFDE from SJS/TEN, but this test is not readily available with time-sensitive results at most institutions, and exact diagnostic ranges for GBFDE vs SJS/TEN are not yet known.

Our study was limited by a small number of patients at a single institution. Another limitation was the retrospective design.

Interestingly, a high proportion of our patients were non-White and clinically obese, which are factors that should be considered for future research. Sixty percent (6/10) of the patients in our study were Black, which is a notable difference from our hospital’s general admission demographics with Black individuals constituting 12% of patients.⁴ Our study also highlighted the utility of etanercept, which has reported mortality benefits and decreased time to re-epithelialization in other severe blistering cutaneous drug reactions including SJS/TEN,⁵ as a potential therapeutic option in GBFDE.

It is imperative that clinicians recognize the differences between GBFDE and SJS/TEN, as correct diagnosis is crucial for identifying the most likely causative drug as well as providing accurate prognostic information and may have future therapeutic implications as we further understand the immunologic profiles of these severe blistering drug reactions.

To the Editor:

Generalized bullous fixed drug eruption (GBFDE) is a rare subtype of fixed drug eruption (FDE) that manifests as widespread blisters and erosions following exposure to a causative drug.¹ Diagnostic criteria include involvement of at least 3 to 6 anatomic sites—head and neck, anterior trunk, posterior trunk, upper extremities, lower extremities, or genitalia—and more than 10% of the body surface area. It can be challenging to differentiate GBFDE from severe drug rashes such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) due to extensive body surface area involvement of blisters and erosions. Specific features distinguishing GBFDE from SJS/TEN include primary lesions consisting of larger erythematous to dusky, circular plaques that progress to bullae and coalesce into widespread erosions; history of FDE; lack of severe mucosal involvement; and better overall prognosis.² Treatment typically involves discontinuation of the culprit medication and supportive care; evidence for systemic therapies is not well established.

Our study aimed to characterize the clinical and demographic features of GBFDE in our institution to highlight potential key differences between this diagnosis and SJS/TEN. An electronic medical record search was performed to identify patients who were clinically diagnosed with GBFDE at New York-Presbyterian/Weill Cornell Medical Center (New York, New York) in both outpatient and inpatient settings from January 2015 to December 2022. This retrospective study was approved by the Weill Cornell Medicine institutional review board (#22-05024777).

Ten patients were identified and included in the analysis (eTable). The mean age of the patients was 56 years (range, 39–76 years). Seven (70%) patients had skin of color (non-White) and 6 (60%) were female. The mean body mass index was 35 (range, 20–57), and 7 (70%) patients were clinically obese (body mass index >30). Only 2 (20%) patients had a history of a documented drug eruption (hives and erythema multiforme), and no patients had a history of FDE. Erythematous dusky patches followed by rapid development of blisters were noted within 3 days of drug initiation in 40% (4/10) and within 5 days in 80% (8/10) of patients. Antibiotics were identified as likely inciting agents in 8 (80%) patients. Biopsies were obtained in 3 (30%) patients and all 3 demonstrated cytotoxic CD8⁺ interface dermatitis with marked epithelial necrosis, neutrophilia, eosinophilia, and melanophage accumulation. Fever was present at initial presentation in only 4 (40%) patients, and only 1 (10%) patient had oral mucosal involvement. All 10 patients had intertriginous involvement (axillae, 90% [9/10]; gluteal cleft, 80% [8/10]; groin, 80% [8/10]; inframammary folds, 20% [2/10]), and there was considerable flank involvement in 9 (90%) patients. All 10 patients had initial erythematous to dusky, circular patches on the trunk and proximal extremities that then denuded most dramatically in the intertriginous areas (Figure). Six (60%) patients received systemic therapy, including 5 patients treated with a single dose of etanercept 50 mg. In patients with continued progression, 1 or 2 additional doses of etanercept 50 mg were administered at 48- to 72-hour intervals until blistering halted. Treatment with etanercept resulted in clinical improvement in all 5 patients, and there were no identifiable adverse events. The mean hospital stay was 19.7 days (range, 1–63 days).

This study highlights notable demographic and clinical features of GBFDE that have not been widely described in the literature. Large erythematous and dusky patches with broad zones of blistering with particular localization to the neck, intertriginous areas, and flanks typically are not described in SJS/TEN and may be helpful in distinguishing these conditions from GBFDE. Mild or complete lack of mucosal and facial involvement as well as more rapid time from drug initiation to rash (as rapid as 1 day) were key factors that aided in distinguishing GBFDE from SJS/TEN in our patients. Although a history of FDE is considered a key characteristic in the diagnosis of GBFDE, none of our patients had a known history of FDE, suggesting GBFDE may be the initial manifestation of FDE in some patients. Histopathology showed similar findings consistent with FDE in the 3 patients in whom a biopsy was performed. The remaining patients were diagnosed clinically based on the presence of distinctive, perfectly circular, dusky plaques present at the periphery of larger denuded areas, which are characteristic of GBFDE. Lower levels of serum granulysin³ have been shown to help distinguish GBFDE from SJS/TEN, but this test is not readily available with time-sensitive results at most institutions, and exact diagnostic ranges for GBFDE vs SJS/TEN are not yet known.

Our study was limited by a small number of patients at a single institution. Another limitation was the retrospective design.

Interestingly, a high proportion of our patients were non-White and clinically obese, which are factors that should be considered for future research. Sixty percent (6/10) of the patients in our study were Black, which is a notable difference from our hospital’s general admission demographics with Black individuals constituting 12% of patients.⁴ Our study also highlighted the utility of etanercept, which has reported mortality benefits and decreased time to re-epithelialization in other severe blistering cutaneous drug reactions including SJS/TEN,⁵ as a potential therapeutic option in GBFDE.

It is imperative that clinicians recognize the differences between GBFDE and SJS/TEN, as correct diagnosis is crucial for identifying the most likely causative drug as well as providing accurate prognostic information and may have future therapeutic implications as we further understand the immunologic profiles of these severe blistering drug reactions.

To the Editor:

Generalized bullous fixed drug eruption (GBFDE) is a rare subtype of fixed drug eruption (FDE) that manifests as widespread blisters and erosions following exposure to a causative drug.¹ Diagnostic criteria include involvement of at least 3 to 6 anatomic sites—head and neck, anterior trunk, posterior trunk, upper extremities, lower extremities, or genitalia—and more than 10% of the body surface area. It can be challenging to differentiate GBFDE from severe drug rashes such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) due to extensive body surface area involvement of blisters and erosions. Specific features distinguishing GBFDE from SJS/TEN include primary lesions consisting of larger erythematous to dusky, circular plaques that progress to bullae and coalesce into widespread erosions; history of FDE; lack of severe mucosal involvement; and better overall prognosis.² Treatment typically involves discontinuation of the culprit medication and supportive care; evidence for systemic therapies is not well established.

Our study aimed to characterize the clinical and demographic features of GBFDE in our institution to highlight potential key differences between this diagnosis and SJS/TEN. An electronic medical record search was performed to identify patients who were clinically diagnosed with GBFDE at New York-Presbyterian/Weill Cornell Medical Center (New York, New York) in both outpatient and inpatient settings from January 2015 to December 2022. This retrospective study was approved by the Weill Cornell Medicine institutional review board (#22-05024777).

Ten patients were identified and included in the analysis (eTable). The mean age of the patients was 56 years (range, 39–76 years). Seven (70%) patients had skin of color (non-White) and 6 (60%) were female. The mean body mass index was 35 (range, 20–57), and 7 (70%) patients were clinically obese (body mass index >30). Only 2 (20%) patients had a history of a documented drug eruption (hives and erythema multiforme), and no patients had a history of FDE. Erythematous dusky patches followed by rapid development of blisters were noted within 3 days of drug initiation in 40% (4/10) and within 5 days in 80% (8/10) of patients. Antibiotics were identified as likely inciting agents in 8 (80%) patients. Biopsies were obtained in 3 (30%) patients and all 3 demonstrated cytotoxic CD8⁺ interface dermatitis with marked epithelial necrosis, neutrophilia, eosinophilia, and melanophage accumulation. Fever was present at initial presentation in only 4 (40%) patients, and only 1 (10%) patient had oral mucosal involvement. All 10 patients had intertriginous involvement (axillae, 90% [9/10]; gluteal cleft, 80% [8/10]; groin, 80% [8/10]; inframammary folds, 20% [2/10]), and there was considerable flank involvement in 9 (90%) patients. All 10 patients had initial erythematous to dusky, circular patches on the trunk and proximal extremities that then denuded most dramatically in the intertriginous areas (Figure). Six (60%) patients received systemic therapy, including 5 patients treated with a single dose of etanercept 50 mg. In patients with continued progression, 1 or 2 additional doses of etanercept 50 mg were administered at 48- to 72-hour intervals until blistering halted. Treatment with etanercept resulted in clinical improvement in all 5 patients, and there were no identifiable adverse events. The mean hospital stay was 19.7 days (range, 1–63 days).

This study highlights notable demographic and clinical features of GBFDE that have not been widely described in the literature. Large erythematous and dusky patches with broad zones of blistering with particular localization to the neck, intertriginous areas, and flanks typically are not described in SJS/TEN and may be helpful in distinguishing these conditions from GBFDE. Mild or complete lack of mucosal and facial involvement as well as more rapid time from drug initiation to rash (as rapid as 1 day) were key factors that aided in distinguishing GBFDE from SJS/TEN in our patients. Although a history of FDE is considered a key characteristic in the diagnosis of GBFDE, none of our patients had a known history of FDE, suggesting GBFDE may be the initial manifestation of FDE in some patients. Histopathology showed similar findings consistent with FDE in the 3 patients in whom a biopsy was performed. The remaining patients were diagnosed clinically based on the presence of distinctive, perfectly circular, dusky plaques present at the periphery of larger denuded areas, which are characteristic of GBFDE. Lower levels of serum granulysin³ have been shown to help distinguish GBFDE from SJS/TEN, but this test is not readily available with time-sensitive results at most institutions, and exact diagnostic ranges for GBFDE vs SJS/TEN are not yet known.

Our study was limited by a small number of patients at a single institution. Another limitation was the retrospective design.

Interestingly, a high proportion of our patients were non-White and clinically obese, which are factors that should be considered for future research. Sixty percent (6/10) of the patients in our study were Black, which is a notable difference from our hospital’s general admission demographics with Black individuals constituting 12% of patients.⁴ Our study also highlighted the utility of etanercept, which has reported mortality benefits and decreased time to re-epithelialization in other severe blistering cutaneous drug reactions including SJS/TEN,⁵ as a potential therapeutic option in GBFDE.

It is imperative that clinicians recognize the differences between GBFDE and SJS/TEN, as correct diagnosis is crucial for identifying the most likely causative drug as well as providing accurate prognostic information and may have future therapeutic implications as we further understand the immunologic profiles of these severe blistering drug reactions.

To the Editor:

We read with interest the case report from Abdelkader et al¹ (Cutis. 2024;113:E22-E24) of a 32-year-old man who received the Sinopharm BBIBP COVID-19 vaccine (BBIBP-CorV) and experienced acute-onset erythroderma and severe itching. The patient did not disclose any recent medication intake and had no noteworthy medical history. Physical examination revealed palmoplantar keratoderma, keratotic follicular papules on the legs and feet, and typical orange-red erythroderma. The laboratory workup was normal, including a negative test result for HIV infection.

The absence of details regarding the patient’s history of allergic reactions or sensitivities is one possible shortcoming in this case report and may have given important information about the possible reason for the erythroderma that occurred following vaccination. Furthermore, more research into the precise Sinopharm BBIBP vaccine ingredients that may have caused the skin reaction would have been helpful in deciphering the underlying mechanisms.

Larger-scale studies examining the frequency of cutaneous reactions following COVID-19 vaccination with various vaccine formulations may be the focus of future research efforts and could assist in determining the risk factors for experiencing such reactions, which would enable health care providers to offer advice on vaccination alternatives or preventative measures for those who are more vulnerable. Furthermore, collaboration among dermatologists and allergists could improve patient outcomes and improve management.

By highlighting an uncommon but noteworthy dermatologic manifestation following COVID-19 immunization, this case report emphasizes how crucial it is to keep an eye out for and report any possible side effects linked to vaccinations to protect patient safety. Subsequent investigations should concentrate on enhancing comprehension of the pathophysiology of cutaneous reactions following immunization and devising tactics to alleviate these hazards. Working together, researchers and health care professionals can effectively tackle the issues raised by these newly discovered vaccine-related skin responses.

To the Editor:

We read with interest the case report from Abdelkader et al¹ (Cutis. 2024;113:E22-E24) of a 32-year-old man who received the Sinopharm BBIBP COVID-19 vaccine (BBIBP-CorV) and experienced acute-onset erythroderma and severe itching. The patient did not disclose any recent medication intake and had no noteworthy medical history. Physical examination revealed palmoplantar keratoderma, keratotic follicular papules on the legs and feet, and typical orange-red erythroderma. The laboratory workup was normal, including a negative test result for HIV infection.

The absence of details regarding the patient’s history of allergic reactions or sensitivities is one possible shortcoming in this case report and may have given important information about the possible reason for the erythroderma that occurred following vaccination. Furthermore, more research into the precise Sinopharm BBIBP vaccine ingredients that may have caused the skin reaction would have been helpful in deciphering the underlying mechanisms.

Larger-scale studies examining the frequency of cutaneous reactions following COVID-19 vaccination with various vaccine formulations may be the focus of future research efforts and could assist in determining the risk factors for experiencing such reactions, which would enable health care providers to offer advice on vaccination alternatives or preventative measures for those who are more vulnerable. Furthermore, collaboration among dermatologists and allergists could improve patient outcomes and improve management.

By highlighting an uncommon but noteworthy dermatologic manifestation following COVID-19 immunization, this case report emphasizes how crucial it is to keep an eye out for and report any possible side effects linked to vaccinations to protect patient safety. Subsequent investigations should concentrate on enhancing comprehension of the pathophysiology of cutaneous reactions following immunization and devising tactics to alleviate these hazards. Working together, researchers and health care professionals can effectively tackle the issues raised by these newly discovered vaccine-related skin responses.

To the Editor:

We read with interest the case report from Abdelkader et al¹ (Cutis. 2024;113:E22-E24) of a 32-year-old man who received the Sinopharm BBIBP COVID-19 vaccine (BBIBP-CorV) and experienced acute-onset erythroderma and severe itching. The patient did not disclose any recent medication intake and had no noteworthy medical history. Physical examination revealed palmoplantar keratoderma, keratotic follicular papules on the legs and feet, and typical orange-red erythroderma. The laboratory workup was normal, including a negative test result for HIV infection.

The absence of details regarding the patient’s history of allergic reactions or sensitivities is one possible shortcoming in this case report and may have given important information about the possible reason for the erythroderma that occurred following vaccination. Furthermore, more research into the precise Sinopharm BBIBP vaccine ingredients that may have caused the skin reaction would have been helpful in deciphering the underlying mechanisms.

Larger-scale studies examining the frequency of cutaneous reactions following COVID-19 vaccination with various vaccine formulations may be the focus of future research efforts and could assist in determining the risk factors for experiencing such reactions, which would enable health care providers to offer advice on vaccination alternatives or preventative measures for those who are more vulnerable. Furthermore, collaboration among dermatologists and allergists could improve patient outcomes and improve management.

By highlighting an uncommon but noteworthy dermatologic manifestation following COVID-19 immunization, this case report emphasizes how crucial it is to keep an eye out for and report any possible side effects linked to vaccinations to protect patient safety. Subsequent investigations should concentrate on enhancing comprehension of the pathophysiology of cutaneous reactions following immunization and devising tactics to alleviate these hazards. Working together, researchers and health care professionals can effectively tackle the issues raised by these newly discovered vaccine-related skin responses.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.