Josh struggled for more than a decade with what his doctors had told him was irritable bowel syndrome (IBS). But curiously, the 39-year-old’s flare-ups were caused by some foods that aren’t typical IBS triggers. Peanuts and shellfish caused “stabbing” abdominal pains, and he would feel lightheaded after simply inhaling the scent of them. He also had severe constipation that lasted up to a week and rectal mucous discharges.

So, Josh (not his real name) sought the care of New York gastroenterologist Yevgenia Pashinsky, MD. She conducted a comprehensive nutritional assessment and sent him for allergy testing. The results: Josh had a little-known condition called systemic nickel allergy syndrome (SNAS), which can mimic some of the symptoms of IBS.

Dr. Pashinsky, of the department of medicine at Icahn School of Medicine at Mount Sinai, New York, and a partner with New York Gastroenterology Associates, presented Josh’s case as part of a seminar on SNAS and IBS “mimickers” at the Food and Nutrition Conference and Expo in Orlando last October, sponsored by the Academy of Nutrition and Dietetics.

She and two registered dietitians in her practice, Suzie Finkel, MS, RD, CDN, and Tamara Duker Freuman, MS, RD, CDN, told seminar attendees that SNAS is rarely diagnosed and can be mistaken for IBS. They noted that it probably strikes more people than doctors suspect.

“Systemic nickel allergy is present in at least 10% of the U.S. population (and much higher in some subgroups),” Dr. Pashinsky told this news organization. “But its connection to GI symptoms and functional GI disorders is still being learned about.

“I think of nickel allergy and other allergic disorders when, in addition to GI symptoms, the patient reports skin and mucous membrane involvement along with their abdominal reactions,” she said.

For patients like Josh with SNAS, the diagnosis and treatment of this condition are surprisingly simple and effective.

“Josh had these really [unusual] symptoms and nontraditional IBS food triggers,” Ms. Finkel said in an interview. “So, that’s a situation where, as dietitians we say, ‘Hmm, that’s weird; if you have IBS, then peanuts and shrimp shouldn’t really cause an issue here.’ But this might be something physicians might not be attuned to because it’s not part of their training.”

Ms. Finkel said that Josh was referred to an allergist. Josh tested positive for skin sensitization to nickel, and he was started on a low-nickel diet, which improved his symptoms.

“So, that was this happy ending,” she added.

The upshot?

“Doctors who treat IBS patients [who are not responding to treatment] need to consider the possibility that they have SNAS and send them for allergy testing,” Ms. Finkel said. “If they come back positive, simple dietary changes can address it.”
 

An underrecognized condition

There has been very little research regarding SNAS in patients with IBS, and there are no standard guidelines for diagnosing and treating it.

What’s more, many gastroenterologists aren’t familiar with it. More than a dozen gastroenterologists who were contacted for comment declined to be interviewed because they didn’t know about SNAS – or enough about it to provide useful information for the story.

Ms. Finkel said she’s not surprised that many gastroenterologists don’t know much about how SNAS can mimic IBS, which is why she and her colleagues presented the seminar last October in Orlando. “It’s really an allergy and not a GI disease. It manifests with GI symptoms, but the root is not in the digestive tract; the root is in a true allergy – a clinical allergy – to nickel.”

Complicating the issue is that people who have IBS and those with SNAS typically share some common symptoms.

Like IBS, SNAS can cause GI symptoms – such as cramping, abdominal pain, heartburn, constipation, gaseous distension, and mucus in the stool. It can be triggered by certain fresh, cooked, and canned foods.

But the food triggers that cause SNAS are not usually those that cause IBS symptoms. Rather, SNAS flare-ups are nearly always triggered by foods with high levels of nickel. Examples include apricots, artichokes, asparagus, beans, cauliflower, chickpeas, cocoa/chocolate, figs, lentils, licorice, oats, onions, peas, peanuts, potatoes, spinach, tomatoes, and tea.

According to the American Academy of Allergy, Asthma & Immunology, a distinguishing feature of SNAS is that it can cause allergic contact dermatitis when a person touches something made with nickel. Coins, jewelry, eyeglasses, home fixtures, keys, zippers, dental devices, and even stainless-steel cookware can contain allergy-triggering nickel.

What Ms. Finkel sees the most are skin reactions from touching a surface containing nickel or from ingesting it, she said.

The other immediate symptom is abdominal pain or changes in bowel movements, such as diarrhea, she added.

Christopher Randolph, MD, an allergist based in Connecticut, told this news organization that it’s important for doctors to realize that patients who have a skin reaction to nickel may also have inflammatory GI symptoms.

“We definitely need more controlled studies,” said Dr. Randolph, of the department of allergy and immunology at Yale University, New Haven, Conn. “But the takeaway here is for patients and certainly providers to be mindful that you can have systemic reactions to nickel, even though you implicate only the contact dermatitis.”
 

Diagnosis and treatment recommendations

Skin patch allergy testing – in which a person’s skin is exposed to nickel – can quickly determine whether a patient with IBS is actually experiencing inflammatory reactions to dietary nickel and would benefit from a low-nickel or no-nickel diet, research shows.

For these patients, Dr. Pashinsky recommends the following:

• Avoiding high-nickel foods.
• Limiting canned foods.
• Using nonstainless cookware, especially for acidic foods.
• Boiling foods for potential nickel reduction, especially grains and vegetables.
• Running the tap before using water to drink or cook with first thing in the morning.

Dr. Pashisky and her team also recommend the following guidelines for doctors:

• Ask patients if symptoms occur immediately after eating certain high-nickel foods or worsen with a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet.
• Determine whether a patient is not responding to typical medical and dietary interventions used to treat IBS.
• Conduct a food/symptom history to identify potential nickel allergy triggers.
• Try a low-nickel dietary intervention to see whether a patient’s symptoms improve in a week or two.
• Refer the patient for additional diagnostic skin-patch testing or treatment.

A multidisciplinary approach

Ms. Finkel said it’s important for doctors, particularly gastroenterologists who treat patients for suspected GI disorders to consider nickel allergy as a cause.

“SNAS is this overlooked condition ... and the research is really in its nascency here,” Ms. Finkel said.

“I would say only give [a low- or no-nickel diet] consideration if the high-nickel foods are a possible trigger,” she said. “It is very specific, looking at their diet history, to have a clear hypothesis based on what their triggers are. It’s not something to try out lightly because it’s a very restrictive diet, so I would never put a patient on a diet that I didn’t think was necessary.”

Ms. Finkel added that treatment of SNAS requires a multidisciplinary approach with a gastroenterologist, an allergist, and a dietitian.

Doctors and dietitians have distinct roles in identifying and treating these patients, Ms. Finkel said.

“If there is a suspicion of IBS symptoms and the patient is not responding to first-line treatments, then it is worth having the input of a dietitian and an allergist,” she said.

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

Josh struggled for more than a decade with what his doctors had told him was irritable bowel syndrome (IBS). But curiously, the 39-year-old’s flare-ups were caused by some foods that aren’t typical IBS triggers. Peanuts and shellfish caused “stabbing” abdominal pains, and he would feel lightheaded after simply inhaling the scent of them. He also had severe constipation that lasted up to a week and rectal mucous discharges.

So, Josh (not his real name) sought the care of New York gastroenterologist Yevgenia Pashinsky, MD. She conducted a comprehensive nutritional assessment and sent him for allergy testing. The results: Josh had a little-known condition called systemic nickel allergy syndrome (SNAS), which can mimic some of the symptoms of IBS.

Dr. Pashinsky, of the department of medicine at Icahn School of Medicine at Mount Sinai, New York, and a partner with New York Gastroenterology Associates, presented Josh’s case as part of a seminar on SNAS and IBS “mimickers” at the Food and Nutrition Conference and Expo in Orlando last October, sponsored by the Academy of Nutrition and Dietetics.

She and two registered dietitians in her practice, Suzie Finkel, MS, RD, CDN, and Tamara Duker Freuman, MS, RD, CDN, told seminar attendees that SNAS is rarely diagnosed and can be mistaken for IBS. They noted that it probably strikes more people than doctors suspect.

“Systemic nickel allergy is present in at least 10% of the U.S. population (and much higher in some subgroups),” Dr. Pashinsky told this news organization. “But its connection to GI symptoms and functional GI disorders is still being learned about.

“I think of nickel allergy and other allergic disorders when, in addition to GI symptoms, the patient reports skin and mucous membrane involvement along with their abdominal reactions,” she said.

For patients like Josh with SNAS, the diagnosis and treatment of this condition are surprisingly simple and effective.

“Josh had these really [unusual] symptoms and nontraditional IBS food triggers,” Ms. Finkel said in an interview. “So, that’s a situation where, as dietitians we say, ‘Hmm, that’s weird; if you have IBS, then peanuts and shrimp shouldn’t really cause an issue here.’ But this might be something physicians might not be attuned to because it’s not part of their training.”

Ms. Finkel said that Josh was referred to an allergist. Josh tested positive for skin sensitization to nickel, and he was started on a low-nickel diet, which improved his symptoms.

“So, that was this happy ending,” she added.

The upshot?

“Doctors who treat IBS patients [who are not responding to treatment] need to consider the possibility that they have SNAS and send them for allergy testing,” Ms. Finkel said. “If they come back positive, simple dietary changes can address it.”
 

An underrecognized condition

There has been very little research regarding SNAS in patients with IBS, and there are no standard guidelines for diagnosing and treating it.

What’s more, many gastroenterologists aren’t familiar with it. More than a dozen gastroenterologists who were contacted for comment declined to be interviewed because they didn’t know about SNAS – or enough about it to provide useful information for the story.

Ms. Finkel said she’s not surprised that many gastroenterologists don’t know much about how SNAS can mimic IBS, which is why she and her colleagues presented the seminar last October in Orlando. “It’s really an allergy and not a GI disease. It manifests with GI symptoms, but the root is not in the digestive tract; the root is in a true allergy – a clinical allergy – to nickel.”

Complicating the issue is that people who have IBS and those with SNAS typically share some common symptoms.

Like IBS, SNAS can cause GI symptoms – such as cramping, abdominal pain, heartburn, constipation, gaseous distension, and mucus in the stool. It can be triggered by certain fresh, cooked, and canned foods.

But the food triggers that cause SNAS are not usually those that cause IBS symptoms. Rather, SNAS flare-ups are nearly always triggered by foods with high levels of nickel. Examples include apricots, artichokes, asparagus, beans, cauliflower, chickpeas, cocoa/chocolate, figs, lentils, licorice, oats, onions, peas, peanuts, potatoes, spinach, tomatoes, and tea.

According to the American Academy of Allergy, Asthma & Immunology, a distinguishing feature of SNAS is that it can cause allergic contact dermatitis when a person touches something made with nickel. Coins, jewelry, eyeglasses, home fixtures, keys, zippers, dental devices, and even stainless-steel cookware can contain allergy-triggering nickel.

What Ms. Finkel sees the most are skin reactions from touching a surface containing nickel or from ingesting it, she said.

The other immediate symptom is abdominal pain or changes in bowel movements, such as diarrhea, she added.

Christopher Randolph, MD, an allergist based in Connecticut, told this news organization that it’s important for doctors to realize that patients who have a skin reaction to nickel may also have inflammatory GI symptoms.

“We definitely need more controlled studies,” said Dr. Randolph, of the department of allergy and immunology at Yale University, New Haven, Conn. “But the takeaway here is for patients and certainly providers to be mindful that you can have systemic reactions to nickel, even though you implicate only the contact dermatitis.”
 

Diagnosis and treatment recommendations

Skin patch allergy testing – in which a person’s skin is exposed to nickel – can quickly determine whether a patient with IBS is actually experiencing inflammatory reactions to dietary nickel and would benefit from a low-nickel or no-nickel diet, research shows.

For these patients, Dr. Pashinsky recommends the following:

• Avoiding high-nickel foods.
• Limiting canned foods.
• Using nonstainless cookware, especially for acidic foods.
• Boiling foods for potential nickel reduction, especially grains and vegetables.
• Running the tap before using water to drink or cook with first thing in the morning.

Dr. Pashisky and her team also recommend the following guidelines for doctors:

• Ask patients if symptoms occur immediately after eating certain high-nickel foods or worsen with a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet.
• Determine whether a patient is not responding to typical medical and dietary interventions used to treat IBS.
• Conduct a food/symptom history to identify potential nickel allergy triggers.
• Try a low-nickel dietary intervention to see whether a patient’s symptoms improve in a week or two.
• Refer the patient for additional diagnostic skin-patch testing or treatment.

A multidisciplinary approach

Ms. Finkel said it’s important for doctors, particularly gastroenterologists who treat patients for suspected GI disorders to consider nickel allergy as a cause.

“SNAS is this overlooked condition ... and the research is really in its nascency here,” Ms. Finkel said.

“I would say only give [a low- or no-nickel diet] consideration if the high-nickel foods are a possible trigger,” she said. “It is very specific, looking at their diet history, to have a clear hypothesis based on what their triggers are. It’s not something to try out lightly because it’s a very restrictive diet, so I would never put a patient on a diet that I didn’t think was necessary.”

Ms. Finkel added that treatment of SNAS requires a multidisciplinary approach with a gastroenterologist, an allergist, and a dietitian.

Doctors and dietitians have distinct roles in identifying and treating these patients, Ms. Finkel said.

“If there is a suspicion of IBS symptoms and the patient is not responding to first-line treatments, then it is worth having the input of a dietitian and an allergist,” she said.

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

Josh struggled for more than a decade with what his doctors had told him was irritable bowel syndrome (IBS). But curiously, the 39-year-old’s flare-ups were caused by some foods that aren’t typical IBS triggers. Peanuts and shellfish caused “stabbing” abdominal pains, and he would feel lightheaded after simply inhaling the scent of them. He also had severe constipation that lasted up to a week and rectal mucous discharges.

So, Josh (not his real name) sought the care of New York gastroenterologist Yevgenia Pashinsky, MD. She conducted a comprehensive nutritional assessment and sent him for allergy testing. The results: Josh had a little-known condition called systemic nickel allergy syndrome (SNAS), which can mimic some of the symptoms of IBS.

Dr. Pashinsky, of the department of medicine at Icahn School of Medicine at Mount Sinai, New York, and a partner with New York Gastroenterology Associates, presented Josh’s case as part of a seminar on SNAS and IBS “mimickers” at the Food and Nutrition Conference and Expo in Orlando last October, sponsored by the Academy of Nutrition and Dietetics.

She and two registered dietitians in her practice, Suzie Finkel, MS, RD, CDN, and Tamara Duker Freuman, MS, RD, CDN, told seminar attendees that SNAS is rarely diagnosed and can be mistaken for IBS. They noted that it probably strikes more people than doctors suspect.

“Systemic nickel allergy is present in at least 10% of the U.S. population (and much higher in some subgroups),” Dr. Pashinsky told this news organization. “But its connection to GI symptoms and functional GI disorders is still being learned about.

“I think of nickel allergy and other allergic disorders when, in addition to GI symptoms, the patient reports skin and mucous membrane involvement along with their abdominal reactions,” she said.

For patients like Josh with SNAS, the diagnosis and treatment of this condition are surprisingly simple and effective.

“Josh had these really [unusual] symptoms and nontraditional IBS food triggers,” Ms. Finkel said in an interview. “So, that’s a situation where, as dietitians we say, ‘Hmm, that’s weird; if you have IBS, then peanuts and shrimp shouldn’t really cause an issue here.’ But this might be something physicians might not be attuned to because it’s not part of their training.”

Ms. Finkel said that Josh was referred to an allergist. Josh tested positive for skin sensitization to nickel, and he was started on a low-nickel diet, which improved his symptoms.

“So, that was this happy ending,” she added.

The upshot?

“Doctors who treat IBS patients [who are not responding to treatment] need to consider the possibility that they have SNAS and send them for allergy testing,” Ms. Finkel said. “If they come back positive, simple dietary changes can address it.”
 

An underrecognized condition

There has been very little research regarding SNAS in patients with IBS, and there are no standard guidelines for diagnosing and treating it.

What’s more, many gastroenterologists aren’t familiar with it. More than a dozen gastroenterologists who were contacted for comment declined to be interviewed because they didn’t know about SNAS – or enough about it to provide useful information for the story.

Ms. Finkel said she’s not surprised that many gastroenterologists don’t know much about how SNAS can mimic IBS, which is why she and her colleagues presented the seminar last October in Orlando. “It’s really an allergy and not a GI disease. It manifests with GI symptoms, but the root is not in the digestive tract; the root is in a true allergy – a clinical allergy – to nickel.”

Complicating the issue is that people who have IBS and those with SNAS typically share some common symptoms.

Like IBS, SNAS can cause GI symptoms – such as cramping, abdominal pain, heartburn, constipation, gaseous distension, and mucus in the stool. It can be triggered by certain fresh, cooked, and canned foods.

But the food triggers that cause SNAS are not usually those that cause IBS symptoms. Rather, SNAS flare-ups are nearly always triggered by foods with high levels of nickel. Examples include apricots, artichokes, asparagus, beans, cauliflower, chickpeas, cocoa/chocolate, figs, lentils, licorice, oats, onions, peas, peanuts, potatoes, spinach, tomatoes, and tea.

According to the American Academy of Allergy, Asthma & Immunology, a distinguishing feature of SNAS is that it can cause allergic contact dermatitis when a person touches something made with nickel. Coins, jewelry, eyeglasses, home fixtures, keys, zippers, dental devices, and even stainless-steel cookware can contain allergy-triggering nickel.

What Ms. Finkel sees the most are skin reactions from touching a surface containing nickel or from ingesting it, she said.

The other immediate symptom is abdominal pain or changes in bowel movements, such as diarrhea, she added.

Christopher Randolph, MD, an allergist based in Connecticut, told this news organization that it’s important for doctors to realize that patients who have a skin reaction to nickel may also have inflammatory GI symptoms.

“We definitely need more controlled studies,” said Dr. Randolph, of the department of allergy and immunology at Yale University, New Haven, Conn. “But the takeaway here is for patients and certainly providers to be mindful that you can have systemic reactions to nickel, even though you implicate only the contact dermatitis.”
 

Diagnosis and treatment recommendations

Skin patch allergy testing – in which a person’s skin is exposed to nickel – can quickly determine whether a patient with IBS is actually experiencing inflammatory reactions to dietary nickel and would benefit from a low-nickel or no-nickel diet, research shows.

For these patients, Dr. Pashinsky recommends the following:

• Avoiding high-nickel foods.
• Limiting canned foods.
• Using nonstainless cookware, especially for acidic foods.
• Boiling foods for potential nickel reduction, especially grains and vegetables.
• Running the tap before using water to drink or cook with first thing in the morning.

Dr. Pashisky and her team also recommend the following guidelines for doctors:

• Ask patients if symptoms occur immediately after eating certain high-nickel foods or worsen with a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet.
• Determine whether a patient is not responding to typical medical and dietary interventions used to treat IBS.
• Conduct a food/symptom history to identify potential nickel allergy triggers.
• Try a low-nickel dietary intervention to see whether a patient’s symptoms improve in a week or two.
• Refer the patient for additional diagnostic skin-patch testing or treatment.

A multidisciplinary approach

Ms. Finkel said it’s important for doctors, particularly gastroenterologists who treat patients for suspected GI disorders to consider nickel allergy as a cause.

“SNAS is this overlooked condition ... and the research is really in its nascency here,” Ms. Finkel said.

“I would say only give [a low- or no-nickel diet] consideration if the high-nickel foods are a possible trigger,” she said. “It is very specific, looking at their diet history, to have a clear hypothesis based on what their triggers are. It’s not something to try out lightly because it’s a very restrictive diet, so I would never put a patient on a diet that I didn’t think was necessary.”

Ms. Finkel added that treatment of SNAS requires a multidisciplinary approach with a gastroenterologist, an allergist, and a dietitian.

Doctors and dietitians have distinct roles in identifying and treating these patients, Ms. Finkel said.

“If there is a suspicion of IBS symptoms and the patient is not responding to first-line treatments, then it is worth having the input of a dietitian and an allergist,” she said.

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

In this issue, Regn and colleagues (page 78) have provided a concise resource for primary care professionals (PCPs) on a lesser known sleep disorder that is increasingly common in veterans.¹ Their review provides a basic understanding of central sleep apnea (CSA) and a systematic clinical approach to diagnosis and treatment in primary care. We applaud the authors for providing education on sleep disorders to the Federal Practitioner audience, since sleep disorders are prevalent among military service members and veterans, with significant implications for health, wellness, productivity, and cost. The American workforce has a long-held sense of pride in working hard, often at the expense of sleep. Early work start times are common in the military and federal government, and sleep medicine specialists have the expertise necessary to diagnose and treat the myriad of sleep disorders that have come to light recently. A massive shortage of sleep medicine specialists limits the evidence-based sleep treatment implementations in medical care.

Medicine has become increasingly complex, necessitating a highly connected web of people, resources, institutions, and processes to keep up with the demands of growing information and technology. The evolution of a systems approach to health care built momentum during the 21st century.1-3 The National Academy of Medicine has published 2 reports that raised concerns about the quality and safety of medical care.4,5 With this expansion, the potential for medical errors at individual components or relationship nodes between actors in the medical system also has grown. Medical errors encompass more than acts of commission and can also take the form of acts of omission by failing to diagnosis and appropriately treat before long-term or irrevocable health consequences occur. A systems approach seeks to aid clinical decision making to improve the quality of medical care and patient outcomes in an otherwise complex medical system that can be difficult to navigate.

Although awareness of obstructive sleep apnea (OSA) has increased, CSA has not received the same level of attention and may not be recognized by PCPs. A lack of education about CSA can contribute to acts of omission in a health care setting. Although CSA is ultimately diagnosed and managed in specialty care sleep medicine clinics, PCPs play an instrumental role in referring patients for evaluation and then collaborating with specialists to optimize care and outcomes. The multidisciplinary approach of CSA management is important because it overlaps with many conditions that are commonly seen in primary care, including obesity, chronic pain, congestive heart failure (CHF), chronic kidney disease, and hypothyroidism. These chronic conditions are also prevalent among veterans. In a national cross-sectional study, veterans had higher prevalence rates of chronic health conditions, including cardiovascular disease and kidney disease, compared with nonveterans (odds ratios, 1.4 and 1.2, respectively).⁶

It is important to understand the relationship between CSA and chronic medical conditions because recognizing the signs of CSA can lead to identification of underlying medical conditions. Likewise, the chronic medical conditions that lead to CSA may cue the PCP’s clinical suspicion for CSA and lead to specialty care referrals if needed. The clinician also serves a significant role in the management of CSA by optimizing medical care for the underlying condition prior to pursuing additional specialty care treatments like positive airway pressure (PAP). For example, PCPs are often involved in the management of atrial fibrillation and cardiac dysfunction, which can minimize or exacerbate CSA. PCPs should also be aware of which drugs are associated with the presentation of CSA as withdrawal or reduction of the medication can resolve symptoms without further evaluation by a specialist.

The review by Regn and colleagues updates readers on developments—and lack thereof—in the literature. Treatment options for CSA have been limited. For most patients, continuous PAP (CPAP), which is the gold standard treatment for OSA, is not an effective CSA treatment. Earlier specialty guidelines endorsed adaptive servo-ventilation (ASV), a more sophisticated respiratory assist device, for treating CSA. In 2015, the SERVE-HF trial examined the effects of ASV in combination with guideline-based medical treatment on survival and cardiovascular outcomes for patients who had CSA and HF with reduced ejection fraction.⁷ They found that ASV had no significant effect on the primary endpoints of first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening HF. However, all-cause and cardiovascular mortality were both increased with ASV. There has not been a more recent large clinical trial that either refutes or reinforces those findings (ADVENT-HF found that ASV effectively treated CSA and OSA in patients with CHF but had no impact on the primary endpoint of mortality).^7,8 We are unlikely to see more studies soon that will put this issue to rest and change the guidance that is currently available for ASV use.

Regn and colleagues also provide an update on the use of acetazolamide as to assist in CSA treatment. This should be done cautiously and potentially deferred to subspecialists in sleep medicine, cardiology, or nephrology. The theoretical benefit of acetazolamide in CSA is based on its promotion of excretion of sodium bicarbonate, leading to metabolic acidosis, which can stimulate central respiratory drive. Since CSA is characterized by episodic loss of central respiratory drive, it seems logical that a respiratory stimulant would provide benefit. However, acetazolamide is not approved by the US Food and Drug Administration for CSA.⁹ In those with impaired respiratory mechanics, CHF, chronic obstructive pulmonary disease, and obesity hypoventilation syndrome, this medication has the potential for harm by adding metabolic acidosis to a patient with concurrent respiratory acidosis or respiratory constraints that limit their ability to compensate effectively for additional acid-base derangements.

It is worth noting that Regn and colleagues do not make claims outside the intended scope. It accomplishes the mission of providing all PCPs with an updated streamlined summary for diagnosing and treating CSA. Such tools are important in an age of growing medical information technology because it can improve the quality of medical care and ultimately, patient outcomes with timely diagnosis and treatment. This is particularly significant in a veteran population with a high burden of chronic medical conditions and polypharmacy.

In this issue, Regn and colleagues (page 78) have provided a concise resource for primary care professionals (PCPs) on a lesser known sleep disorder that is increasingly common in veterans.¹ Their review provides a basic understanding of central sleep apnea (CSA) and a systematic clinical approach to diagnosis and treatment in primary care. We applaud the authors for providing education on sleep disorders to the Federal Practitioner audience, since sleep disorders are prevalent among military service members and veterans, with significant implications for health, wellness, productivity, and cost. The American workforce has a long-held sense of pride in working hard, often at the expense of sleep. Early work start times are common in the military and federal government, and sleep medicine specialists have the expertise necessary to diagnose and treat the myriad of sleep disorders that have come to light recently. A massive shortage of sleep medicine specialists limits the evidence-based sleep treatment implementations in medical care.

Medicine has become increasingly complex, necessitating a highly connected web of people, resources, institutions, and processes to keep up with the demands of growing information and technology. The evolution of a systems approach to health care built momentum during the 21st century.1-3 The National Academy of Medicine has published 2 reports that raised concerns about the quality and safety of medical care.4,5 With this expansion, the potential for medical errors at individual components or relationship nodes between actors in the medical system also has grown. Medical errors encompass more than acts of commission and can also take the form of acts of omission by failing to diagnosis and appropriately treat before long-term or irrevocable health consequences occur. A systems approach seeks to aid clinical decision making to improve the quality of medical care and patient outcomes in an otherwise complex medical system that can be difficult to navigate.

Although awareness of obstructive sleep apnea (OSA) has increased, CSA has not received the same level of attention and may not be recognized by PCPs. A lack of education about CSA can contribute to acts of omission in a health care setting. Although CSA is ultimately diagnosed and managed in specialty care sleep medicine clinics, PCPs play an instrumental role in referring patients for evaluation and then collaborating with specialists to optimize care and outcomes. The multidisciplinary approach of CSA management is important because it overlaps with many conditions that are commonly seen in primary care, including obesity, chronic pain, congestive heart failure (CHF), chronic kidney disease, and hypothyroidism. These chronic conditions are also prevalent among veterans. In a national cross-sectional study, veterans had higher prevalence rates of chronic health conditions, including cardiovascular disease and kidney disease, compared with nonveterans (odds ratios, 1.4 and 1.2, respectively).⁶

It is important to understand the relationship between CSA and chronic medical conditions because recognizing the signs of CSA can lead to identification of underlying medical conditions. Likewise, the chronic medical conditions that lead to CSA may cue the PCP’s clinical suspicion for CSA and lead to specialty care referrals if needed. The clinician also serves a significant role in the management of CSA by optimizing medical care for the underlying condition prior to pursuing additional specialty care treatments like positive airway pressure (PAP). For example, PCPs are often involved in the management of atrial fibrillation and cardiac dysfunction, which can minimize or exacerbate CSA. PCPs should also be aware of which drugs are associated with the presentation of CSA as withdrawal or reduction of the medication can resolve symptoms without further evaluation by a specialist.

The review by Regn and colleagues updates readers on developments—and lack thereof—in the literature. Treatment options for CSA have been limited. For most patients, continuous PAP (CPAP), which is the gold standard treatment for OSA, is not an effective CSA treatment. Earlier specialty guidelines endorsed adaptive servo-ventilation (ASV), a more sophisticated respiratory assist device, for treating CSA. In 2015, the SERVE-HF trial examined the effects of ASV in combination with guideline-based medical treatment on survival and cardiovascular outcomes for patients who had CSA and HF with reduced ejection fraction.⁷ They found that ASV had no significant effect on the primary endpoints of first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening HF. However, all-cause and cardiovascular mortality were both increased with ASV. There has not been a more recent large clinical trial that either refutes or reinforces those findings (ADVENT-HF found that ASV effectively treated CSA and OSA in patients with CHF but had no impact on the primary endpoint of mortality).^7,8 We are unlikely to see more studies soon that will put this issue to rest and change the guidance that is currently available for ASV use.

Regn and colleagues also provide an update on the use of acetazolamide as to assist in CSA treatment. This should be done cautiously and potentially deferred to subspecialists in sleep medicine, cardiology, or nephrology. The theoretical benefit of acetazolamide in CSA is based on its promotion of excretion of sodium bicarbonate, leading to metabolic acidosis, which can stimulate central respiratory drive. Since CSA is characterized by episodic loss of central respiratory drive, it seems logical that a respiratory stimulant would provide benefit. However, acetazolamide is not approved by the US Food and Drug Administration for CSA.⁹ In those with impaired respiratory mechanics, CHF, chronic obstructive pulmonary disease, and obesity hypoventilation syndrome, this medication has the potential for harm by adding metabolic acidosis to a patient with concurrent respiratory acidosis or respiratory constraints that limit their ability to compensate effectively for additional acid-base derangements.

It is worth noting that Regn and colleagues do not make claims outside the intended scope. It accomplishes the mission of providing all PCPs with an updated streamlined summary for diagnosing and treating CSA. Such tools are important in an age of growing medical information technology because it can improve the quality of medical care and ultimately, patient outcomes with timely diagnosis and treatment. This is particularly significant in a veteran population with a high burden of chronic medical conditions and polypharmacy.

In this issue, Regn and colleagues (page 78) have provided a concise resource for primary care professionals (PCPs) on a lesser known sleep disorder that is increasingly common in veterans.¹ Their review provides a basic understanding of central sleep apnea (CSA) and a systematic clinical approach to diagnosis and treatment in primary care. We applaud the authors for providing education on sleep disorders to the Federal Practitioner audience, since sleep disorders are prevalent among military service members and veterans, with significant implications for health, wellness, productivity, and cost. The American workforce has a long-held sense of pride in working hard, often at the expense of sleep. Early work start times are common in the military and federal government, and sleep medicine specialists have the expertise necessary to diagnose and treat the myriad of sleep disorders that have come to light recently. A massive shortage of sleep medicine specialists limits the evidence-based sleep treatment implementations in medical care.

Medicine has become increasingly complex, necessitating a highly connected web of people, resources, institutions, and processes to keep up with the demands of growing information and technology. The evolution of a systems approach to health care built momentum during the 21st century.1-3 The National Academy of Medicine has published 2 reports that raised concerns about the quality and safety of medical care.4,5 With this expansion, the potential for medical errors at individual components or relationship nodes between actors in the medical system also has grown. Medical errors encompass more than acts of commission and can also take the form of acts of omission by failing to diagnosis and appropriately treat before long-term or irrevocable health consequences occur. A systems approach seeks to aid clinical decision making to improve the quality of medical care and patient outcomes in an otherwise complex medical system that can be difficult to navigate.

Although awareness of obstructive sleep apnea (OSA) has increased, CSA has not received the same level of attention and may not be recognized by PCPs. A lack of education about CSA can contribute to acts of omission in a health care setting. Although CSA is ultimately diagnosed and managed in specialty care sleep medicine clinics, PCPs play an instrumental role in referring patients for evaluation and then collaborating with specialists to optimize care and outcomes. The multidisciplinary approach of CSA management is important because it overlaps with many conditions that are commonly seen in primary care, including obesity, chronic pain, congestive heart failure (CHF), chronic kidney disease, and hypothyroidism. These chronic conditions are also prevalent among veterans. In a national cross-sectional study, veterans had higher prevalence rates of chronic health conditions, including cardiovascular disease and kidney disease, compared with nonveterans (odds ratios, 1.4 and 1.2, respectively).⁶

It is important to understand the relationship between CSA and chronic medical conditions because recognizing the signs of CSA can lead to identification of underlying medical conditions. Likewise, the chronic medical conditions that lead to CSA may cue the PCP’s clinical suspicion for CSA and lead to specialty care referrals if needed. The clinician also serves a significant role in the management of CSA by optimizing medical care for the underlying condition prior to pursuing additional specialty care treatments like positive airway pressure (PAP). For example, PCPs are often involved in the management of atrial fibrillation and cardiac dysfunction, which can minimize or exacerbate CSA. PCPs should also be aware of which drugs are associated with the presentation of CSA as withdrawal or reduction of the medication can resolve symptoms without further evaluation by a specialist.

The review by Regn and colleagues updates readers on developments—and lack thereof—in the literature. Treatment options for CSA have been limited. For most patients, continuous PAP (CPAP), which is the gold standard treatment for OSA, is not an effective CSA treatment. Earlier specialty guidelines endorsed adaptive servo-ventilation (ASV), a more sophisticated respiratory assist device, for treating CSA. In 2015, the SERVE-HF trial examined the effects of ASV in combination with guideline-based medical treatment on survival and cardiovascular outcomes for patients who had CSA and HF with reduced ejection fraction.⁷ They found that ASV had no significant effect on the primary endpoints of first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening HF. However, all-cause and cardiovascular mortality were both increased with ASV. There has not been a more recent large clinical trial that either refutes or reinforces those findings (ADVENT-HF found that ASV effectively treated CSA and OSA in patients with CHF but had no impact on the primary endpoint of mortality).^7,8 We are unlikely to see more studies soon that will put this issue to rest and change the guidance that is currently available for ASV use.

Regn and colleagues also provide an update on the use of acetazolamide as to assist in CSA treatment. This should be done cautiously and potentially deferred to subspecialists in sleep medicine, cardiology, or nephrology. The theoretical benefit of acetazolamide in CSA is based on its promotion of excretion of sodium bicarbonate, leading to metabolic acidosis, which can stimulate central respiratory drive. Since CSA is characterized by episodic loss of central respiratory drive, it seems logical that a respiratory stimulant would provide benefit. However, acetazolamide is not approved by the US Food and Drug Administration for CSA.⁹ In those with impaired respiratory mechanics, CHF, chronic obstructive pulmonary disease, and obesity hypoventilation syndrome, this medication has the potential for harm by adding metabolic acidosis to a patient with concurrent respiratory acidosis or respiratory constraints that limit their ability to compensate effectively for additional acid-base derangements.

It is worth noting that Regn and colleagues do not make claims outside the intended scope. It accomplishes the mission of providing all PCPs with an updated streamlined summary for diagnosing and treating CSA. Such tools are important in an age of growing medical information technology because it can improve the quality of medical care and ultimately, patient outcomes with timely diagnosis and treatment. This is particularly significant in a veteran population with a high burden of chronic medical conditions and polypharmacy.

Sleep Medicine Network

Home-Based Mechanical Ventilation & Neuromuscular Disease Section

Novel therapies for neuromuscular disease: What are the respiratory and sleep implications?

The natural history of respiratory impairment in children and adults with progressive neuromuscular disease (NMD) often follows a predictable progression. Muscle weakness leads to sleep-disordered breathing and sleep-related hypoventilation, followed by diurnal hypoventilation, and, ultimately leads to respiratory failure. A number of disease-specific and society guidelines provide protocols for anticipatory respiratory monitoring, such as the role of polysomnography, pulmonary function testing, and respiratory muscle strength testing. They also guide the treatment of respiratory symptoms, such as when to initiate cough augmentation and assisted ventilation.

The emergence of disease-modifying therapies over the last decade has changed the landscape of a number of neuromuscular diseases, including spinal muscular atrophy (SMA) and Duchenne muscular dystrophy. There are now cases of children with SMA type 1, who subsequent to treatment, are walking independently. Studies examining the impact of these therapies on motor function use standardized assessments, but there are limited studies assessing pulmonary and sleep outcomes (Gurbani N, et al. Pediatr Pulmonol. 2021;56[4]:700).

Researchers are also assessing the role of home testing to diagnose hypoventilation (Shi J, et al. Sleep Med. 2023;101:221-7) and using tools like positive airway pressure device data to guide treatment with noninvasive ventilation (Perrem L et al. Pediatr Pulmonol. 2020;55[1]:58-67). While these advances in therapy are exciting, we still do not know what the long-term respiratory function, prognosis, or disease progression may be. Questions remain regarding how to best monitor, and at what frequency to assess, the respiratory status in these patients.

Moshe Y. Prero, MD
Section Member-at-Large

Sleep Medicine Network

Home-Based Mechanical Ventilation & Neuromuscular Disease Section

Novel therapies for neuromuscular disease: What are the respiratory and sleep implications?

The natural history of respiratory impairment in children and adults with progressive neuromuscular disease (NMD) often follows a predictable progression. Muscle weakness leads to sleep-disordered breathing and sleep-related hypoventilation, followed by diurnal hypoventilation, and, ultimately leads to respiratory failure. A number of disease-specific and society guidelines provide protocols for anticipatory respiratory monitoring, such as the role of polysomnography, pulmonary function testing, and respiratory muscle strength testing. They also guide the treatment of respiratory symptoms, such as when to initiate cough augmentation and assisted ventilation.

The emergence of disease-modifying therapies over the last decade has changed the landscape of a number of neuromuscular diseases, including spinal muscular atrophy (SMA) and Duchenne muscular dystrophy. There are now cases of children with SMA type 1, who subsequent to treatment, are walking independently. Studies examining the impact of these therapies on motor function use standardized assessments, but there are limited studies assessing pulmonary and sleep outcomes (Gurbani N, et al. Pediatr Pulmonol. 2021;56[4]:700).

Researchers are also assessing the role of home testing to diagnose hypoventilation (Shi J, et al. Sleep Med. 2023;101:221-7) and using tools like positive airway pressure device data to guide treatment with noninvasive ventilation (Perrem L et al. Pediatr Pulmonol. 2020;55[1]:58-67). While these advances in therapy are exciting, we still do not know what the long-term respiratory function, prognosis, or disease progression may be. Questions remain regarding how to best monitor, and at what frequency to assess, the respiratory status in these patients.

Moshe Y. Prero, MD
Section Member-at-Large

Sleep Medicine Network

Home-Based Mechanical Ventilation & Neuromuscular Disease Section

Novel therapies for neuromuscular disease: What are the respiratory and sleep implications?

The natural history of respiratory impairment in children and adults with progressive neuromuscular disease (NMD) often follows a predictable progression. Muscle weakness leads to sleep-disordered breathing and sleep-related hypoventilation, followed by diurnal hypoventilation, and, ultimately leads to respiratory failure. A number of disease-specific and society guidelines provide protocols for anticipatory respiratory monitoring, such as the role of polysomnography, pulmonary function testing, and respiratory muscle strength testing. They also guide the treatment of respiratory symptoms, such as when to initiate cough augmentation and assisted ventilation.

The emergence of disease-modifying therapies over the last decade has changed the landscape of a number of neuromuscular diseases, including spinal muscular atrophy (SMA) and Duchenne muscular dystrophy. There are now cases of children with SMA type 1, who subsequent to treatment, are walking independently. Studies examining the impact of these therapies on motor function use standardized assessments, but there are limited studies assessing pulmonary and sleep outcomes (Gurbani N, et al. Pediatr Pulmonol. 2021;56[4]:700).

Researchers are also assessing the role of home testing to diagnose hypoventilation (Shi J, et al. Sleep Med. 2023;101:221-7) and using tools like positive airway pressure device data to guide treatment with noninvasive ventilation (Perrem L et al. Pediatr Pulmonol. 2020;55[1]:58-67). While these advances in therapy are exciting, we still do not know what the long-term respiratory function, prognosis, or disease progression may be. Questions remain regarding how to best monitor, and at what frequency to assess, the respiratory status in these patients.

Moshe Y. Prero, MD
Section Member-at-Large

Despite their convenience and low cost, handheld point-of-care (POC) devices lack precision for measuring neonatal bilirubin and need refinement in order to tailor jaundice management in newborns, a systematic review and meta-analysis reports in JAMA Pediatrics. Lauren E.H. Westenberg, MD, of the division of neonatology at Erasmus MC Sophia Children’s Hospital in Rotterdam, the Netherlands, and colleagues reported that POC meters tended to underestimate neonatal bilirubin levels, compared with conventional laboratory-based quantification.

A.H. Westenberg

Furthermore, pooled estimates from 10 studies found these devices to be too imprecise overall, with substantial outer-confidence bounds. On the plus side, Dr. Westenberg’s group said POC bilirubin testing was as much as 60 times faster than lab measurement, and used 40-60 times less blood. “Conventional laboratory-based bilirubin quantification usually requires up to 500 mcL, but sometimes even 1,500 mcL, while POC tests require up to 50 mcL, which means less stress for the baby,” Dr. Westenberg said in an interview. “Especially when infants are cared for at home, it usually takes a few hours between deciding to quantify bilirubin and obtaining the test result. Meanwhile, bilirubin levels may rise unnoticed.”

On the positive side, POC devices are useful where laboratories in low-resource areas may be remote, poorly equipped, and not always able to provide an accurate bilirubin level. “As a result, the diagnosis of jaundice relies mainly on visual inspection, which is known to be unreliable,” she said. POC devices, however, need near-perfect conditions for optimal use, and results can be affected by humidity, preanalytic conditions such as test strip saturation, and hematocrit.

Yet results from these devices have recently proven to have acceptable accuracy, resulting, for example, in the same clinical decisions as the reference standard in 90.7% of times according to a 2022 study in a hospital in Malawi.

Nevertheless, the authors concluded that the devices’ imprecision limits their widespread use in neonatal jaundice management, especially when accurate lab-based bilirubin quantification is available. Results from these POC tests should be interpreted with caution, Dr. Westenberg said. In terms of clinical decision-making, POC devices entail a risk of missing neonates with jaundice who need phototherapy or, in the case of overestimation, of starting phototherapy too early.

The study

The meta-analysis included nine cross-sectional and one prospective cohort study representing 3,122 neonates in Europe, Africa, and East and Southeast Asia. Two tests with 30-minute turnaround times were evaluated in neonates 0-28 days old. The Bilistick device was evaluated in eight studies and the BiliSpec (now called BiliDX) in just two studies. Three of the studies had a high risk of bias.

A total of 3,122 measurements paired with lab quantification showed a pooled mean difference in total bilirubin levels for the POC devices of –14 micromol/L, with pooled 95% confidence bounds (CBs) of –106 to 78 micromol/L. For the Bilistick, the pooled mean difference was –17 micromol/L (95% CBs, –114 to 80 micromol/L). Of the two devices, the Bilistick was more likely to have a failed quantification against the reference standard.
 

Context for POC devices

Commenting on the meta-analysis but not involved in it, Rebecca Richards-Kortum, PhD, a professor of biomedical engineering at Rice University in Houston, noted that both devices were developed specifically to address needs in low-resource settings. “I don’t think the meta-analysis acknowledges this rationale sufficiently,” she said. “It feels like this paper is comparing apples to oranges and then criticizing the apples for not being oranges,” said Dr. Richards-Kortum, who helped develop the BiliSpec test.

John D. and Catherine T. MacArthur Foundation

Similarly, Anne S. Lee, MD, MPH, an associate professor of pediatrics at Brigham and Women’s Hospital in Boston, and not a participant in the meta-analysis, also stressed that POC devices are designed for scenarios where lab-based results are not widely available. “In a broad sense, the devices fill an important gap, both in low- and middle-income countries, as well as in the U.S. when laboratory capacity is not readily available,” said Dr. Lee. She was involved the development of the Bili-ruler icterometer, which proved to be diagnostically accurate in Bangladeshi newborns.

“Access to this technology is a critical way to address health disparities even in the U.S.,” Dr. Lee continued. “We have heard of the need for this technology from the Indian health services and Alaskan health services, where decisions are made to airlift a child based on a visual inspection alone.”

More broadly, however, cautioned Dr. Westenberg, the total allowable error and the permissible limits of uncertainty in neonatal bilirubin quantification need to be defined – irrespective of the method used. “Accurate measurement of bilirubin is difficult as has been demonstrated in so-called external quality assessment (EQA) programs that exist for laboratory-based bilirubin methods,” she said. “EQA programs for POC bilirubin devices that include a reference method as a gold standard may contribute to adaptation of the device and improving POC test imprecision.”

This work was supported by the Netherlands Organization for Health Research and Development. The authors had no conflicts of interest to disclose. Dr. Richards-Kortum and Dr. Lee have both been involved in the development of POC devices for assessing neonatal bilirubin levels.
 

Despite their convenience and low cost, handheld point-of-care (POC) devices lack precision for measuring neonatal bilirubin and need refinement in order to tailor jaundice management in newborns, a systematic review and meta-analysis reports in JAMA Pediatrics. Lauren E.H. Westenberg, MD, of the division of neonatology at Erasmus MC Sophia Children’s Hospital in Rotterdam, the Netherlands, and colleagues reported that POC meters tended to underestimate neonatal bilirubin levels, compared with conventional laboratory-based quantification.

A.H. Westenberg

Furthermore, pooled estimates from 10 studies found these devices to be too imprecise overall, with substantial outer-confidence bounds. On the plus side, Dr. Westenberg’s group said POC bilirubin testing was as much as 60 times faster than lab measurement, and used 40-60 times less blood. “Conventional laboratory-based bilirubin quantification usually requires up to 500 mcL, but sometimes even 1,500 mcL, while POC tests require up to 50 mcL, which means less stress for the baby,” Dr. Westenberg said in an interview. “Especially when infants are cared for at home, it usually takes a few hours between deciding to quantify bilirubin and obtaining the test result. Meanwhile, bilirubin levels may rise unnoticed.”

On the positive side, POC devices are useful where laboratories in low-resource areas may be remote, poorly equipped, and not always able to provide an accurate bilirubin level. “As a result, the diagnosis of jaundice relies mainly on visual inspection, which is known to be unreliable,” she said. POC devices, however, need near-perfect conditions for optimal use, and results can be affected by humidity, preanalytic conditions such as test strip saturation, and hematocrit.

Yet results from these devices have recently proven to have acceptable accuracy, resulting, for example, in the same clinical decisions as the reference standard in 90.7% of times according to a 2022 study in a hospital in Malawi.

Nevertheless, the authors concluded that the devices’ imprecision limits their widespread use in neonatal jaundice management, especially when accurate lab-based bilirubin quantification is available. Results from these POC tests should be interpreted with caution, Dr. Westenberg said. In terms of clinical decision-making, POC devices entail a risk of missing neonates with jaundice who need phototherapy or, in the case of overestimation, of starting phototherapy too early.

The study

The meta-analysis included nine cross-sectional and one prospective cohort study representing 3,122 neonates in Europe, Africa, and East and Southeast Asia. Two tests with 30-minute turnaround times were evaluated in neonates 0-28 days old. The Bilistick device was evaluated in eight studies and the BiliSpec (now called BiliDX) in just two studies. Three of the studies had a high risk of bias.

A total of 3,122 measurements paired with lab quantification showed a pooled mean difference in total bilirubin levels for the POC devices of –14 micromol/L, with pooled 95% confidence bounds (CBs) of –106 to 78 micromol/L. For the Bilistick, the pooled mean difference was –17 micromol/L (95% CBs, –114 to 80 micromol/L). Of the two devices, the Bilistick was more likely to have a failed quantification against the reference standard.
 

Context for POC devices

Commenting on the meta-analysis but not involved in it, Rebecca Richards-Kortum, PhD, a professor of biomedical engineering at Rice University in Houston, noted that both devices were developed specifically to address needs in low-resource settings. “I don’t think the meta-analysis acknowledges this rationale sufficiently,” she said. “It feels like this paper is comparing apples to oranges and then criticizing the apples for not being oranges,” said Dr. Richards-Kortum, who helped develop the BiliSpec test.

John D. and Catherine T. MacArthur Foundation

Similarly, Anne S. Lee, MD, MPH, an associate professor of pediatrics at Brigham and Women’s Hospital in Boston, and not a participant in the meta-analysis, also stressed that POC devices are designed for scenarios where lab-based results are not widely available. “In a broad sense, the devices fill an important gap, both in low- and middle-income countries, as well as in the U.S. when laboratory capacity is not readily available,” said Dr. Lee. She was involved the development of the Bili-ruler icterometer, which proved to be diagnostically accurate in Bangladeshi newborns.

“Access to this technology is a critical way to address health disparities even in the U.S.,” Dr. Lee continued. “We have heard of the need for this technology from the Indian health services and Alaskan health services, where decisions are made to airlift a child based on a visual inspection alone.”

More broadly, however, cautioned Dr. Westenberg, the total allowable error and the permissible limits of uncertainty in neonatal bilirubin quantification need to be defined – irrespective of the method used. “Accurate measurement of bilirubin is difficult as has been demonstrated in so-called external quality assessment (EQA) programs that exist for laboratory-based bilirubin methods,” she said. “EQA programs for POC bilirubin devices that include a reference method as a gold standard may contribute to adaptation of the device and improving POC test imprecision.”

This work was supported by the Netherlands Organization for Health Research and Development. The authors had no conflicts of interest to disclose. Dr. Richards-Kortum and Dr. Lee have both been involved in the development of POC devices for assessing neonatal bilirubin levels.
 

Despite their convenience and low cost, handheld point-of-care (POC) devices lack precision for measuring neonatal bilirubin and need refinement in order to tailor jaundice management in newborns, a systematic review and meta-analysis reports in JAMA Pediatrics. Lauren E.H. Westenberg, MD, of the division of neonatology at Erasmus MC Sophia Children’s Hospital in Rotterdam, the Netherlands, and colleagues reported that POC meters tended to underestimate neonatal bilirubin levels, compared with conventional laboratory-based quantification.

A.H. Westenberg

Furthermore, pooled estimates from 10 studies found these devices to be too imprecise overall, with substantial outer-confidence bounds. On the plus side, Dr. Westenberg’s group said POC bilirubin testing was as much as 60 times faster than lab measurement, and used 40-60 times less blood. “Conventional laboratory-based bilirubin quantification usually requires up to 500 mcL, but sometimes even 1,500 mcL, while POC tests require up to 50 mcL, which means less stress for the baby,” Dr. Westenberg said in an interview. “Especially when infants are cared for at home, it usually takes a few hours between deciding to quantify bilirubin and obtaining the test result. Meanwhile, bilirubin levels may rise unnoticed.”

On the positive side, POC devices are useful where laboratories in low-resource areas may be remote, poorly equipped, and not always able to provide an accurate bilirubin level. “As a result, the diagnosis of jaundice relies mainly on visual inspection, which is known to be unreliable,” she said. POC devices, however, need near-perfect conditions for optimal use, and results can be affected by humidity, preanalytic conditions such as test strip saturation, and hematocrit.

Yet results from these devices have recently proven to have acceptable accuracy, resulting, for example, in the same clinical decisions as the reference standard in 90.7% of times according to a 2022 study in a hospital in Malawi.

Nevertheless, the authors concluded that the devices’ imprecision limits their widespread use in neonatal jaundice management, especially when accurate lab-based bilirubin quantification is available. Results from these POC tests should be interpreted with caution, Dr. Westenberg said. In terms of clinical decision-making, POC devices entail a risk of missing neonates with jaundice who need phototherapy or, in the case of overestimation, of starting phototherapy too early.

The study

The meta-analysis included nine cross-sectional and one prospective cohort study representing 3,122 neonates in Europe, Africa, and East and Southeast Asia. Two tests with 30-minute turnaround times were evaluated in neonates 0-28 days old. The Bilistick device was evaluated in eight studies and the BiliSpec (now called BiliDX) in just two studies. Three of the studies had a high risk of bias.

A total of 3,122 measurements paired with lab quantification showed a pooled mean difference in total bilirubin levels for the POC devices of –14 micromol/L, with pooled 95% confidence bounds (CBs) of –106 to 78 micromol/L. For the Bilistick, the pooled mean difference was –17 micromol/L (95% CBs, –114 to 80 micromol/L). Of the two devices, the Bilistick was more likely to have a failed quantification against the reference standard.
 

Context for POC devices

Commenting on the meta-analysis but not involved in it, Rebecca Richards-Kortum, PhD, a professor of biomedical engineering at Rice University in Houston, noted that both devices were developed specifically to address needs in low-resource settings. “I don’t think the meta-analysis acknowledges this rationale sufficiently,” she said. “It feels like this paper is comparing apples to oranges and then criticizing the apples for not being oranges,” said Dr. Richards-Kortum, who helped develop the BiliSpec test.

John D. and Catherine T. MacArthur Foundation

Similarly, Anne S. Lee, MD, MPH, an associate professor of pediatrics at Brigham and Women’s Hospital in Boston, and not a participant in the meta-analysis, also stressed that POC devices are designed for scenarios where lab-based results are not widely available. “In a broad sense, the devices fill an important gap, both in low- and middle-income countries, as well as in the U.S. when laboratory capacity is not readily available,” said Dr. Lee. She was involved the development of the Bili-ruler icterometer, which proved to be diagnostically accurate in Bangladeshi newborns.

“Access to this technology is a critical way to address health disparities even in the U.S.,” Dr. Lee continued. “We have heard of the need for this technology from the Indian health services and Alaskan health services, where decisions are made to airlift a child based on a visual inspection alone.”

More broadly, however, cautioned Dr. Westenberg, the total allowable error and the permissible limits of uncertainty in neonatal bilirubin quantification need to be defined – irrespective of the method used. “Accurate measurement of bilirubin is difficult as has been demonstrated in so-called external quality assessment (EQA) programs that exist for laboratory-based bilirubin methods,” she said. “EQA programs for POC bilirubin devices that include a reference method as a gold standard may contribute to adaptation of the device and improving POC test imprecision.”

This work was supported by the Netherlands Organization for Health Research and Development. The authors had no conflicts of interest to disclose. Dr. Richards-Kortum and Dr. Lee have both been involved in the development of POC devices for assessing neonatal bilirubin levels.
 

Radiation dermatitis is one of the most common side effects of radiotherapy for women with breast cancer. Results from a phase 3 trial add to previous evidence from smaller trials that show that a silicone-based film can protect skin from this side effect. 

But it is not being used much in clinical practice. Instead, radiation dermatitis is usually treated after the fact, most often with aqueous creams.

The product is Mepitel film, from Swedish medical device company Mölnlycke Health Care.

It should be used for women who are at high risk for developing radiation dermatitis, said Edward Chow, MBBS, PhD, of the department of radiation oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, who was the senior author of the phase 3 study published recently in the Journal of Clinical Oncology.

“Other doctors think that because radiation dermatitis isn’t life-threatening it isn’t as important, but the condition does affect the quality of life for patients,” Dr. Chow said. “If we can lessen the pain and discomfort, why wouldn’t we as physicians?”

Dr. Chow’s open-label, multicenter trial was conducted in 376 women with large breasts (bra cup size C or larger) who were undergoing radiotherapy after lumpectomy or mastectomy. The primary endpoint was grade 2 or 3 radiation dermatitis using the Common Terminology Criteria for Adverse Events. (Grade 2 is described as moderate, whereas grade 3 is severe.) 

The film significantly reduced the incidence of grade 2 or 3 radiation dermatitis, down to  15.5% compared with 45.6% in patients receiving standard care (odds ratio, 0.20, 95% confidence interval, 0.12-0.34, P < .0001). 

There was also a significant reduction in grade 3 radiation dermatitis (2.8% vs. 13.6%; OR, 0.19; P < .0002) and moist desquamation (8% vs. 19.2%; OR, 0.36; P = .002).

“The film was remarkably effective and helped protect patients from potentially debilitating side effects,” commented Corey Speers, MD, PhD, a radiation oncologist with University Hospitals, Cleveland, who saw the study data presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

He believes that preventing radiation dermatitis before it develops is the best way to care for patients. 

“[Radiation dermatitis] is usually associated with pain and discomfort and can lead to more serious issues like infection or delayed wound healing, and unfortunately, there aren’t effective treatments for it once it’s developed, so preventing it is our most effective strategy,” Dr. Speers said. 

One reason for the film not being used much could be that it takes time apply the film, suggested Patries Herst, PhD, department of radiation therapy, University of Otago, Wellington, New Zealand. She was the lead author of a study published in 2014 that also analyzed the effectiveness of the film in preventing radiation dermatitis.

In their trial, a research radiation therapist applied the film to women when they were starting their radiotherapy. The film is applied to a portion of the breast or chest wall, and Dr. Herst emphasized the importance of applying the film correctly, making sure the film is not stretched during application and not overlapping other pieces of the film, while also making sure that it conforms to the breast shape. The film was replaced when it would curl too much around the sides, approximately every 1 or 2 weeks. 

“Radiation therapy itself is very short. And so you have about 10 minutes for every patient,” she explained.

“But applying the film adds 20-30 minutes and it’s really awkward to apply properly,” Dr. Herst said. “You have to tap it in and then have to maybe cut it so that it fits better. And hospitals say, ‘We don’t have the time’ and that is still the biggest issue that we’re seeing right now.”

In Dr. Chow’s study, the average time spent applying the film on lumpectomy patients was 55 minutes and was slightly shorter at 45 minutes for mastectomy patients. He acknowledged that it does take time that staff at most hospitals and clinics simply don’t have.

Dr. Chow suggested that perhaps a family member or other caregiver could apply the film, and he referenced an educational video from the manufacturer that provides in-depth instructions on the correct way to apply the film for radiotherapy patients. However, this could lead to errors and a waste of product if not the film was not applied properly. 

The cost of Mepitel film may also be a deterrent. Dr. Chow’s study noted that, during the entire course of radiotherapy, the cost for the film was about $80-$100 per patient. However, he believes the benefits outweigh the cost. 

In addition, there have been issues with supplies, and it has been difficult for people to get their hands on the actual product.

Currently, the Mayo Clinic is also conducting a study testing Mepitel Film for radiation dermatitis in breast cancer patients following mastectomy. Mayo Clinic principal investigator Kimberly Corbin, MD, could not go into great detail about the ongoing trial, but she said it has been difficult to get the product. 

“We have been using the film at Mayo for a number of years,” Dr. Corbin said, but we “have found that it is challenging to get supplies.”

“While we have generally been able to have some supply established through our store here, we know that is not typical and it is difficult for patients to access,” she said. In addition, “there are not a ton of centers with experience in application.”

A representative with Mölnlycke Health Care, Allyson Bower-Willner, could not comment on the distribution of Mepitel film in the United States or if the company plans to increase the amount of product shipped. The film is available “to a limited set of customers,” she said.

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

Radiation dermatitis is one of the most common side effects of radiotherapy for women with breast cancer. Results from a phase 3 trial add to previous evidence from smaller trials that show that a silicone-based film can protect skin from this side effect. 

But it is not being used much in clinical practice. Instead, radiation dermatitis is usually treated after the fact, most often with aqueous creams.

The product is Mepitel film, from Swedish medical device company Mölnlycke Health Care.

It should be used for women who are at high risk for developing radiation dermatitis, said Edward Chow, MBBS, PhD, of the department of radiation oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, who was the senior author of the phase 3 study published recently in the Journal of Clinical Oncology.

“Other doctors think that because radiation dermatitis isn’t life-threatening it isn’t as important, but the condition does affect the quality of life for patients,” Dr. Chow said. “If we can lessen the pain and discomfort, why wouldn’t we as physicians?”

Dr. Chow’s open-label, multicenter trial was conducted in 376 women with large breasts (bra cup size C or larger) who were undergoing radiotherapy after lumpectomy or mastectomy. The primary endpoint was grade 2 or 3 radiation dermatitis using the Common Terminology Criteria for Adverse Events. (Grade 2 is described as moderate, whereas grade 3 is severe.) 

The film significantly reduced the incidence of grade 2 or 3 radiation dermatitis, down to  15.5% compared with 45.6% in patients receiving standard care (odds ratio, 0.20, 95% confidence interval, 0.12-0.34, P < .0001). 

There was also a significant reduction in grade 3 radiation dermatitis (2.8% vs. 13.6%; OR, 0.19; P < .0002) and moist desquamation (8% vs. 19.2%; OR, 0.36; P = .002).

“The film was remarkably effective and helped protect patients from potentially debilitating side effects,” commented Corey Speers, MD, PhD, a radiation oncologist with University Hospitals, Cleveland, who saw the study data presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

He believes that preventing radiation dermatitis before it develops is the best way to care for patients. 

“[Radiation dermatitis] is usually associated with pain and discomfort and can lead to more serious issues like infection or delayed wound healing, and unfortunately, there aren’t effective treatments for it once it’s developed, so preventing it is our most effective strategy,” Dr. Speers said. 

One reason for the film not being used much could be that it takes time apply the film, suggested Patries Herst, PhD, department of radiation therapy, University of Otago, Wellington, New Zealand. She was the lead author of a study published in 2014 that also analyzed the effectiveness of the film in preventing radiation dermatitis.

In their trial, a research radiation therapist applied the film to women when they were starting their radiotherapy. The film is applied to a portion of the breast or chest wall, and Dr. Herst emphasized the importance of applying the film correctly, making sure the film is not stretched during application and not overlapping other pieces of the film, while also making sure that it conforms to the breast shape. The film was replaced when it would curl too much around the sides, approximately every 1 or 2 weeks. 

“Radiation therapy itself is very short. And so you have about 10 minutes for every patient,” she explained.

“But applying the film adds 20-30 minutes and it’s really awkward to apply properly,” Dr. Herst said. “You have to tap it in and then have to maybe cut it so that it fits better. And hospitals say, ‘We don’t have the time’ and that is still the biggest issue that we’re seeing right now.”

In Dr. Chow’s study, the average time spent applying the film on lumpectomy patients was 55 minutes and was slightly shorter at 45 minutes for mastectomy patients. He acknowledged that it does take time that staff at most hospitals and clinics simply don’t have.

Dr. Chow suggested that perhaps a family member or other caregiver could apply the film, and he referenced an educational video from the manufacturer that provides in-depth instructions on the correct way to apply the film for radiotherapy patients. However, this could lead to errors and a waste of product if not the film was not applied properly. 

The cost of Mepitel film may also be a deterrent. Dr. Chow’s study noted that, during the entire course of radiotherapy, the cost for the film was about $80-$100 per patient. However, he believes the benefits outweigh the cost. 

In addition, there have been issues with supplies, and it has been difficult for people to get their hands on the actual product.

Currently, the Mayo Clinic is also conducting a study testing Mepitel Film for radiation dermatitis in breast cancer patients following mastectomy. Mayo Clinic principal investigator Kimberly Corbin, MD, could not go into great detail about the ongoing trial, but she said it has been difficult to get the product. 

“We have been using the film at Mayo for a number of years,” Dr. Corbin said, but we “have found that it is challenging to get supplies.”

“While we have generally been able to have some supply established through our store here, we know that is not typical and it is difficult for patients to access,” she said. In addition, “there are not a ton of centers with experience in application.”

A representative with Mölnlycke Health Care, Allyson Bower-Willner, could not comment on the distribution of Mepitel film in the United States or if the company plans to increase the amount of product shipped. The film is available “to a limited set of customers,” she said.

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

Radiation dermatitis is one of the most common side effects of radiotherapy for women with breast cancer. Results from a phase 3 trial add to previous evidence from smaller trials that show that a silicone-based film can protect skin from this side effect. 

But it is not being used much in clinical practice. Instead, radiation dermatitis is usually treated after the fact, most often with aqueous creams.

The product is Mepitel film, from Swedish medical device company Mölnlycke Health Care.

It should be used for women who are at high risk for developing radiation dermatitis, said Edward Chow, MBBS, PhD, of the department of radiation oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, who was the senior author of the phase 3 study published recently in the Journal of Clinical Oncology.

“Other doctors think that because radiation dermatitis isn’t life-threatening it isn’t as important, but the condition does affect the quality of life for patients,” Dr. Chow said. “If we can lessen the pain and discomfort, why wouldn’t we as physicians?”

Dr. Chow’s open-label, multicenter trial was conducted in 376 women with large breasts (bra cup size C or larger) who were undergoing radiotherapy after lumpectomy or mastectomy. The primary endpoint was grade 2 or 3 radiation dermatitis using the Common Terminology Criteria for Adverse Events. (Grade 2 is described as moderate, whereas grade 3 is severe.) 

The film significantly reduced the incidence of grade 2 or 3 radiation dermatitis, down to  15.5% compared with 45.6% in patients receiving standard care (odds ratio, 0.20, 95% confidence interval, 0.12-0.34, P < .0001). 

There was also a significant reduction in grade 3 radiation dermatitis (2.8% vs. 13.6%; OR, 0.19; P < .0002) and moist desquamation (8% vs. 19.2%; OR, 0.36; P = .002).

“The film was remarkably effective and helped protect patients from potentially debilitating side effects,” commented Corey Speers, MD, PhD, a radiation oncologist with University Hospitals, Cleveland, who saw the study data presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

He believes that preventing radiation dermatitis before it develops is the best way to care for patients. 

“[Radiation dermatitis] is usually associated with pain and discomfort and can lead to more serious issues like infection or delayed wound healing, and unfortunately, there aren’t effective treatments for it once it’s developed, so preventing it is our most effective strategy,” Dr. Speers said. 

One reason for the film not being used much could be that it takes time apply the film, suggested Patries Herst, PhD, department of radiation therapy, University of Otago, Wellington, New Zealand. She was the lead author of a study published in 2014 that also analyzed the effectiveness of the film in preventing radiation dermatitis.

In their trial, a research radiation therapist applied the film to women when they were starting their radiotherapy. The film is applied to a portion of the breast or chest wall, and Dr. Herst emphasized the importance of applying the film correctly, making sure the film is not stretched during application and not overlapping other pieces of the film, while also making sure that it conforms to the breast shape. The film was replaced when it would curl too much around the sides, approximately every 1 or 2 weeks. 

“Radiation therapy itself is very short. And so you have about 10 minutes for every patient,” she explained.

“But applying the film adds 20-30 minutes and it’s really awkward to apply properly,” Dr. Herst said. “You have to tap it in and then have to maybe cut it so that it fits better. And hospitals say, ‘We don’t have the time’ and that is still the biggest issue that we’re seeing right now.”

In Dr. Chow’s study, the average time spent applying the film on lumpectomy patients was 55 minutes and was slightly shorter at 45 minutes for mastectomy patients. He acknowledged that it does take time that staff at most hospitals and clinics simply don’t have.

Dr. Chow suggested that perhaps a family member or other caregiver could apply the film, and he referenced an educational video from the manufacturer that provides in-depth instructions on the correct way to apply the film for radiotherapy patients. However, this could lead to errors and a waste of product if not the film was not applied properly. 

The cost of Mepitel film may also be a deterrent. Dr. Chow’s study noted that, during the entire course of radiotherapy, the cost for the film was about $80-$100 per patient. However, he believes the benefits outweigh the cost. 

In addition, there have been issues with supplies, and it has been difficult for people to get their hands on the actual product.

Currently, the Mayo Clinic is also conducting a study testing Mepitel Film for radiation dermatitis in breast cancer patients following mastectomy. Mayo Clinic principal investigator Kimberly Corbin, MD, could not go into great detail about the ongoing trial, but she said it has been difficult to get the product. 

“We have been using the film at Mayo for a number of years,” Dr. Corbin said, but we “have found that it is challenging to get supplies.”

“While we have generally been able to have some supply established through our store here, we know that is not typical and it is difficult for patients to access,” she said. In addition, “there are not a ton of centers with experience in application.”

A representative with Mölnlycke Health Care, Allyson Bower-Willner, could not comment on the distribution of Mepitel film in the United States or if the company plans to increase the amount of product shipped. The film is available “to a limited set of customers,” she said.

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

Several years after xylazine first began appearing as an additive in illicit street drugs – and as its use spreads nationwide – the Food and Drug Administration says it will more closely monitor imports.

The agency issued an import alert, which gives it the power to detain raw ingredients or bulk finished product if the shipments are suspected to be in violation of the law. Xylazine was first approved by the FDA in 1972 as a sedative and analgesic for use only in animals.

bankrx/Getty Images

It is increasingly being detected and is usually mixed with fentanyl, cocaine, methamphetamine, and other illicit drugs. A January 2023 study by Nashville-based testing company Aegis Sciences found xylazine in 413 of about 60,000 urine samples and in 25 of 39 states that submitted tests. The vast majority of xylazine-positive samples also tested positive for fentanyl.

The FDA said it would continue to ensure the availability of xylazine for veterinary use, and the American Veterinary Medicine Association said in a statement that it “supports such efforts to combat illicit drug use.”

FDA Commissioner Robert M. Califf, MD, said in a statement that the agency “remains concerned about the increasing prevalence of xylazine mixed with illicit drugs, and this action is one part of broader efforts the agency is undertaking to address this issue.”

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

Several years after xylazine first began appearing as an additive in illicit street drugs – and as its use spreads nationwide – the Food and Drug Administration says it will more closely monitor imports.

The agency issued an import alert, which gives it the power to detain raw ingredients or bulk finished product if the shipments are suspected to be in violation of the law. Xylazine was first approved by the FDA in 1972 as a sedative and analgesic for use only in animals.

bankrx/Getty Images

It is increasingly being detected and is usually mixed with fentanyl, cocaine, methamphetamine, and other illicit drugs. A January 2023 study by Nashville-based testing company Aegis Sciences found xylazine in 413 of about 60,000 urine samples and in 25 of 39 states that submitted tests. The vast majority of xylazine-positive samples also tested positive for fentanyl.

The FDA said it would continue to ensure the availability of xylazine for veterinary use, and the American Veterinary Medicine Association said in a statement that it “supports such efforts to combat illicit drug use.”

FDA Commissioner Robert M. Califf, MD, said in a statement that the agency “remains concerned about the increasing prevalence of xylazine mixed with illicit drugs, and this action is one part of broader efforts the agency is undertaking to address this issue.”

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

Several years after xylazine first began appearing as an additive in illicit street drugs – and as its use spreads nationwide – the Food and Drug Administration says it will more closely monitor imports.

The agency issued an import alert, which gives it the power to detain raw ingredients or bulk finished product if the shipments are suspected to be in violation of the law. Xylazine was first approved by the FDA in 1972 as a sedative and analgesic for use only in animals.

bankrx/Getty Images

It is increasingly being detected and is usually mixed with fentanyl, cocaine, methamphetamine, and other illicit drugs. A January 2023 study by Nashville-based testing company Aegis Sciences found xylazine in 413 of about 60,000 urine samples and in 25 of 39 states that submitted tests. The vast majority of xylazine-positive samples also tested positive for fentanyl.

The FDA said it would continue to ensure the availability of xylazine for veterinary use, and the American Veterinary Medicine Association said in a statement that it “supports such efforts to combat illicit drug use.”

FDA Commissioner Robert M. Califf, MD, said in a statement that the agency “remains concerned about the increasing prevalence of xylazine mixed with illicit drugs, and this action is one part of broader efforts the agency is undertaking to address this issue.”

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

Researchers are calling for the extent of skin erythema to be considered as an outcome measure in patients who develop chronic cutaneous graft-versus-host disease (ccGVHD) after allogeneic stem cell transplants for various blood cancers.

“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.

They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.

Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.

With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.

At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.

The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.

Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.

The study was published online in JAMA Dermatology.
 

Study details

The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.

All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.

They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.

Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.

The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.

Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”

The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.

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

Researchers are calling for the extent of skin erythema to be considered as an outcome measure in patients who develop chronic cutaneous graft-versus-host disease (ccGVHD) after allogeneic stem cell transplants for various blood cancers.

“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.

They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.

Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.

With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.

At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.

The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.

Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.

The study was published online in JAMA Dermatology.
 

Study details

The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.

All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.

They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.

Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.

The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.

Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”

The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.

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

Researchers are calling for the extent of skin erythema to be considered as an outcome measure in patients who develop chronic cutaneous graft-versus-host disease (ccGVHD) after allogeneic stem cell transplants for various blood cancers.

“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.

They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.

Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.

With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.

At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.

The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.

Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.

The study was published online in JAMA Dermatology.
 

Study details

The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.

All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.

They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.

Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.

The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.

Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”

The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.

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

Two U.S. Drug Enforcement Administration proposals on how telehealth can be used going forward to prescribe controlled substances are drawing criticism from mental health and addiction treatment specialists.

The proposed rules – one for Schedule III-V substances, and the other for buprenorphine – are due to go into effect on May 11, when the COVID-19 public health emergency (PHE), and temporary flexibilities, end.

Essentially, both proposals would allow providers to prescribe a 30-day supply of a controlled substance or buprenorphine, but then require a face-to-face meeting for patients to receive additional prescriptions.

The DEA says that the rules are aimed at preventing abuse and diversion of the substances, but clinicians claim they are creating unnecessary hurdles that will probably lead to some patients dropping out of treatment.

“We were happy to see that there is ongoing flexibility to be able to initiate buprenorphine through telehealth, but we were disappointed to see that the DEA set an arbitrary time frame, in this case, a 30-day time frame after which the patient would have to be seen in person before ongoing care with buprenorphine for opioid use disorder could be provided,” Brian Hurley, MD, MBA, the president-elect of the American Society of Addiction Medicine told this news organization.

Dr. Hurley agreed that it is best practice to see patients in person for ongoing care, but he noted they have many reasons why they might not be able to make it into an office every month.

“What this rule would do if instituted as written is prevent me from continuing care for patients unless I can get them in in person,” he said. “And while I’d make every effort as a clinician, it’s not always feasible to do so.”

The addiction specialist noted that only about 20% of Americans with opioid use disorder have access to medications for the disorder. “I would posit that untreated opioid use disorder is a bigger threat to public safety currently than the risk of diversion,” he said.

The DEA is also proposing to allow state laws to supersede its regulations, which concerns Dr. Hurley and other clinicians because some states are more restrictive. “Our position is that state laws that restrict access to medications for opioid use disorder through telehealth means are inconsistent with our policy recommendation. I certainly hope that the DEA hears our concerns and amends the proposal,” said Dr. Hurley.

A potential ‘telehealth cliff’

Shabana Khan, MD, chair of the American Psychiatric Association’s telepsychiatry committee, said that “because of potential overlap with state rules that may be more stringent than these new regulations, APA is concerned that the proposed rules will create a telehealth cliff for those in most need of critical psychiatric and opioid use disorder treatment, particularly in communities where this specialty care is limited or nonexistent.”

NYU Langone Health

Dr. Khan noted that “clarification is necessary on how patients who started treatment during the PHE can continue treatment with a prescribing provider, if at all, through an in-person evaluation with a DEA-registered provider referral.”

Telehealth companies were also disappointed in the DEA proposals.

“The continuity of care for countless Americans will be severed, potentially leaving these patients to fall through the cracks of our health care system without access to needed medications,” said Kyle Zebley, the American Telemedicine Association’s senior vice president of public policy, in a statement.

American Telemedicine Association

“Requiring every patient who has initiated treatment via telemedicine during the pandemic to now visit a provider in person clearly falls on the side of being overly restrictive,” Mr. Zebley added.

The DEA is proposing to allow patients who have been receiving telehealth over the past 3 years to continue to do so for 180 days after the PHE ends.

But the American Telemedicine Association and others said that they still want to see a change in the proposal as written. “Our hope is that the DEA works with us to avoid unnecessary and inappropriate restrictions on the prescription of essential medications for these vulnerable and underserved populations,” Mr. Zebley said in the statement.

DEA Administrator Anne Milgram said in a statement that the agency believes that “the telemedicine regulations would continue to expand access to buprenorphine for patients with opioid use disorder,” and that the DEA “is committed to the expansion of telemedicine with guardrails that prevent the online overprescribing of controlled medications that can cause harm.”

Rahul Gupta, MD, director of the White House Office of National Drug Control Policy, said in a statement that “This proposed rule builds on President Biden’s historic move to eliminate the X-waiver that prevented many prescribers from treating patients with buprenorphine.” He added, “Thanks to these changes, millions of Americans will be able to access the lifesaving care they need.”

The DEA estimated that there were 15.7 million prescriptions for buprenorphine in 2021 and that about 67,000 were for initial prescriptions.

Ketamine confusion

The rule on controlled substances has also caused some consternation, especially given that it does not differentiate between racemic ketamine and esketamine, said Lisa Marie Harding, MD, vice president of the board of the American Society of Ketamine Physicians, Psychotherapists & Practitioners.

Lisa Harding

Esketamine (Spravato) is approved by the Food and Drug Administration and, under a Risk Evaluation and Mitigation Strategy, can only be administered in FDA-monitored treatment facilities. Racemic ketamine is being prescribed – often for home use – with almost no regulatory oversight.

Dr. Harding, who is an approved Spravato provider and also administers intravenous ketamine in her practice, does not believe that ketamine should be used at home without supervision.

“I had a patient who had a very powerful dissociative experience in my office earlier this week,” Dr. Harding said in an interview. One of her staff asked what would happen if the patient had experienced that at home. “We don’t know. Nor do we want this to happen,” said Dr. Harding.

However, the DEA proposal would continue to allow for home use, at least initially. “If it’s open to interpretation, those people that prescribe ketamine for home use can use that leeway to then continue to do it,” she said. “That is not safe.”

Dr. Harding approves of the proposed DEA requirement for face-to-face visits. “It’s good patient care,” she said. But she wants the administration to adjust the rules to make it harder to offer home ketamine therapy.

“Lots of people are using racemic ketamine off-label for treating depression with success but doing it in treatment settings that are appropriate,” said Dr. Harding.

Dr. Hurley and Dr. Harding report no relevant financial relationships.

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

Two U.S. Drug Enforcement Administration proposals on how telehealth can be used going forward to prescribe controlled substances are drawing criticism from mental health and addiction treatment specialists.

The proposed rules – one for Schedule III-V substances, and the other for buprenorphine – are due to go into effect on May 11, when the COVID-19 public health emergency (PHE), and temporary flexibilities, end.

Essentially, both proposals would allow providers to prescribe a 30-day supply of a controlled substance or buprenorphine, but then require a face-to-face meeting for patients to receive additional prescriptions.

The DEA says that the rules are aimed at preventing abuse and diversion of the substances, but clinicians claim they are creating unnecessary hurdles that will probably lead to some patients dropping out of treatment.

“We were happy to see that there is ongoing flexibility to be able to initiate buprenorphine through telehealth, but we were disappointed to see that the DEA set an arbitrary time frame, in this case, a 30-day time frame after which the patient would have to be seen in person before ongoing care with buprenorphine for opioid use disorder could be provided,” Brian Hurley, MD, MBA, the president-elect of the American Society of Addiction Medicine told this news organization.

Dr. Hurley agreed that it is best practice to see patients in person for ongoing care, but he noted they have many reasons why they might not be able to make it into an office every month.

“What this rule would do if instituted as written is prevent me from continuing care for patients unless I can get them in in person,” he said. “And while I’d make every effort as a clinician, it’s not always feasible to do so.”

The addiction specialist noted that only about 20% of Americans with opioid use disorder have access to medications for the disorder. “I would posit that untreated opioid use disorder is a bigger threat to public safety currently than the risk of diversion,” he said.

The DEA is also proposing to allow state laws to supersede its regulations, which concerns Dr. Hurley and other clinicians because some states are more restrictive. “Our position is that state laws that restrict access to medications for opioid use disorder through telehealth means are inconsistent with our policy recommendation. I certainly hope that the DEA hears our concerns and amends the proposal,” said Dr. Hurley.

A potential ‘telehealth cliff’

Shabana Khan, MD, chair of the American Psychiatric Association’s telepsychiatry committee, said that “because of potential overlap with state rules that may be more stringent than these new regulations, APA is concerned that the proposed rules will create a telehealth cliff for those in most need of critical psychiatric and opioid use disorder treatment, particularly in communities where this specialty care is limited or nonexistent.”

NYU Langone Health

Dr. Khan noted that “clarification is necessary on how patients who started treatment during the PHE can continue treatment with a prescribing provider, if at all, through an in-person evaluation with a DEA-registered provider referral.”

Telehealth companies were also disappointed in the DEA proposals.

“The continuity of care for countless Americans will be severed, potentially leaving these patients to fall through the cracks of our health care system without access to needed medications,” said Kyle Zebley, the American Telemedicine Association’s senior vice president of public policy, in a statement.

American Telemedicine Association

“Requiring every patient who has initiated treatment via telemedicine during the pandemic to now visit a provider in person clearly falls on the side of being overly restrictive,” Mr. Zebley added.

The DEA is proposing to allow patients who have been receiving telehealth over the past 3 years to continue to do so for 180 days after the PHE ends.

But the American Telemedicine Association and others said that they still want to see a change in the proposal as written. “Our hope is that the DEA works with us to avoid unnecessary and inappropriate restrictions on the prescription of essential medications for these vulnerable and underserved populations,” Mr. Zebley said in the statement.

DEA Administrator Anne Milgram said in a statement that the agency believes that “the telemedicine regulations would continue to expand access to buprenorphine for patients with opioid use disorder,” and that the DEA “is committed to the expansion of telemedicine with guardrails that prevent the online overprescribing of controlled medications that can cause harm.”

Rahul Gupta, MD, director of the White House Office of National Drug Control Policy, said in a statement that “This proposed rule builds on President Biden’s historic move to eliminate the X-waiver that prevented many prescribers from treating patients with buprenorphine.” He added, “Thanks to these changes, millions of Americans will be able to access the lifesaving care they need.”

The DEA estimated that there were 15.7 million prescriptions for buprenorphine in 2021 and that about 67,000 were for initial prescriptions.

Ketamine confusion

The rule on controlled substances has also caused some consternation, especially given that it does not differentiate between racemic ketamine and esketamine, said Lisa Marie Harding, MD, vice president of the board of the American Society of Ketamine Physicians, Psychotherapists & Practitioners.

Lisa Harding

Esketamine (Spravato) is approved by the Food and Drug Administration and, under a Risk Evaluation and Mitigation Strategy, can only be administered in FDA-monitored treatment facilities. Racemic ketamine is being prescribed – often for home use – with almost no regulatory oversight.

Dr. Harding, who is an approved Spravato provider and also administers intravenous ketamine in her practice, does not believe that ketamine should be used at home without supervision.

“I had a patient who had a very powerful dissociative experience in my office earlier this week,” Dr. Harding said in an interview. One of her staff asked what would happen if the patient had experienced that at home. “We don’t know. Nor do we want this to happen,” said Dr. Harding.

However, the DEA proposal would continue to allow for home use, at least initially. “If it’s open to interpretation, those people that prescribe ketamine for home use can use that leeway to then continue to do it,” she said. “That is not safe.”

Dr. Harding approves of the proposed DEA requirement for face-to-face visits. “It’s good patient care,” she said. But she wants the administration to adjust the rules to make it harder to offer home ketamine therapy.

“Lots of people are using racemic ketamine off-label for treating depression with success but doing it in treatment settings that are appropriate,” said Dr. Harding.

Dr. Hurley and Dr. Harding report no relevant financial relationships.

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

Two U.S. Drug Enforcement Administration proposals on how telehealth can be used going forward to prescribe controlled substances are drawing criticism from mental health and addiction treatment specialists.

The proposed rules – one for Schedule III-V substances, and the other for buprenorphine – are due to go into effect on May 11, when the COVID-19 public health emergency (PHE), and temporary flexibilities, end.

Essentially, both proposals would allow providers to prescribe a 30-day supply of a controlled substance or buprenorphine, but then require a face-to-face meeting for patients to receive additional prescriptions.

The DEA says that the rules are aimed at preventing abuse and diversion of the substances, but clinicians claim they are creating unnecessary hurdles that will probably lead to some patients dropping out of treatment.

“We were happy to see that there is ongoing flexibility to be able to initiate buprenorphine through telehealth, but we were disappointed to see that the DEA set an arbitrary time frame, in this case, a 30-day time frame after which the patient would have to be seen in person before ongoing care with buprenorphine for opioid use disorder could be provided,” Brian Hurley, MD, MBA, the president-elect of the American Society of Addiction Medicine told this news organization.

Dr. Hurley agreed that it is best practice to see patients in person for ongoing care, but he noted they have many reasons why they might not be able to make it into an office every month.

“What this rule would do if instituted as written is prevent me from continuing care for patients unless I can get them in in person,” he said. “And while I’d make every effort as a clinician, it’s not always feasible to do so.”

The addiction specialist noted that only about 20% of Americans with opioid use disorder have access to medications for the disorder. “I would posit that untreated opioid use disorder is a bigger threat to public safety currently than the risk of diversion,” he said.

The DEA is also proposing to allow state laws to supersede its regulations, which concerns Dr. Hurley and other clinicians because some states are more restrictive. “Our position is that state laws that restrict access to medications for opioid use disorder through telehealth means are inconsistent with our policy recommendation. I certainly hope that the DEA hears our concerns and amends the proposal,” said Dr. Hurley.

A potential ‘telehealth cliff’

Shabana Khan, MD, chair of the American Psychiatric Association’s telepsychiatry committee, said that “because of potential overlap with state rules that may be more stringent than these new regulations, APA is concerned that the proposed rules will create a telehealth cliff for those in most need of critical psychiatric and opioid use disorder treatment, particularly in communities where this specialty care is limited or nonexistent.”

NYU Langone Health

Dr. Khan noted that “clarification is necessary on how patients who started treatment during the PHE can continue treatment with a prescribing provider, if at all, through an in-person evaluation with a DEA-registered provider referral.”

Telehealth companies were also disappointed in the DEA proposals.

“The continuity of care for countless Americans will be severed, potentially leaving these patients to fall through the cracks of our health care system without access to needed medications,” said Kyle Zebley, the American Telemedicine Association’s senior vice president of public policy, in a statement.

American Telemedicine Association

“Requiring every patient who has initiated treatment via telemedicine during the pandemic to now visit a provider in person clearly falls on the side of being overly restrictive,” Mr. Zebley added.

The DEA is proposing to allow patients who have been receiving telehealth over the past 3 years to continue to do so for 180 days after the PHE ends.

But the American Telemedicine Association and others said that they still want to see a change in the proposal as written. “Our hope is that the DEA works with us to avoid unnecessary and inappropriate restrictions on the prescription of essential medications for these vulnerable and underserved populations,” Mr. Zebley said in the statement.

DEA Administrator Anne Milgram said in a statement that the agency believes that “the telemedicine regulations would continue to expand access to buprenorphine for patients with opioid use disorder,” and that the DEA “is committed to the expansion of telemedicine with guardrails that prevent the online overprescribing of controlled medications that can cause harm.”

Rahul Gupta, MD, director of the White House Office of National Drug Control Policy, said in a statement that “This proposed rule builds on President Biden’s historic move to eliminate the X-waiver that prevented many prescribers from treating patients with buprenorphine.” He added, “Thanks to these changes, millions of Americans will be able to access the lifesaving care they need.”

The DEA estimated that there were 15.7 million prescriptions for buprenorphine in 2021 and that about 67,000 were for initial prescriptions.

Ketamine confusion

The rule on controlled substances has also caused some consternation, especially given that it does not differentiate between racemic ketamine and esketamine, said Lisa Marie Harding, MD, vice president of the board of the American Society of Ketamine Physicians, Psychotherapists & Practitioners.

Lisa Harding

Esketamine (Spravato) is approved by the Food and Drug Administration and, under a Risk Evaluation and Mitigation Strategy, can only be administered in FDA-monitored treatment facilities. Racemic ketamine is being prescribed – often for home use – with almost no regulatory oversight.

Dr. Harding, who is an approved Spravato provider and also administers intravenous ketamine in her practice, does not believe that ketamine should be used at home without supervision.

“I had a patient who had a very powerful dissociative experience in my office earlier this week,” Dr. Harding said in an interview. One of her staff asked what would happen if the patient had experienced that at home. “We don’t know. Nor do we want this to happen,” said Dr. Harding.

However, the DEA proposal would continue to allow for home use, at least initially. “If it’s open to interpretation, those people that prescribe ketamine for home use can use that leeway to then continue to do it,” she said. “That is not safe.”

Dr. Harding approves of the proposed DEA requirement for face-to-face visits. “It’s good patient care,” she said. But she wants the administration to adjust the rules to make it harder to offer home ketamine therapy.

“Lots of people are using racemic ketamine off-label for treating depression with success but doing it in treatment settings that are appropriate,” said Dr. Harding.

Dr. Hurley and Dr. Harding report no relevant financial relationships.

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

Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.

The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.

The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.

Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.

Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.

More recent experience has calmed AKI concerns, however.

Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.

The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).

Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk

“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.

Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.

Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.

One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.

Early AKI concern has diminished

Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.

In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.

Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.

The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.

During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.

A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.

The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.

He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.

The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.

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

Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.

The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.

The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.

Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.

Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.

More recent experience has calmed AKI concerns, however.

Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.

The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).

Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk

“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.

Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.

Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.

One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.

Early AKI concern has diminished

Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.

In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.

Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.

The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.

During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.

A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.

The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.

He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.

The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.

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

Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.

The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.

The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.

Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.

Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.

More recent experience has calmed AKI concerns, however.

Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.

The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).

Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk

“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.

Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.

Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.

One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.

Early AKI concern has diminished

Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.

In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.

Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.

The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.

During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.

A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.

The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.

He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.

The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.

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

Airway Disorders Network

Bronchiectasis Section

Bronchiectasis is a condition of dilated, inflamed airways and mucous production caused by a myriad of diseases. Bronchiectasis entails chronic productive cough and an increased risk of infections leading to exacerbations. Chronic bacterial infections are often a hallmark of severe disease, especially with Pseudomonas aeruginosa (O’Donnell AE. N Engl J Med. 2022;387[6]:533). Prophylactic inhaled antibiotics have been used as off-label therapies with mixed evidence, particularly in non-cystic fibrosis bronchiectasis (Rubin BK, et al. Respiration. 2014;88[3]:177). As the incidence of bronchiectasis increases worldwide, the need for evidence-based therapies to reduce symptom burden is increasing.

In a recent publication, Guan and colleagues evaluated the efficacy and safety of tobramycin inhaled solution (TIS) for bronchiectasis with chronic P. aeruginosa in a phase 3, 16-week, multicenter, double-blind randomized, controlled trial (Guan W-J, et al. Chest. 2023;163[1]:64). A regimen of twice-daily TIS, compared with nebulized normal saline, demonstrated a more significant reduction in P. aeruginosa sputum density after two cycles of 28 days on-treatment and 28 days off-treatment (adjusted mean difference, 1.74 log10 colony-forming units/g; 95% CI, 1.12-2.35; (P < .001), and more patients became culture-negative for P. aeruginosa in the TIS group than in the placebo group on day 29 (29.3% vs 10.6%). Adverse events were similar in both groups. Importantly, there was an improvement in quality-of-life bronchiectasis respiratory symptom score by 7.91 points at day 29 and 6.72 points at day 85; all three were statistically significant but just below the minimal clinically important difference of 8 points.

Dr. Conroy Wong and Dr. Miguel Angel Martinez-Garcia (Chest. 2023 Jan;163[1]:3) highlighted in their accompanying editorial that use of health-related quality of life score was a “distinguishing feature” of the trial as “most studies have used the change in microbial density as the primary outcome measure alone.”

Future studies evaluating cyclical vs continuous antibiotic administration, treatment duration, and impact on exacerbations continue to be needed.

Alicia Mirza, MD
Section Member-at-Large

Airway Disorders Network

Bronchiectasis Section

Bronchiectasis is a condition of dilated, inflamed airways and mucous production caused by a myriad of diseases. Bronchiectasis entails chronic productive cough and an increased risk of infections leading to exacerbations. Chronic bacterial infections are often a hallmark of severe disease, especially with Pseudomonas aeruginosa (O’Donnell AE. N Engl J Med. 2022;387[6]:533). Prophylactic inhaled antibiotics have been used as off-label therapies with mixed evidence, particularly in non-cystic fibrosis bronchiectasis (Rubin BK, et al. Respiration. 2014;88[3]:177). As the incidence of bronchiectasis increases worldwide, the need for evidence-based therapies to reduce symptom burden is increasing.

In a recent publication, Guan and colleagues evaluated the efficacy and safety of tobramycin inhaled solution (TIS) for bronchiectasis with chronic P. aeruginosa in a phase 3, 16-week, multicenter, double-blind randomized, controlled trial (Guan W-J, et al. Chest. 2023;163[1]:64). A regimen of twice-daily TIS, compared with nebulized normal saline, demonstrated a more significant reduction in P. aeruginosa sputum density after two cycles of 28 days on-treatment and 28 days off-treatment (adjusted mean difference, 1.74 log10 colony-forming units/g; 95% CI, 1.12-2.35; (P < .001), and more patients became culture-negative for P. aeruginosa in the TIS group than in the placebo group on day 29 (29.3% vs 10.6%). Adverse events were similar in both groups. Importantly, there was an improvement in quality-of-life bronchiectasis respiratory symptom score by 7.91 points at day 29 and 6.72 points at day 85; all three were statistically significant but just below the minimal clinically important difference of 8 points.

Dr. Conroy Wong and Dr. Miguel Angel Martinez-Garcia (Chest. 2023 Jan;163[1]:3) highlighted in their accompanying editorial that use of health-related quality of life score was a “distinguishing feature” of the trial as “most studies have used the change in microbial density as the primary outcome measure alone.”

Future studies evaluating cyclical vs continuous antibiotic administration, treatment duration, and impact on exacerbations continue to be needed.

Alicia Mirza, MD
Section Member-at-Large

Airway Disorders Network

Bronchiectasis Section

Bronchiectasis is a condition of dilated, inflamed airways and mucous production caused by a myriad of diseases. Bronchiectasis entails chronic productive cough and an increased risk of infections leading to exacerbations. Chronic bacterial infections are often a hallmark of severe disease, especially with Pseudomonas aeruginosa (O’Donnell AE. N Engl J Med. 2022;387[6]:533). Prophylactic inhaled antibiotics have been used as off-label therapies with mixed evidence, particularly in non-cystic fibrosis bronchiectasis (Rubin BK, et al. Respiration. 2014;88[3]:177). As the incidence of bronchiectasis increases worldwide, the need for evidence-based therapies to reduce symptom burden is increasing.

In a recent publication, Guan and colleagues evaluated the efficacy and safety of tobramycin inhaled solution (TIS) for bronchiectasis with chronic P. aeruginosa in a phase 3, 16-week, multicenter, double-blind randomized, controlled trial (Guan W-J, et al. Chest. 2023;163[1]:64). A regimen of twice-daily TIS, compared with nebulized normal saline, demonstrated a more significant reduction in P. aeruginosa sputum density after two cycles of 28 days on-treatment and 28 days off-treatment (adjusted mean difference, 1.74 log10 colony-forming units/g; 95% CI, 1.12-2.35; (P < .001), and more patients became culture-negative for P. aeruginosa in the TIS group than in the placebo group on day 29 (29.3% vs 10.6%). Adverse events were similar in both groups. Importantly, there was an improvement in quality-of-life bronchiectasis respiratory symptom score by 7.91 points at day 29 and 6.72 points at day 85; all three were statistically significant but just below the minimal clinically important difference of 8 points.

Dr. Conroy Wong and Dr. Miguel Angel Martinez-Garcia (Chest. 2023 Jan;163[1]:3) highlighted in their accompanying editorial that use of health-related quality of life score was a “distinguishing feature” of the trial as “most studies have used the change in microbial density as the primary outcome measure alone.”

Future studies evaluating cyclical vs continuous antibiotic administration, treatment duration, and impact on exacerbations continue to be needed.

Alicia Mirza, MD
Section Member-at-Large