Young adults who developed type 2 diabetes as children often do not take medications to control blood pressure or cholesterol, according to a new study in JAMA Network Open. Researchers expressed alarm that young people who forgo these medications increase their chances of developing kidney disease or having a stroke.

“We’re learning more and more that those with youth onset [type 2 diabetes] really differ from those with adult onset: It looks like a more virulent form of the disease because kids are getting complications and comorbidities at much earlier ages and more severe levels,” said study author Paula Trief, PhD, a professor of psychiatry and behavioral science at State University of New York, Syracuse.

Participants in the new study were on average aged 26 years. They also had previously been part of the Treating Options for Type 2 Diabetes in Adolescents and Youth study, known as TODAY, which took place from 2004 to 2011. TODAY enrolled children between ages 10 and 17 years with type 2 diabetes who received either metformin, metformin plus rosiglitazone, or metformin plus a lifestyle intervention.

The study included extensive education and contact from medical professionals to the participants about managing diabetes.

“This cohort was followed a long time and they had a lot of support. It may be better than the real world where people haven’t had the history of this much attention,” said Lorraine Katz, MD, who specializes in endocrinology and diabetes at the Children’s Hospital of Philadelphia. Dr. Katz has enrolled participants in TODAY and published about medication adherence rates but was not part of the recent analysis.
 

Unannounced pill counts, addressing concerns about medication

The analysis, known as iCount, included 243 participants from the original TODAY study (159 girls) who had hypertension, neuropathy, or dyslipidemia that required ongoing medication. As the TODAY study was concluding between 2017 and 2019, researchers made unannounced phone calls to participants to request the numbers of pills they had prescribed, number of refills, and the refill date. Participants also counted aloud every pill in their possession twice.

Those phone calls continued for 3 consecutive months after iCount began and again at the same intervals 1 year later.

If the number of pills counted at a later time was at least 80% of the starting total, researchers considered this rate as low adherence. Anything less than 80% was considered high adherence.

“That’s kind of an arbitrary cutoff, but it’s one that’s used consistently in the literature” to measure medication adherence for many conditions including cancer and heart disease, Dr. Trief said. Unannounced calls to initiate pill counts were first used to understand how often people took medications for HIV, and this method was found to be a more reliable method than are self-reports.

Of 196 participants with hypertension or neuropathy, 157 (80.1%) had low adherence. And of the 146 people with high cholesterol, 137 (93.8%) had low adherence. Ninety-nine people with high cholesterol also had neuropathy or diabetes.

“This is new to the literature: We don’t really know as much about this age group,” because medication adherence studies of people who have had diabetes for more than a decade and are still in their 20s are rare, Dr. Katz said.

During the core TODAY study period, all medications were provided for free. In contrast, in the current study, participants had to obtain their prescriptions on their own. The researchers found that many participants who showed low adherence to blood pressure medications reported sometimes having trouble obtaining food (n = 62), struggling with securing stable housing (n = 47), or lacking reliable health care insurance (n = 28), all factors linked to medication adherence success, according to the analysis authors.

Researchers also assessed the impact of concerns that taking blood pressure medications may be harmful and found that people with these concerns were 37% less likely to maintain high adherence than others were by the 1-year follow-up point (odds ratio, 0.63; 95% confidence interval, 0.40-0.96; P = .01).

To some extent, the reasons people avoid medications are understandable, according to pediatric endocrinologist Tamara Hannon, MD, of Indiana University, Indianapolis.

“Rather than taking a medicine to feel better, you’re taking one not to have a problem in the future: You might not feel blood pressure, you certainly don’t feel cholesterol,” Dr. Hannon, who was not involved in the analysis, said. “Scolding them or telling them you’re going to be sorry one day doesn’t generally work.”

Dr. Hannon added that education alone about the benefits of medications does not generally drive people to adherence but that adding reminders to their phone calendar when refills are due could help. Or, the clinician could reach out to a trusted person in the patient’s life and enlist their support in taking medications consistently.

Dr. Trief advised that clinicians should carve out time for people to express their concerns about medications rather than simply writing a prescription and sending them on their way and to ask patients open-ended questions.

“If you just say to people do you have any questions, they usually say, ‘no.’ ”

No disclosures were reported.

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

Young adults who developed type 2 diabetes as children often do not take medications to control blood pressure or cholesterol, according to a new study in JAMA Network Open. Researchers expressed alarm that young people who forgo these medications increase their chances of developing kidney disease or having a stroke.

“We’re learning more and more that those with youth onset [type 2 diabetes] really differ from those with adult onset: It looks like a more virulent form of the disease because kids are getting complications and comorbidities at much earlier ages and more severe levels,” said study author Paula Trief, PhD, a professor of psychiatry and behavioral science at State University of New York, Syracuse.

Participants in the new study were on average aged 26 years. They also had previously been part of the Treating Options for Type 2 Diabetes in Adolescents and Youth study, known as TODAY, which took place from 2004 to 2011. TODAY enrolled children between ages 10 and 17 years with type 2 diabetes who received either metformin, metformin plus rosiglitazone, or metformin plus a lifestyle intervention.

The study included extensive education and contact from medical professionals to the participants about managing diabetes.

“This cohort was followed a long time and they had a lot of support. It may be better than the real world where people haven’t had the history of this much attention,” said Lorraine Katz, MD, who specializes in endocrinology and diabetes at the Children’s Hospital of Philadelphia. Dr. Katz has enrolled participants in TODAY and published about medication adherence rates but was not part of the recent analysis.
 

Unannounced pill counts, addressing concerns about medication

The analysis, known as iCount, included 243 participants from the original TODAY study (159 girls) who had hypertension, neuropathy, or dyslipidemia that required ongoing medication. As the TODAY study was concluding between 2017 and 2019, researchers made unannounced phone calls to participants to request the numbers of pills they had prescribed, number of refills, and the refill date. Participants also counted aloud every pill in their possession twice.

Those phone calls continued for 3 consecutive months after iCount began and again at the same intervals 1 year later.

If the number of pills counted at a later time was at least 80% of the starting total, researchers considered this rate as low adherence. Anything less than 80% was considered high adherence.

“That’s kind of an arbitrary cutoff, but it’s one that’s used consistently in the literature” to measure medication adherence for many conditions including cancer and heart disease, Dr. Trief said. Unannounced calls to initiate pill counts were first used to understand how often people took medications for HIV, and this method was found to be a more reliable method than are self-reports.

Of 196 participants with hypertension or neuropathy, 157 (80.1%) had low adherence. And of the 146 people with high cholesterol, 137 (93.8%) had low adherence. Ninety-nine people with high cholesterol also had neuropathy or diabetes.

“This is new to the literature: We don’t really know as much about this age group,” because medication adherence studies of people who have had diabetes for more than a decade and are still in their 20s are rare, Dr. Katz said.

During the core TODAY study period, all medications were provided for free. In contrast, in the current study, participants had to obtain their prescriptions on their own. The researchers found that many participants who showed low adherence to blood pressure medications reported sometimes having trouble obtaining food (n = 62), struggling with securing stable housing (n = 47), or lacking reliable health care insurance (n = 28), all factors linked to medication adherence success, according to the analysis authors.

Researchers also assessed the impact of concerns that taking blood pressure medications may be harmful and found that people with these concerns were 37% less likely to maintain high adherence than others were by the 1-year follow-up point (odds ratio, 0.63; 95% confidence interval, 0.40-0.96; P = .01).

To some extent, the reasons people avoid medications are understandable, according to pediatric endocrinologist Tamara Hannon, MD, of Indiana University, Indianapolis.

“Rather than taking a medicine to feel better, you’re taking one not to have a problem in the future: You might not feel blood pressure, you certainly don’t feel cholesterol,” Dr. Hannon, who was not involved in the analysis, said. “Scolding them or telling them you’re going to be sorry one day doesn’t generally work.”

Dr. Hannon added that education alone about the benefits of medications does not generally drive people to adherence but that adding reminders to their phone calendar when refills are due could help. Or, the clinician could reach out to a trusted person in the patient’s life and enlist their support in taking medications consistently.

Dr. Trief advised that clinicians should carve out time for people to express their concerns about medications rather than simply writing a prescription and sending them on their way and to ask patients open-ended questions.

“If you just say to people do you have any questions, they usually say, ‘no.’ ”

No disclosures were reported.

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

Young adults who developed type 2 diabetes as children often do not take medications to control blood pressure or cholesterol, according to a new study in JAMA Network Open. Researchers expressed alarm that young people who forgo these medications increase their chances of developing kidney disease or having a stroke.

“We’re learning more and more that those with youth onset [type 2 diabetes] really differ from those with adult onset: It looks like a more virulent form of the disease because kids are getting complications and comorbidities at much earlier ages and more severe levels,” said study author Paula Trief, PhD, a professor of psychiatry and behavioral science at State University of New York, Syracuse.

Participants in the new study were on average aged 26 years. They also had previously been part of the Treating Options for Type 2 Diabetes in Adolescents and Youth study, known as TODAY, which took place from 2004 to 2011. TODAY enrolled children between ages 10 and 17 years with type 2 diabetes who received either metformin, metformin plus rosiglitazone, or metformin plus a lifestyle intervention.

The study included extensive education and contact from medical professionals to the participants about managing diabetes.

“This cohort was followed a long time and they had a lot of support. It may be better than the real world where people haven’t had the history of this much attention,” said Lorraine Katz, MD, who specializes in endocrinology and diabetes at the Children’s Hospital of Philadelphia. Dr. Katz has enrolled participants in TODAY and published about medication adherence rates but was not part of the recent analysis.
 

Unannounced pill counts, addressing concerns about medication

The analysis, known as iCount, included 243 participants from the original TODAY study (159 girls) who had hypertension, neuropathy, or dyslipidemia that required ongoing medication. As the TODAY study was concluding between 2017 and 2019, researchers made unannounced phone calls to participants to request the numbers of pills they had prescribed, number of refills, and the refill date. Participants also counted aloud every pill in their possession twice.

Those phone calls continued for 3 consecutive months after iCount began and again at the same intervals 1 year later.

If the number of pills counted at a later time was at least 80% of the starting total, researchers considered this rate as low adherence. Anything less than 80% was considered high adherence.

“That’s kind of an arbitrary cutoff, but it’s one that’s used consistently in the literature” to measure medication adherence for many conditions including cancer and heart disease, Dr. Trief said. Unannounced calls to initiate pill counts were first used to understand how often people took medications for HIV, and this method was found to be a more reliable method than are self-reports.

Of 196 participants with hypertension or neuropathy, 157 (80.1%) had low adherence. And of the 146 people with high cholesterol, 137 (93.8%) had low adherence. Ninety-nine people with high cholesterol also had neuropathy or diabetes.

“This is new to the literature: We don’t really know as much about this age group,” because medication adherence studies of people who have had diabetes for more than a decade and are still in their 20s are rare, Dr. Katz said.

During the core TODAY study period, all medications were provided for free. In contrast, in the current study, participants had to obtain their prescriptions on their own. The researchers found that many participants who showed low adherence to blood pressure medications reported sometimes having trouble obtaining food (n = 62), struggling with securing stable housing (n = 47), or lacking reliable health care insurance (n = 28), all factors linked to medication adherence success, according to the analysis authors.

Researchers also assessed the impact of concerns that taking blood pressure medications may be harmful and found that people with these concerns were 37% less likely to maintain high adherence than others were by the 1-year follow-up point (odds ratio, 0.63; 95% confidence interval, 0.40-0.96; P = .01).

To some extent, the reasons people avoid medications are understandable, according to pediatric endocrinologist Tamara Hannon, MD, of Indiana University, Indianapolis.

“Rather than taking a medicine to feel better, you’re taking one not to have a problem in the future: You might not feel blood pressure, you certainly don’t feel cholesterol,” Dr. Hannon, who was not involved in the analysis, said. “Scolding them or telling them you’re going to be sorry one day doesn’t generally work.”

Dr. Hannon added that education alone about the benefits of medications does not generally drive people to adherence but that adding reminders to their phone calendar when refills are due could help. Or, the clinician could reach out to a trusted person in the patient’s life and enlist their support in taking medications consistently.

Dr. Trief advised that clinicians should carve out time for people to express their concerns about medications rather than simply writing a prescription and sending them on their way and to ask patients open-ended questions.

“If you just say to people do you have any questions, they usually say, ‘no.’ ”

No disclosures were reported.

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

Children with atopic dermatitis (AD) were significantly more likely to have positive patch test results than were children without AD, according to a study of over 900 children evaluated for allergic contact dermatitis (ACD) with patch testing, a finding that investigators say underscores the value of considering ACD in patients with AD and referring more children for testing.

ACD is underdetected in children with AD. In some cases, it may be misconstrued to be AD, and patch testing, the gold standard for diagnosing ACD, is often not performed, said senior author JiaDe Yu, MD, MS, a pediatric dermatologist and director of contact and occupational dermatology at Massachusetts General Hospital, Boston, and his co-authors, in the study published in the Journal of the American Academy of Dermatology.

Dr. JiaDe Yu

UCHealth

Top allergens

The top 10 allergens between children with and without AD were largely similar, the authors of the study report. Nickel was the most common allergen identified in both groups, and cobalt was in the top five for both groups. Fragrances (including hydroperoxides of linalool), preservatives (including methylisothiazolinone [MI]), and neomycin ranked in the top 10 in both groups, though prevalence differed.

MI, a preservative frequently used in personal care products and in other products like school glue and paint, was the second most common allergen identified in children with AD. Allergy to MI has “recently become an epidemic in the United States, with rapidly increasing prevalence and importance as a source of ACD among both children and adults,” the authors note.

Children with AD were significantly more likely, however, to have ACD to bacitracin (OR, 3.23; P = .030) and to cocamidopropyl betaine (OR, 3.69; P = .0007), the latter of which is a popular surfactant used in “baby” and “gentle” skincare products. This is unsurprising, given that children with AD are “more often exposed to a myriad of topical treatments,” Dr. Yu and his colleagues write.

Although not a top 10 allergen for either group, ACD to “carba mix,” a combination of three chemicals used to make medical adhesives and other rubber products (such as pacifiers, toys, school supplies, and rubber gloves) was significantly more common in children with AD than in those without (OR, 3.36; P = .025).

Among other findings from the study: Children with AD were more likely to have a longer history of dermatitis (4.1 vs. 1.6 years, P < .0001) prior to patch testing. Testing occurred at a mean age of 11 and 12.3 years for children with and without AD, respectively.

The number of allergens tested and the patch testing series chosen per patient were “not statistically different” between the children with and without AD, the researchers report.

Patch testing availability

Clinicians may be hesitant to subject a child to patch testing, but the process is well tolerated in most children, Dr. Perryman said. She uses a modified panel for children that omits less relevant allergens and usually limits patch testing to age 2 years or older due to a young child’s smaller surface area.

Dr. Yu, who developed an interest in patch testing during his residency at the Medical College of Wisconsin, Milwaukee, where he worked with a patch-testing expert, will test children as young as 3-4 months with a “small selection of patches.”

The challenge with a call for more patch testing is a shortage of trained physicians. “In all of Boston, where we have hundreds of dermatologists, there are only about four of us who really do patch testing. My wait time is about 6 months,” said Dr. Yu, who is also an assistant professor at Harvard Medical School, Boston.

Allergists at Massachusetts General Hospital do “some patch testing ... but they refer a lot of the most complicated cases to me,” he said, noting that patch testing and management of ACD involves detailed counseling for patients about avoidance of allergens. “Overall dermatologists represent the largest group of doctors who have proficiency in patch testing, and there just aren’t many of us.”

Dr. Perryman also said that patch testing is often performed by dermatologists who specialize in treating ACD and AD, though there seems to be “regional variance” in the level of involvement of dermatologists and allergists in patch testing.

Not all residency programs have hands-on patch testing opportunities, Dr. Yu said. A study published in Dermatitis, which he co-authored, showed that in 2020, 47.5% of dermatology residency programs had formal patch testing rotations. This represented improvement but is still not enough, he said.

The American Contact Dermatitis Society offers patch-testing mentorship programs, and the American Academy of Dermatology has recently begun offered a patch testing workshop at its annual meetings, said Dr. Yu, who received 4 weeks of training in the Society’s mentorship program and is now involved in the American Academy of Dermatology’s workshops and as a trainer/lecturer at the Contact Dermatitis Institute.

The study was supported by the Dermatology Foundation. Dr. Yu and his co-investigators reported no conflicts of interest. Dr. Perryman had no disclosures.

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

Children with atopic dermatitis (AD) were significantly more likely to have positive patch test results than were children without AD, according to a study of over 900 children evaluated for allergic contact dermatitis (ACD) with patch testing, a finding that investigators say underscores the value of considering ACD in patients with AD and referring more children for testing.

ACD is underdetected in children with AD. In some cases, it may be misconstrued to be AD, and patch testing, the gold standard for diagnosing ACD, is often not performed, said senior author JiaDe Yu, MD, MS, a pediatric dermatologist and director of contact and occupational dermatology at Massachusetts General Hospital, Boston, and his co-authors, in the study published in the Journal of the American Academy of Dermatology.

Dr. JiaDe Yu

UCHealth

Top allergens

The top 10 allergens between children with and without AD were largely similar, the authors of the study report. Nickel was the most common allergen identified in both groups, and cobalt was in the top five for both groups. Fragrances (including hydroperoxides of linalool), preservatives (including methylisothiazolinone [MI]), and neomycin ranked in the top 10 in both groups, though prevalence differed.

MI, a preservative frequently used in personal care products and in other products like school glue and paint, was the second most common allergen identified in children with AD. Allergy to MI has “recently become an epidemic in the United States, with rapidly increasing prevalence and importance as a source of ACD among both children and adults,” the authors note.

Children with AD were significantly more likely, however, to have ACD to bacitracin (OR, 3.23; P = .030) and to cocamidopropyl betaine (OR, 3.69; P = .0007), the latter of which is a popular surfactant used in “baby” and “gentle” skincare products. This is unsurprising, given that children with AD are “more often exposed to a myriad of topical treatments,” Dr. Yu and his colleagues write.

Although not a top 10 allergen for either group, ACD to “carba mix,” a combination of three chemicals used to make medical adhesives and other rubber products (such as pacifiers, toys, school supplies, and rubber gloves) was significantly more common in children with AD than in those without (OR, 3.36; P = .025).

Among other findings from the study: Children with AD were more likely to have a longer history of dermatitis (4.1 vs. 1.6 years, P < .0001) prior to patch testing. Testing occurred at a mean age of 11 and 12.3 years for children with and without AD, respectively.

The number of allergens tested and the patch testing series chosen per patient were “not statistically different” between the children with and without AD, the researchers report.

Patch testing availability

Clinicians may be hesitant to subject a child to patch testing, but the process is well tolerated in most children, Dr. Perryman said. She uses a modified panel for children that omits less relevant allergens and usually limits patch testing to age 2 years or older due to a young child’s smaller surface area.

Dr. Yu, who developed an interest in patch testing during his residency at the Medical College of Wisconsin, Milwaukee, where he worked with a patch-testing expert, will test children as young as 3-4 months with a “small selection of patches.”

The challenge with a call for more patch testing is a shortage of trained physicians. “In all of Boston, where we have hundreds of dermatologists, there are only about four of us who really do patch testing. My wait time is about 6 months,” said Dr. Yu, who is also an assistant professor at Harvard Medical School, Boston.

Allergists at Massachusetts General Hospital do “some patch testing ... but they refer a lot of the most complicated cases to me,” he said, noting that patch testing and management of ACD involves detailed counseling for patients about avoidance of allergens. “Overall dermatologists represent the largest group of doctors who have proficiency in patch testing, and there just aren’t many of us.”

Dr. Perryman also said that patch testing is often performed by dermatologists who specialize in treating ACD and AD, though there seems to be “regional variance” in the level of involvement of dermatologists and allergists in patch testing.

Not all residency programs have hands-on patch testing opportunities, Dr. Yu said. A study published in Dermatitis, which he co-authored, showed that in 2020, 47.5% of dermatology residency programs had formal patch testing rotations. This represented improvement but is still not enough, he said.

The American Contact Dermatitis Society offers patch-testing mentorship programs, and the American Academy of Dermatology has recently begun offered a patch testing workshop at its annual meetings, said Dr. Yu, who received 4 weeks of training in the Society’s mentorship program and is now involved in the American Academy of Dermatology’s workshops and as a trainer/lecturer at the Contact Dermatitis Institute.

The study was supported by the Dermatology Foundation. Dr. Yu and his co-investigators reported no conflicts of interest. Dr. Perryman had no disclosures.

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

Children with atopic dermatitis (AD) were significantly more likely to have positive patch test results than were children without AD, according to a study of over 900 children evaluated for allergic contact dermatitis (ACD) with patch testing, a finding that investigators say underscores the value of considering ACD in patients with AD and referring more children for testing.

ACD is underdetected in children with AD. In some cases, it may be misconstrued to be AD, and patch testing, the gold standard for diagnosing ACD, is often not performed, said senior author JiaDe Yu, MD, MS, a pediatric dermatologist and director of contact and occupational dermatology at Massachusetts General Hospital, Boston, and his co-authors, in the study published in the Journal of the American Academy of Dermatology.

Dr. JiaDe Yu

UCHealth

Top allergens

The top 10 allergens between children with and without AD were largely similar, the authors of the study report. Nickel was the most common allergen identified in both groups, and cobalt was in the top five for both groups. Fragrances (including hydroperoxides of linalool), preservatives (including methylisothiazolinone [MI]), and neomycin ranked in the top 10 in both groups, though prevalence differed.

MI, a preservative frequently used in personal care products and in other products like school glue and paint, was the second most common allergen identified in children with AD. Allergy to MI has “recently become an epidemic in the United States, with rapidly increasing prevalence and importance as a source of ACD among both children and adults,” the authors note.

Children with AD were significantly more likely, however, to have ACD to bacitracin (OR, 3.23; P = .030) and to cocamidopropyl betaine (OR, 3.69; P = .0007), the latter of which is a popular surfactant used in “baby” and “gentle” skincare products. This is unsurprising, given that children with AD are “more often exposed to a myriad of topical treatments,” Dr. Yu and his colleagues write.

Although not a top 10 allergen for either group, ACD to “carba mix,” a combination of three chemicals used to make medical adhesives and other rubber products (such as pacifiers, toys, school supplies, and rubber gloves) was significantly more common in children with AD than in those without (OR, 3.36; P = .025).

Among other findings from the study: Children with AD were more likely to have a longer history of dermatitis (4.1 vs. 1.6 years, P < .0001) prior to patch testing. Testing occurred at a mean age of 11 and 12.3 years for children with and without AD, respectively.

The number of allergens tested and the patch testing series chosen per patient were “not statistically different” between the children with and without AD, the researchers report.

Patch testing availability

Clinicians may be hesitant to subject a child to patch testing, but the process is well tolerated in most children, Dr. Perryman said. She uses a modified panel for children that omits less relevant allergens and usually limits patch testing to age 2 years or older due to a young child’s smaller surface area.

Dr. Yu, who developed an interest in patch testing during his residency at the Medical College of Wisconsin, Milwaukee, where he worked with a patch-testing expert, will test children as young as 3-4 months with a “small selection of patches.”

The challenge with a call for more patch testing is a shortage of trained physicians. “In all of Boston, where we have hundreds of dermatologists, there are only about four of us who really do patch testing. My wait time is about 6 months,” said Dr. Yu, who is also an assistant professor at Harvard Medical School, Boston.

Allergists at Massachusetts General Hospital do “some patch testing ... but they refer a lot of the most complicated cases to me,” he said, noting that patch testing and management of ACD involves detailed counseling for patients about avoidance of allergens. “Overall dermatologists represent the largest group of doctors who have proficiency in patch testing, and there just aren’t many of us.”

Dr. Perryman also said that patch testing is often performed by dermatologists who specialize in treating ACD and AD, though there seems to be “regional variance” in the level of involvement of dermatologists and allergists in patch testing.

Not all residency programs have hands-on patch testing opportunities, Dr. Yu said. A study published in Dermatitis, which he co-authored, showed that in 2020, 47.5% of dermatology residency programs had formal patch testing rotations. This represented improvement but is still not enough, he said.

The American Contact Dermatitis Society offers patch-testing mentorship programs, and the American Academy of Dermatology has recently begun offered a patch testing workshop at its annual meetings, said Dr. Yu, who received 4 weeks of training in the Society’s mentorship program and is now involved in the American Academy of Dermatology’s workshops and as a trainer/lecturer at the Contact Dermatitis Institute.

The study was supported by the Dermatology Foundation. Dr. Yu and his co-investigators reported no conflicts of interest. Dr. Perryman had no disclosures.

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

The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.

At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.

courtesy UNC-Chapel Hill

What is zuranolone?

Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABA_A receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABA_A receptor to GABA.

Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
 

What does zuranolone treat?

Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.

How does zuranolone work?

courtesy UNC-Chapel Hill

Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.

How was it studied?

Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.

The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
 

When will we be able to start using it?

It is anticipated that zuranolone will become commercially available in early 2024.

Who can prescribe it?

courtesy UNC-Chapel Hill

Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.

How much will it cost?

The manufacturers have not released this information as of August 2023.

What sort of doses and duration is recommended?

The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.

What happens if the patient relapses after a 14-day trial?

While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.

What are the side effects?

courtesy UNC-Chapel Hill

Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.

Are there any boxed warnings?

Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.

Can it be used with other medications?

Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.

Are there any medicines to avoid?

We recommend caution with other medications which may increase sedation, such as benzodiazepines.

Can it be used with birth control?

Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.

Can it be used in pregnancy?

As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
 

Long-term side effects?

Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.

Breastfeeding?

Use in lactation has not yet been studied. Continued research is needed.

Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?

The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.

Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?

Zuranolone is currently only approved for the treatment of postpartum depression. It has not received FDA approval for major depression outside of the perinatal period at this time. Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.

Anxiety?

Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.

However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
 

Insomnia?

In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.

How is it different from brexanolone?

The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.

Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
 

When would you consider zuranolone vs. brexanolone vs. other antidepressants?

Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).

Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
 

Where can I find more information?

Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.

We plan to update this entry upon market release and access to new information.

Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.

References

Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.

Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.

Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.

Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.

FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression

ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf

The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.

At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.

courtesy UNC-Chapel Hill

What is zuranolone?

Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABA_A receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABA_A receptor to GABA.

Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
 

What does zuranolone treat?

Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.

How does zuranolone work?

courtesy UNC-Chapel Hill

Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.

How was it studied?

Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.

The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
 

When will we be able to start using it?

It is anticipated that zuranolone will become commercially available in early 2024.

Who can prescribe it?

courtesy UNC-Chapel Hill

Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.

How much will it cost?

The manufacturers have not released this information as of August 2023.

What sort of doses and duration is recommended?

The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.

What happens if the patient relapses after a 14-day trial?

While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.

What are the side effects?

courtesy UNC-Chapel Hill

Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.

Are there any boxed warnings?

Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.

Can it be used with other medications?

Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.

Are there any medicines to avoid?

We recommend caution with other medications which may increase sedation, such as benzodiazepines.

Can it be used with birth control?

Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.

Can it be used in pregnancy?

As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
 

Long-term side effects?

Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.

Breastfeeding?

Use in lactation has not yet been studied. Continued research is needed.

Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?

The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.

Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?

Zuranolone is currently only approved for the treatment of postpartum depression. It has not received FDA approval for major depression outside of the perinatal period at this time. Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.

Anxiety?

Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.

However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
 

Insomnia?

In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.

How is it different from brexanolone?

The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.

Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
 

When would you consider zuranolone vs. brexanolone vs. other antidepressants?

Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).

Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
 

Where can I find more information?

Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.

We plan to update this entry upon market release and access to new information.

Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.

References

Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.

Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.

Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.

Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.

FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression

ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf

The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.

At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.

courtesy UNC-Chapel Hill

What is zuranolone?

Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABA_A receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABA_A receptor to GABA.

Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
 

What does zuranolone treat?

Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.

How does zuranolone work?

courtesy UNC-Chapel Hill

Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.

How was it studied?

Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.

The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
 

When will we be able to start using it?

It is anticipated that zuranolone will become commercially available in early 2024.

Who can prescribe it?

courtesy UNC-Chapel Hill

Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.

How much will it cost?

The manufacturers have not released this information as of August 2023.

What sort of doses and duration is recommended?

The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.

What happens if the patient relapses after a 14-day trial?

While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.

What are the side effects?

courtesy UNC-Chapel Hill

Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.

Are there any boxed warnings?

Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.

Can it be used with other medications?

Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.

Are there any medicines to avoid?

We recommend caution with other medications which may increase sedation, such as benzodiazepines.

Can it be used with birth control?

Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.

Can it be used in pregnancy?

As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
 

Long-term side effects?

Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.

Breastfeeding?

Use in lactation has not yet been studied. Continued research is needed.

Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?

The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.

Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?

Zuranolone is currently only approved for the treatment of postpartum depression. It has not received FDA approval for major depression outside of the perinatal period at this time. Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.

Anxiety?

Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.

However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
 

Insomnia?

In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.

How is it different from brexanolone?

The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.

Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
 

When would you consider zuranolone vs. brexanolone vs. other antidepressants?

Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).

Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
 

Where can I find more information?

Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.

We plan to update this entry upon market release and access to new information.

Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.

References

Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.

Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.

Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.

Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.

FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression

ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf

A variety of probiotics may relieve symptoms in patients with irritable bowel syndrome (IBS), but most evidence from randomized controlled trials remains low certainty or very low certainty, with many studies suffering from bias, according to a recent review and meta-analysis.

These shortcomings in the probiotic research landscape should be kept in mind when making treatment recommendations, reported researchers who were led by Alexander C. Ford, MBChB, of the Leeds Gastroenterology Institute, University of Leeds (England). They suggested these issues need to be addressed in the methodology of future clinical trials.

“Although multiple probiotics have been tested in IBS in randomized clinical trials, understanding of which probiotics may be beneficial is limited,” the investigators wrote in Gastroenterology.

They noted that previous efforts – including their own – to meta-analyze these findings have been hindered by a scarcity of trial data coupled with heterogeneity across probiotic strains, combinations, and doses, resulting in clinical uncertainty.

“Making recommendations concerning which probiotics, or combinations of probiotics, are beneficial according to IBS subtype or individual symptom has been difficult to date,” they wrote.

To narrow this knowledge gap, the researchers conducted an updated systematic review and meta-analysis with newly identified trials.

“There is continued interest in the role of probiotics in the management of IBS, as evidenced by the publication of more than 20 new randomized clinical trials since the prior version of this meta-analysis in 2018,” they wrote.

The new dataset included 82 RCTs comprising 10,332 patients with IBS. Along with safety, three separate efficacy endpoints were evaluated: global symptoms, abdominal pain, and abdominal bloating or distension.

For global symptoms, moderate-certainty evidence supported the efficacy of Escherichia coli strains; low-certainty data supported Lactobacillus plantarum 299V and other Lactobacillus strains; and very-low-certainty evidence supported Bacillus, LacClean Gold S, and Duolac 7s strains, and combination probiotics.

For abdominal pain, low-certainty evidence supported Bifidobacterium strains and Saccharomyces cerevisiae I-3856. Very-low-certainty data supported Lactobacillus, Saccharomyces, and Bacillus strains, and combination probiotics.

Very-low-certainty evidence supported the benefits of Bacillus strains and combination probiotics for alleviating abdominal bloating or distension.

In a safety analysis of 55 trials involving more than 7,000 patients, risk of adverse events was no higher for probiotics than placebo.

“Our analyses provide some support for the use of certain probiotics in IBS, and also for particular strains for specific symptoms,” the investigators wrote. “However, there is a paucity of data for their use in patients with IBS-C [IBS with constipation], with only seven RCTs reporting efficacy in this subtype, and no evidence of efficacy in any of these analyses. Their use in patients with IBS-C is, therefore, not supported by current evidence.”

A broader discussion in the publication called out the general lack of high certainty evidence in this area of clinical research.

“Only 24 of 82 eligible RCTs were low risk of bias across all domains, and there was significant heterogeneity between trials in many of our analyses, as well as evidence of publication bias, or other small study effects, in some of our analyses,” the researchers wrote. “The fact that few of the included studies were low risk of bias across all domains should be borne in mind when making treatment recommendations.”

The investigators disclosed relationships with Salix, Biocodex, 4D Pharma, and others.

A variety of probiotics may relieve symptoms in patients with irritable bowel syndrome (IBS), but most evidence from randomized controlled trials remains low certainty or very low certainty, with many studies suffering from bias, according to a recent review and meta-analysis.

These shortcomings in the probiotic research landscape should be kept in mind when making treatment recommendations, reported researchers who were led by Alexander C. Ford, MBChB, of the Leeds Gastroenterology Institute, University of Leeds (England). They suggested these issues need to be addressed in the methodology of future clinical trials.

“Although multiple probiotics have been tested in IBS in randomized clinical trials, understanding of which probiotics may be beneficial is limited,” the investigators wrote in Gastroenterology.

They noted that previous efforts – including their own – to meta-analyze these findings have been hindered by a scarcity of trial data coupled with heterogeneity across probiotic strains, combinations, and doses, resulting in clinical uncertainty.

“Making recommendations concerning which probiotics, or combinations of probiotics, are beneficial according to IBS subtype or individual symptom has been difficult to date,” they wrote.

To narrow this knowledge gap, the researchers conducted an updated systematic review and meta-analysis with newly identified trials.

“There is continued interest in the role of probiotics in the management of IBS, as evidenced by the publication of more than 20 new randomized clinical trials since the prior version of this meta-analysis in 2018,” they wrote.

The new dataset included 82 RCTs comprising 10,332 patients with IBS. Along with safety, three separate efficacy endpoints were evaluated: global symptoms, abdominal pain, and abdominal bloating or distension.

For global symptoms, moderate-certainty evidence supported the efficacy of Escherichia coli strains; low-certainty data supported Lactobacillus plantarum 299V and other Lactobacillus strains; and very-low-certainty evidence supported Bacillus, LacClean Gold S, and Duolac 7s strains, and combination probiotics.

For abdominal pain, low-certainty evidence supported Bifidobacterium strains and Saccharomyces cerevisiae I-3856. Very-low-certainty data supported Lactobacillus, Saccharomyces, and Bacillus strains, and combination probiotics.

Very-low-certainty evidence supported the benefits of Bacillus strains and combination probiotics for alleviating abdominal bloating or distension.

In a safety analysis of 55 trials involving more than 7,000 patients, risk of adverse events was no higher for probiotics than placebo.

“Our analyses provide some support for the use of certain probiotics in IBS, and also for particular strains for specific symptoms,” the investigators wrote. “However, there is a paucity of data for their use in patients with IBS-C [IBS with constipation], with only seven RCTs reporting efficacy in this subtype, and no evidence of efficacy in any of these analyses. Their use in patients with IBS-C is, therefore, not supported by current evidence.”

A broader discussion in the publication called out the general lack of high certainty evidence in this area of clinical research.

“Only 24 of 82 eligible RCTs were low risk of bias across all domains, and there was significant heterogeneity between trials in many of our analyses, as well as evidence of publication bias, or other small study effects, in some of our analyses,” the researchers wrote. “The fact that few of the included studies were low risk of bias across all domains should be borne in mind when making treatment recommendations.”

The investigators disclosed relationships with Salix, Biocodex, 4D Pharma, and others.

A variety of probiotics may relieve symptoms in patients with irritable bowel syndrome (IBS), but most evidence from randomized controlled trials remains low certainty or very low certainty, with many studies suffering from bias, according to a recent review and meta-analysis.

These shortcomings in the probiotic research landscape should be kept in mind when making treatment recommendations, reported researchers who were led by Alexander C. Ford, MBChB, of the Leeds Gastroenterology Institute, University of Leeds (England). They suggested these issues need to be addressed in the methodology of future clinical trials.

“Although multiple probiotics have been tested in IBS in randomized clinical trials, understanding of which probiotics may be beneficial is limited,” the investigators wrote in Gastroenterology.

They noted that previous efforts – including their own – to meta-analyze these findings have been hindered by a scarcity of trial data coupled with heterogeneity across probiotic strains, combinations, and doses, resulting in clinical uncertainty.

“Making recommendations concerning which probiotics, or combinations of probiotics, are beneficial according to IBS subtype or individual symptom has been difficult to date,” they wrote.

To narrow this knowledge gap, the researchers conducted an updated systematic review and meta-analysis with newly identified trials.

“There is continued interest in the role of probiotics in the management of IBS, as evidenced by the publication of more than 20 new randomized clinical trials since the prior version of this meta-analysis in 2018,” they wrote.

The new dataset included 82 RCTs comprising 10,332 patients with IBS. Along with safety, three separate efficacy endpoints were evaluated: global symptoms, abdominal pain, and abdominal bloating or distension.

For global symptoms, moderate-certainty evidence supported the efficacy of Escherichia coli strains; low-certainty data supported Lactobacillus plantarum 299V and other Lactobacillus strains; and very-low-certainty evidence supported Bacillus, LacClean Gold S, and Duolac 7s strains, and combination probiotics.

For abdominal pain, low-certainty evidence supported Bifidobacterium strains and Saccharomyces cerevisiae I-3856. Very-low-certainty data supported Lactobacillus, Saccharomyces, and Bacillus strains, and combination probiotics.

Very-low-certainty evidence supported the benefits of Bacillus strains and combination probiotics for alleviating abdominal bloating or distension.

In a safety analysis of 55 trials involving more than 7,000 patients, risk of adverse events was no higher for probiotics than placebo.

“Our analyses provide some support for the use of certain probiotics in IBS, and also for particular strains for specific symptoms,” the investigators wrote. “However, there is a paucity of data for their use in patients with IBS-C [IBS with constipation], with only seven RCTs reporting efficacy in this subtype, and no evidence of efficacy in any of these analyses. Their use in patients with IBS-C is, therefore, not supported by current evidence.”

A broader discussion in the publication called out the general lack of high certainty evidence in this area of clinical research.

“Only 24 of 82 eligible RCTs were low risk of bias across all domains, and there was significant heterogeneity between trials in many of our analyses, as well as evidence of publication bias, or other small study effects, in some of our analyses,” the researchers wrote. “The fact that few of the included studies were low risk of bias across all domains should be borne in mind when making treatment recommendations.”

The investigators disclosed relationships with Salix, Biocodex, 4D Pharma, and others.

ILLUSTRATIVE CASE

A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.

The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?

Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.²The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).³

Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, ⁴ the Eighth Joint National Committee (JNC 8), ⁵ the International Society of Hypertension, ⁶ and the European Society of Cardiology ⁷ use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. ⁸

When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the Dietary Approaches to Stop Hypertension (DASH) diet. Other lifestyle modifications include weight loss, tobacco cessation, reduced daily alcohol intake, and increased physical activity. ⁹

Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. ^10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. ¹³ Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of ­patient-oriented evidence that demonstrates improvement in CV disease and mortality.

The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. ¹⁴ Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. ¹³

Continue to: In this 2022 systematic review...

In this 2022 systematic review and meta-analysis, ¹ Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-­randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of ­potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.

The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.

The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I ² > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.

Consistent reduction in BP and clinical outcomes across diverse populations and regions suggests potential worldwide benefit from the use of potassium-enriched salt in appropriate patients.

Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was ­associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.

Continue to: Only 2 of the studes...

Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that ­potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.

CAVEATS

Some patient populations, comorbidities excluded from study

The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-­sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.

ILLUSTRATIVE CASE

A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.

The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?

Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.²The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).³

Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, ⁴ the Eighth Joint National Committee (JNC 8), ⁵ the International Society of Hypertension, ⁶ and the European Society of Cardiology ⁷ use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. ⁸

When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the Dietary Approaches to Stop Hypertension (DASH) diet. Other lifestyle modifications include weight loss, tobacco cessation, reduced daily alcohol intake, and increased physical activity. ⁹

Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. ^10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. ¹³ Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of ­patient-oriented evidence that demonstrates improvement in CV disease and mortality.

The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. ¹⁴ Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. ¹³

Continue to: In this 2022 systematic review...

In this 2022 systematic review and meta-analysis, ¹ Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-­randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of ­potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.

The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.

The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I ² > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.

Consistent reduction in BP and clinical outcomes across diverse populations and regions suggests potential worldwide benefit from the use of potassium-enriched salt in appropriate patients.

Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was ­associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.

Continue to: Only 2 of the studes...

Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that ­potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.

CAVEATS

Some patient populations, comorbidities excluded from study

The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-­sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.

ILLUSTRATIVE CASE

A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.

The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?

Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.²The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).³

Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, ⁴ the Eighth Joint National Committee (JNC 8), ⁵ the International Society of Hypertension, ⁶ and the European Society of Cardiology ⁷ use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. ⁸

When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the Dietary Approaches to Stop Hypertension (DASH) diet. Other lifestyle modifications include weight loss, tobacco cessation, reduced daily alcohol intake, and increased physical activity. ⁹

Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. ^10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. ¹³ Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of ­patient-oriented evidence that demonstrates improvement in CV disease and mortality.

The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. ¹⁴ Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. ¹³

Continue to: In this 2022 systematic review...

In this 2022 systematic review and meta-analysis, ¹ Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-­randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of ­potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.

The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.

The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I ² > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.

Consistent reduction in BP and clinical outcomes across diverse populations and regions suggests potential worldwide benefit from the use of potassium-enriched salt in appropriate patients.

Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was ­associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.

Continue to: Only 2 of the studes...

Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that ­potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.

CAVEATS

Some patient populations, comorbidities excluded from study

The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-­sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.

The World Health Organization (WHO) recently released its inaugural report on the devastating global effects of hypertension, including recommendations for combatting this “silent killer.”¹ Notable in the 276-page report is the emphasis on improving access to antihypertensive medications, in part through team-based care and simple evidence-based protocols. This strategy is not surprising given that in clinical medicine we focus on the “high-risk” strategy for prevention­—ie, identify people at increased risk for an adverse health outcome (in this case, cardiovascular disease events) and offer them medication to reduce that risk.²

Should we replace even a small amount of the sodium in processed foods with potassium?

As part of the high-risk strategy, we also counsel at the individual level about lifestyle modifications—but unfortunately, we tend not to get very far. Given the substantial evidence demonstrating its benefits, a low-sodium DASH (Dietary Approaches to Stop Hypertension) eating plan is one of the lifestyle recommendations we make for our patients with hypertension.^3,4 The DASH part of the diet involves getting our patients to eat more fruits, vegetables, and whole grains and limit sugar and saturated fats. To achieve the low-sodium part, we might counsel against added table salt, but mostly we discourage consumption of canned and other foods that are commercially processed, packaged, and prepared, because that’s the source of more than 70% of our sodium intake.⁵ It’s not difficult to understand why real-world uptake of the low-sodium DASH eating plan is low.⁶

This issue of The Journal of Family Practice features a PURL that supports a much more prominent role for salt substitutes in our counseling recommendations.⁷ Potassium­-enriched salt substitutes not only lower blood pressure (BP) but also reduce the risk for cardiovascular events and death.⁸ They are widely available, and while more expensive per ounce than regular salt (sodium chloride), are still affordable.

Still, encouraging salt substitution with one patient at a time is relying on the high-risk strategy, with its inherently limited potential.² An alternative is the population strategy. For hypertension, that would mean doing something for the entire population that would lead to a downward shift in the distribution of BP.² The shift does not have to be large. We’ve known for more than 3 decades that just a 2–mm Hg reduction in the population’s average systolic BP would reduce stroke mortality by about 6%, coronary heart disease mortality by 4%, and total mortality by 3%.⁹ A 5–mm Hg reduction more than doubles those benefits. We are talking about tens of thousands fewer patients with heart disease and stroke each year and billions of dollars in health care cost savings.

Reducing our nation’s sodium intake, a quintessential population approach, has proven difficult. Our average daily sodium intake is about 3600 mg.¹⁰ Guidance on sodium reduction from the US Food and Drug Administration (targeted to industry) has aimed to reduce Americans’ average sodium intake to 3000 mg/d over the short term, fully acknowledging that the recommended sodium limit is 2300 mg/d.¹¹ We’ve got a long way to go.

Might salt substitution at the population level be a way to simultaneously reduce our sodium intake and increase our potassium intake?¹² The closest I found to a population­wide substitution study was a cluster randomized trial conducted in 6 villages in Peru.¹³ In a stepped-wedge design, households had 25% of their regular salt replaced with potassium salt. Small shops, bakeries, community kitchens, and food vendors also had salt replacement. The intention-to-treat analysis showed a small reduction in systolic BP (1.3 mm Hg) among those with hypertension at baseline (n = 428) and a 51% reduced incidence of developing hypertension among the other 1891 participants over the 4673 ­person-years of follow-up.

I found this study interesting and its results compelling, leading me to wonder: In the United States, where most of our sodium comes from the food industry, should we replace even a small amount of the sodium in processed foods with potassium? We’re not getting there with DASH alone. 

The World Health Organization (WHO) recently released its inaugural report on the devastating global effects of hypertension, including recommendations for combatting this “silent killer.”¹ Notable in the 276-page report is the emphasis on improving access to antihypertensive medications, in part through team-based care and simple evidence-based protocols. This strategy is not surprising given that in clinical medicine we focus on the “high-risk” strategy for prevention­—ie, identify people at increased risk for an adverse health outcome (in this case, cardiovascular disease events) and offer them medication to reduce that risk.²

Should we replace even a small amount of the sodium in processed foods with potassium?

As part of the high-risk strategy, we also counsel at the individual level about lifestyle modifications—but unfortunately, we tend not to get very far. Given the substantial evidence demonstrating its benefits, a low-sodium DASH (Dietary Approaches to Stop Hypertension) eating plan is one of the lifestyle recommendations we make for our patients with hypertension.^3,4 The DASH part of the diet involves getting our patients to eat more fruits, vegetables, and whole grains and limit sugar and saturated fats. To achieve the low-sodium part, we might counsel against added table salt, but mostly we discourage consumption of canned and other foods that are commercially processed, packaged, and prepared, because that’s the source of more than 70% of our sodium intake.⁵ It’s not difficult to understand why real-world uptake of the low-sodium DASH eating plan is low.⁶

This issue of The Journal of Family Practice features a PURL that supports a much more prominent role for salt substitutes in our counseling recommendations.⁷ Potassium­-enriched salt substitutes not only lower blood pressure (BP) but also reduce the risk for cardiovascular events and death.⁸ They are widely available, and while more expensive per ounce than regular salt (sodium chloride), are still affordable.

Still, encouraging salt substitution with one patient at a time is relying on the high-risk strategy, with its inherently limited potential.² An alternative is the population strategy. For hypertension, that would mean doing something for the entire population that would lead to a downward shift in the distribution of BP.² The shift does not have to be large. We’ve known for more than 3 decades that just a 2–mm Hg reduction in the population’s average systolic BP would reduce stroke mortality by about 6%, coronary heart disease mortality by 4%, and total mortality by 3%.⁹ A 5–mm Hg reduction more than doubles those benefits. We are talking about tens of thousands fewer patients with heart disease and stroke each year and billions of dollars in health care cost savings.

Reducing our nation’s sodium intake, a quintessential population approach, has proven difficult. Our average daily sodium intake is about 3600 mg.¹⁰ Guidance on sodium reduction from the US Food and Drug Administration (targeted to industry) has aimed to reduce Americans’ average sodium intake to 3000 mg/d over the short term, fully acknowledging that the recommended sodium limit is 2300 mg/d.¹¹ We’ve got a long way to go.

Might salt substitution at the population level be a way to simultaneously reduce our sodium intake and increase our potassium intake?¹² The closest I found to a population­wide substitution study was a cluster randomized trial conducted in 6 villages in Peru.¹³ In a stepped-wedge design, households had 25% of their regular salt replaced with potassium salt. Small shops, bakeries, community kitchens, and food vendors also had salt replacement. The intention-to-treat analysis showed a small reduction in systolic BP (1.3 mm Hg) among those with hypertension at baseline (n = 428) and a 51% reduced incidence of developing hypertension among the other 1891 participants over the 4673 ­person-years of follow-up.

I found this study interesting and its results compelling, leading me to wonder: In the United States, where most of our sodium comes from the food industry, should we replace even a small amount of the sodium in processed foods with potassium? We’re not getting there with DASH alone. 

The World Health Organization (WHO) recently released its inaugural report on the devastating global effects of hypertension, including recommendations for combatting this “silent killer.”¹ Notable in the 276-page report is the emphasis on improving access to antihypertensive medications, in part through team-based care and simple evidence-based protocols. This strategy is not surprising given that in clinical medicine we focus on the “high-risk” strategy for prevention­—ie, identify people at increased risk for an adverse health outcome (in this case, cardiovascular disease events) and offer them medication to reduce that risk.²

Should we replace even a small amount of the sodium in processed foods with potassium?

As part of the high-risk strategy, we also counsel at the individual level about lifestyle modifications—but unfortunately, we tend not to get very far. Given the substantial evidence demonstrating its benefits, a low-sodium DASH (Dietary Approaches to Stop Hypertension) eating plan is one of the lifestyle recommendations we make for our patients with hypertension.^3,4 The DASH part of the diet involves getting our patients to eat more fruits, vegetables, and whole grains and limit sugar and saturated fats. To achieve the low-sodium part, we might counsel against added table salt, but mostly we discourage consumption of canned and other foods that are commercially processed, packaged, and prepared, because that’s the source of more than 70% of our sodium intake.⁵ It’s not difficult to understand why real-world uptake of the low-sodium DASH eating plan is low.⁶

This issue of The Journal of Family Practice features a PURL that supports a much more prominent role for salt substitutes in our counseling recommendations.⁷ Potassium­-enriched salt substitutes not only lower blood pressure (BP) but also reduce the risk for cardiovascular events and death.⁸ They are widely available, and while more expensive per ounce than regular salt (sodium chloride), are still affordable.

Still, encouraging salt substitution with one patient at a time is relying on the high-risk strategy, with its inherently limited potential.² An alternative is the population strategy. For hypertension, that would mean doing something for the entire population that would lead to a downward shift in the distribution of BP.² The shift does not have to be large. We’ve known for more than 3 decades that just a 2–mm Hg reduction in the population’s average systolic BP would reduce stroke mortality by about 6%, coronary heart disease mortality by 4%, and total mortality by 3%.⁹ A 5–mm Hg reduction more than doubles those benefits. We are talking about tens of thousands fewer patients with heart disease and stroke each year and billions of dollars in health care cost savings.

Reducing our nation’s sodium intake, a quintessential population approach, has proven difficult. Our average daily sodium intake is about 3600 mg.¹⁰ Guidance on sodium reduction from the US Food and Drug Administration (targeted to industry) has aimed to reduce Americans’ average sodium intake to 3000 mg/d over the short term, fully acknowledging that the recommended sodium limit is 2300 mg/d.¹¹ We’ve got a long way to go.

Might salt substitution at the population level be a way to simultaneously reduce our sodium intake and increase our potassium intake?¹² The closest I found to a population­wide substitution study was a cluster randomized trial conducted in 6 villages in Peru.¹³ In a stepped-wedge design, households had 25% of their regular salt replaced with potassium salt. Small shops, bakeries, community kitchens, and food vendors also had salt replacement. The intention-to-treat analysis showed a small reduction in systolic BP (1.3 mm Hg) among those with hypertension at baseline (n = 428) and a 51% reduced incidence of developing hypertension among the other 1891 participants over the 4673 ­person-years of follow-up.

I found this study interesting and its results compelling, leading me to wonder: In the United States, where most of our sodium comes from the food industry, should we replace even a small amount of the sodium in processed foods with potassium? We’re not getting there with DASH alone. 

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; [email protected]

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; [email protected]

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; [email protected]

The American Gastroenterological Association (AGA) has published a Clinical Practice Update for managing exocrine pancreatic insufficiency (EPI). The update, which was led by Anna M. Buchner, MD, PhD, University of Pennsylvania, Philadelphia, includes 15 best practice advice statements based on available literature and expert opinion.

“EPI is frequently underdiagnosed and, as a result, patients are often not treated appropriately,” the authors wrote in Gastroenterology. “There is an urgent need to increase awareness of and treatment for this condition.”

To this end, the authors offered guidance spanning the patient journey, with recommendations broadly grouped into four categories: clinical features and risk factors, diagnostic strategies, treatment approaches, and disease monitoring.
 

Clinical features and risk factors

The CPU begins by listing the key clinical features of EPI, including bloating, excessive flatulence, fat-soluble vitamin deficiencies, protein-calorie malnutrition, steatorrhea with or without diarrhea, and weight loss.

The authors went on to suggest that EPI should also be considered in patients with high-risk clinical conditions, including previous pancreatic surgery, chronic pancreatitis, cystic fibrosis, pancreatic ductal adenocarcinoma, and relapsing acute pancreatitis.

Similarly, suspicion should be increased for individuals with moderate-risk clinical conditions, such as prior intestinal surgery, Zollinger-Ellison syndrome, longstanding diabetes mellitus, and duodenal diseases such as celiac and Crohn’s disease.
 

Diagnostic strategies

The primary diagnostic tool for EPI is the fecal elastase test, according to the update. Levels below 100 mcg/g indicate EPI, whereas levels between 100-200 mcg/g are considered indeterminate. The investigators noted that this test can be conducted even during pancreatic enzyme replacement therapy (PERT).

Other tests for EPI are rarely used, such as fecal fat testing, which must be performed on a high-fat diet, and quantitative testing, which is generally impractical for routine clinical use.

The authors also noted that a therapeutic trial of PERT is an unreliable method for diagnosing EPI.

“Patients with nonspecific symptoms, such as bloating, excess gas, and foul-smelling or floating stools may note some improvement in these symptoms while taking PERT, but these symptoms are nonspecific and symptomatic changes may be a placebo effect or masking other disorders, such as celiac disease, causing delays in a correct diagnosis,” they wrote.

While cross-sectional imaging methods such as CT scans, MRI, and endoscopic ultrasound play a significant role in detecting other pancreatic diseases, they cannot identify EPI. Breath tests and direct pancreatic function tests do hold promise, but they are not widely available in the United States.
 

Treatment strategies

Once EPI is diagnosed, treatment with PERT is indicated to prevent complications related to fat malabsorption and malnutrition.

PERT formulations are all equally effective at equivalent doses, according to the update, but non–enteric-coated preparations require concurrent H2 or proton pump inhibitor therapy. PERT should be taken during meals, with an initial adult dose of at least 40,000 USP units of lipase during each meal. Half that dose may be considered for snacks, with further dosage refinements based on meal size and fat content.

Dietary modifications may include supplementation with fat-soluble vitamins alongside smaller, more frequent, low- to moderate-fat meals. Very-low-fat diets should be avoided, the authors cautioned.
 

Surveillance

EPI treatment success can be identified by reduction in steatorrhea and associated gastrointestinal symptoms, as well as weight gain, improved muscle mass and function, and enhanced fat-soluble vitamin levels, Dr. Whitcomb and colleagues wrote, noting that a dual-energy x-ray absorptiometry scan also should be performed at baseline, then repeated every 1-2 years.

The update was commissioned and approved by the AGA. The investigators disclosed relationships with AbbVie, Nestlé, Regeneron, and others.

The American Gastroenterological Association (AGA) has published a Clinical Practice Update for managing exocrine pancreatic insufficiency (EPI). The update, which was led by Anna M. Buchner, MD, PhD, University of Pennsylvania, Philadelphia, includes 15 best practice advice statements based on available literature and expert opinion.

“EPI is frequently underdiagnosed and, as a result, patients are often not treated appropriately,” the authors wrote in Gastroenterology. “There is an urgent need to increase awareness of and treatment for this condition.”

To this end, the authors offered guidance spanning the patient journey, with recommendations broadly grouped into four categories: clinical features and risk factors, diagnostic strategies, treatment approaches, and disease monitoring.
 

Clinical features and risk factors

The CPU begins by listing the key clinical features of EPI, including bloating, excessive flatulence, fat-soluble vitamin deficiencies, protein-calorie malnutrition, steatorrhea with or without diarrhea, and weight loss.

The authors went on to suggest that EPI should also be considered in patients with high-risk clinical conditions, including previous pancreatic surgery, chronic pancreatitis, cystic fibrosis, pancreatic ductal adenocarcinoma, and relapsing acute pancreatitis.

Similarly, suspicion should be increased for individuals with moderate-risk clinical conditions, such as prior intestinal surgery, Zollinger-Ellison syndrome, longstanding diabetes mellitus, and duodenal diseases such as celiac and Crohn’s disease.
 

Diagnostic strategies

The primary diagnostic tool for EPI is the fecal elastase test, according to the update. Levels below 100 mcg/g indicate EPI, whereas levels between 100-200 mcg/g are considered indeterminate. The investigators noted that this test can be conducted even during pancreatic enzyme replacement therapy (PERT).

Other tests for EPI are rarely used, such as fecal fat testing, which must be performed on a high-fat diet, and quantitative testing, which is generally impractical for routine clinical use.

The authors also noted that a therapeutic trial of PERT is an unreliable method for diagnosing EPI.

“Patients with nonspecific symptoms, such as bloating, excess gas, and foul-smelling or floating stools may note some improvement in these symptoms while taking PERT, but these symptoms are nonspecific and symptomatic changes may be a placebo effect or masking other disorders, such as celiac disease, causing delays in a correct diagnosis,” they wrote.

While cross-sectional imaging methods such as CT scans, MRI, and endoscopic ultrasound play a significant role in detecting other pancreatic diseases, they cannot identify EPI. Breath tests and direct pancreatic function tests do hold promise, but they are not widely available in the United States.
 

Treatment strategies

Once EPI is diagnosed, treatment with PERT is indicated to prevent complications related to fat malabsorption and malnutrition.

PERT formulations are all equally effective at equivalent doses, according to the update, but non–enteric-coated preparations require concurrent H2 or proton pump inhibitor therapy. PERT should be taken during meals, with an initial adult dose of at least 40,000 USP units of lipase during each meal. Half that dose may be considered for snacks, with further dosage refinements based on meal size and fat content.

Dietary modifications may include supplementation with fat-soluble vitamins alongside smaller, more frequent, low- to moderate-fat meals. Very-low-fat diets should be avoided, the authors cautioned.
 

Surveillance

EPI treatment success can be identified by reduction in steatorrhea and associated gastrointestinal symptoms, as well as weight gain, improved muscle mass and function, and enhanced fat-soluble vitamin levels, Dr. Whitcomb and colleagues wrote, noting that a dual-energy x-ray absorptiometry scan also should be performed at baseline, then repeated every 1-2 years.

The update was commissioned and approved by the AGA. The investigators disclosed relationships with AbbVie, Nestlé, Regeneron, and others.

The American Gastroenterological Association (AGA) has published a Clinical Practice Update for managing exocrine pancreatic insufficiency (EPI). The update, which was led by Anna M. Buchner, MD, PhD, University of Pennsylvania, Philadelphia, includes 15 best practice advice statements based on available literature and expert opinion.

“EPI is frequently underdiagnosed and, as a result, patients are often not treated appropriately,” the authors wrote in Gastroenterology. “There is an urgent need to increase awareness of and treatment for this condition.”

To this end, the authors offered guidance spanning the patient journey, with recommendations broadly grouped into four categories: clinical features and risk factors, diagnostic strategies, treatment approaches, and disease monitoring.
 

Clinical features and risk factors

The CPU begins by listing the key clinical features of EPI, including bloating, excessive flatulence, fat-soluble vitamin deficiencies, protein-calorie malnutrition, steatorrhea with or without diarrhea, and weight loss.

The authors went on to suggest that EPI should also be considered in patients with high-risk clinical conditions, including previous pancreatic surgery, chronic pancreatitis, cystic fibrosis, pancreatic ductal adenocarcinoma, and relapsing acute pancreatitis.

Similarly, suspicion should be increased for individuals with moderate-risk clinical conditions, such as prior intestinal surgery, Zollinger-Ellison syndrome, longstanding diabetes mellitus, and duodenal diseases such as celiac and Crohn’s disease.
 

Diagnostic strategies

The primary diagnostic tool for EPI is the fecal elastase test, according to the update. Levels below 100 mcg/g indicate EPI, whereas levels between 100-200 mcg/g are considered indeterminate. The investigators noted that this test can be conducted even during pancreatic enzyme replacement therapy (PERT).

Other tests for EPI are rarely used, such as fecal fat testing, which must be performed on a high-fat diet, and quantitative testing, which is generally impractical for routine clinical use.

The authors also noted that a therapeutic trial of PERT is an unreliable method for diagnosing EPI.

“Patients with nonspecific symptoms, such as bloating, excess gas, and foul-smelling or floating stools may note some improvement in these symptoms while taking PERT, but these symptoms are nonspecific and symptomatic changes may be a placebo effect or masking other disorders, such as celiac disease, causing delays in a correct diagnosis,” they wrote.

While cross-sectional imaging methods such as CT scans, MRI, and endoscopic ultrasound play a significant role in detecting other pancreatic diseases, they cannot identify EPI. Breath tests and direct pancreatic function tests do hold promise, but they are not widely available in the United States.
 

Treatment strategies

Once EPI is diagnosed, treatment with PERT is indicated to prevent complications related to fat malabsorption and malnutrition.

PERT formulations are all equally effective at equivalent doses, according to the update, but non–enteric-coated preparations require concurrent H2 or proton pump inhibitor therapy. PERT should be taken during meals, with an initial adult dose of at least 40,000 USP units of lipase during each meal. Half that dose may be considered for snacks, with further dosage refinements based on meal size and fat content.

Dietary modifications may include supplementation with fat-soluble vitamins alongside smaller, more frequent, low- to moderate-fat meals. Very-low-fat diets should be avoided, the authors cautioned.
 

Surveillance

EPI treatment success can be identified by reduction in steatorrhea and associated gastrointestinal symptoms, as well as weight gain, improved muscle mass and function, and enhanced fat-soluble vitamin levels, Dr. Whitcomb and colleagues wrote, noting that a dual-energy x-ray absorptiometry scan also should be performed at baseline, then repeated every 1-2 years.

The update was commissioned and approved by the AGA. The investigators disclosed relationships with AbbVie, Nestlé, Regeneron, and others.

When the Advisory Committee on Immunization Practices (ACIP) met in June and adopted recommendations for influenza vaccines for the 2023-2024 season, the major discussions focused on the timing of vaccine administration, the composition of the vaccine, and what (if any) special precautions are needed when administering an egg-based vaccine to a person with a history of egg allergy. Here are the takeaways.

When should flu vaccine be administered?

Influenza activity usually peaks between December and the end of March; only twice between 1982 and 2022 did it peak before December. Thus, most people should receive the vaccine in September or October, a recommendation that has not changed from last year. This is early enough to provide adequate protection in most influenza seasons, but late enough to allow protection to persist through the entire season. Vaccination should continue to be offered to those who are unvaccinated throughout the influenza season, as long as influenza viruses are circulating.

Earlier administration is not recommended for most people and is recommended against for those ages 65 years and older (because their immunity from the vaccine may wane faster) and for pregnant people in their first or second trimester (because the vaccine is more effective in preventing influenza in newborns if administered in the third trimester). Evidence regarding waning immunity is inconsistent; however, some studies have shown greater loss of immunity in the elderly compared to younger age groups, as time from vaccination increases.¹

What’s in this year’s vaccines?

The composition of the vaccines used in North America was determined by the World Health Organization in February, based on the most commonly circulating strains. All vaccines approved for use in the 2023-2024 season are quadrivalent and contain 1 influenza A (H1N1) strain, 1 influenza A (H3N2) strain, and 2 influenza B strains. The specifics of each strain are listed in TABLE 1.² The 2 influenza A strains are slightly different for the egg-based and non-egg-based vaccines.² There is no known effectiveness advantage of one antigen strain vs the other.

Should you take special precautions with egg allergy?

There is new wording to the recommendations on the use of egg-based influenza vaccines for those with a history of egg allergy (TABLE 2²). Previously, the ACIP had recommended that if an egg-based vaccine is given to a person with a history of egg allergy, it should be administered in an inpatient or outpatient medical setting (eg, hospital, clinic, health department, physician office) and should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. These added precautions were out of step with other organizations, including the American Academy of Pediatrics and allergy-related specialty societies, all of whom recommend no special procedures or precautions when administering any influenza vaccine to those with a history of egg allergy.³

Why the change? Several factors contributed to ACIP’s decision to reword its recommendation. One is that the ovalbumin content of all current influenza vaccines ­(TABLE 3³) is considered too low to trigger an allergic reaction.

Another is the paucity of evidence that egg-based vaccines convey increased risk beyond that for any other vaccine. Although 1% to 3% of children are reported to have an egg allergy, there is no evidence that they are at increased risk for a serious allergic reaction if administered an egg-based vaccine.³ A systematic review of 31 studies (mostly low-quality observational studies and case series) conducted by the ACIP Influenza Work Group found no risk for severe anaphylaxis, hospitalization, or death, even in those with a history of an anaphylactic reaction to eggs.² A review of Vaccine Adverse Events Reporting System (VAERS) data identified 18 cases of reported anaphylaxis after receipt of an inactivated influenza vaccine over a 5-year period, but clinical review confirmed only 7.²

Continue to: And finally, appropriate precautions already...

And finally, appropriate precautions already are recommended for administration of any vaccine. The CDC guidance for best practices for administering vaccines states: “Although allergic reactions are a common concern for vaccine providers, these reactions are uncommon and anaphylaxis following vaccines is rare, occurring at a rate of approximately one per million doses for many vaccines. Epinephrine and equipment for managing an airway should be available for immediate use.”⁴

What does this mean in practice? Family physicians who administer influenza vaccines do not need to use special precautions for any influenza vaccine, or use non-egg-based vaccines, for those who have a history of egg allergy. However, they should be prepared to respond to a severe allergic reaction just as they would for any other vaccine. Any vestigial practices pertaining to egg allergy and influenza vaccines—such as vaccine skin testing prior to vaccination (with dilution of vaccine if positive), vaccination deferral or administration via alternative dosing protocols, and split dosing of vaccine—are unnecessary and should be abandoned. 

When the Advisory Committee on Immunization Practices (ACIP) met in June and adopted recommendations for influenza vaccines for the 2023-2024 season, the major discussions focused on the timing of vaccine administration, the composition of the vaccine, and what (if any) special precautions are needed when administering an egg-based vaccine to a person with a history of egg allergy. Here are the takeaways.

When should flu vaccine be administered?

Influenza activity usually peaks between December and the end of March; only twice between 1982 and 2022 did it peak before December. Thus, most people should receive the vaccine in September or October, a recommendation that has not changed from last year. This is early enough to provide adequate protection in most influenza seasons, but late enough to allow protection to persist through the entire season. Vaccination should continue to be offered to those who are unvaccinated throughout the influenza season, as long as influenza viruses are circulating.

Earlier administration is not recommended for most people and is recommended against for those ages 65 years and older (because their immunity from the vaccine may wane faster) and for pregnant people in their first or second trimester (because the vaccine is more effective in preventing influenza in newborns if administered in the third trimester). Evidence regarding waning immunity is inconsistent; however, some studies have shown greater loss of immunity in the elderly compared to younger age groups, as time from vaccination increases.¹

What’s in this year’s vaccines?

The composition of the vaccines used in North America was determined by the World Health Organization in February, based on the most commonly circulating strains. All vaccines approved for use in the 2023-2024 season are quadrivalent and contain 1 influenza A (H1N1) strain, 1 influenza A (H3N2) strain, and 2 influenza B strains. The specifics of each strain are listed in TABLE 1.² The 2 influenza A strains are slightly different for the egg-based and non-egg-based vaccines.² There is no known effectiveness advantage of one antigen strain vs the other.

Should you take special precautions with egg allergy?

There is new wording to the recommendations on the use of egg-based influenza vaccines for those with a history of egg allergy (TABLE 2²). Previously, the ACIP had recommended that if an egg-based vaccine is given to a person with a history of egg allergy, it should be administered in an inpatient or outpatient medical setting (eg, hospital, clinic, health department, physician office) and should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. These added precautions were out of step with other organizations, including the American Academy of Pediatrics and allergy-related specialty societies, all of whom recommend no special procedures or precautions when administering any influenza vaccine to those with a history of egg allergy.³

Why the change? Several factors contributed to ACIP’s decision to reword its recommendation. One is that the ovalbumin content of all current influenza vaccines ­(TABLE 3³) is considered too low to trigger an allergic reaction.

Another is the paucity of evidence that egg-based vaccines convey increased risk beyond that for any other vaccine. Although 1% to 3% of children are reported to have an egg allergy, there is no evidence that they are at increased risk for a serious allergic reaction if administered an egg-based vaccine.³ A systematic review of 31 studies (mostly low-quality observational studies and case series) conducted by the ACIP Influenza Work Group found no risk for severe anaphylaxis, hospitalization, or death, even in those with a history of an anaphylactic reaction to eggs.² A review of Vaccine Adverse Events Reporting System (VAERS) data identified 18 cases of reported anaphylaxis after receipt of an inactivated influenza vaccine over a 5-year period, but clinical review confirmed only 7.²

Continue to: And finally, appropriate precautions already...

And finally, appropriate precautions already are recommended for administration of any vaccine. The CDC guidance for best practices for administering vaccines states: “Although allergic reactions are a common concern for vaccine providers, these reactions are uncommon and anaphylaxis following vaccines is rare, occurring at a rate of approximately one per million doses for many vaccines. Epinephrine and equipment for managing an airway should be available for immediate use.”⁴

What does this mean in practice? Family physicians who administer influenza vaccines do not need to use special precautions for any influenza vaccine, or use non-egg-based vaccines, for those who have a history of egg allergy. However, they should be prepared to respond to a severe allergic reaction just as they would for any other vaccine. Any vestigial practices pertaining to egg allergy and influenza vaccines—such as vaccine skin testing prior to vaccination (with dilution of vaccine if positive), vaccination deferral or administration via alternative dosing protocols, and split dosing of vaccine—are unnecessary and should be abandoned. 

When the Advisory Committee on Immunization Practices (ACIP) met in June and adopted recommendations for influenza vaccines for the 2023-2024 season, the major discussions focused on the timing of vaccine administration, the composition of the vaccine, and what (if any) special precautions are needed when administering an egg-based vaccine to a person with a history of egg allergy. Here are the takeaways.

When should flu vaccine be administered?

Influenza activity usually peaks between December and the end of March; only twice between 1982 and 2022 did it peak before December. Thus, most people should receive the vaccine in September or October, a recommendation that has not changed from last year. This is early enough to provide adequate protection in most influenza seasons, but late enough to allow protection to persist through the entire season. Vaccination should continue to be offered to those who are unvaccinated throughout the influenza season, as long as influenza viruses are circulating.

Earlier administration is not recommended for most people and is recommended against for those ages 65 years and older (because their immunity from the vaccine may wane faster) and for pregnant people in their first or second trimester (because the vaccine is more effective in preventing influenza in newborns if administered in the third trimester). Evidence regarding waning immunity is inconsistent; however, some studies have shown greater loss of immunity in the elderly compared to younger age groups, as time from vaccination increases.¹

What’s in this year’s vaccines?

The composition of the vaccines used in North America was determined by the World Health Organization in February, based on the most commonly circulating strains. All vaccines approved for use in the 2023-2024 season are quadrivalent and contain 1 influenza A (H1N1) strain, 1 influenza A (H3N2) strain, and 2 influenza B strains. The specifics of each strain are listed in TABLE 1.² The 2 influenza A strains are slightly different for the egg-based and non-egg-based vaccines.² There is no known effectiveness advantage of one antigen strain vs the other.

Should you take special precautions with egg allergy?

There is new wording to the recommendations on the use of egg-based influenza vaccines for those with a history of egg allergy (TABLE 2²). Previously, the ACIP had recommended that if an egg-based vaccine is given to a person with a history of egg allergy, it should be administered in an inpatient or outpatient medical setting (eg, hospital, clinic, health department, physician office) and should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. These added precautions were out of step with other organizations, including the American Academy of Pediatrics and allergy-related specialty societies, all of whom recommend no special procedures or precautions when administering any influenza vaccine to those with a history of egg allergy.³

Why the change? Several factors contributed to ACIP’s decision to reword its recommendation. One is that the ovalbumin content of all current influenza vaccines ­(TABLE 3³) is considered too low to trigger an allergic reaction.

Another is the paucity of evidence that egg-based vaccines convey increased risk beyond that for any other vaccine. Although 1% to 3% of children are reported to have an egg allergy, there is no evidence that they are at increased risk for a serious allergic reaction if administered an egg-based vaccine.³ A systematic review of 31 studies (mostly low-quality observational studies and case series) conducted by the ACIP Influenza Work Group found no risk for severe anaphylaxis, hospitalization, or death, even in those with a history of an anaphylactic reaction to eggs.² A review of Vaccine Adverse Events Reporting System (VAERS) data identified 18 cases of reported anaphylaxis after receipt of an inactivated influenza vaccine over a 5-year period, but clinical review confirmed only 7.²

Continue to: And finally, appropriate precautions already...

And finally, appropriate precautions already are recommended for administration of any vaccine. The CDC guidance for best practices for administering vaccines states: “Although allergic reactions are a common concern for vaccine providers, these reactions are uncommon and anaphylaxis following vaccines is rare, occurring at a rate of approximately one per million doses for many vaccines. Epinephrine and equipment for managing an airway should be available for immediate use.”⁴

What does this mean in practice? Family physicians who administer influenza vaccines do not need to use special precautions for any influenza vaccine, or use non-egg-based vaccines, for those who have a history of egg allergy. However, they should be prepared to respond to a severe allergic reaction just as they would for any other vaccine. Any vestigial practices pertaining to egg allergy and influenza vaccines—such as vaccine skin testing prior to vaccination (with dilution of vaccine if positive), vaccination deferral or administration via alternative dosing protocols, and split dosing of vaccine—are unnecessary and should be abandoned. 

The American Gastroenterological Association has published a Clinical Practice Update with new best practice advice for colorectal cancer screening (CRC) and postpolypectomy surveillance.

Led by Rachel B. Issaka, MD, of Fred Hutchinson Cancer Center, Seattle, the Clinical Practice Update focuses primarily on time frames for surveillance based on known risk factors, plus a caution against widespread use of emerging risk-stratification tools that need more real-world evidence among diverse populations.

“Based on current evidence, risk stratification for initiating CRC screening or surveillance should be based on age, family history, predisposing hereditary CRC syndromes, prior screening, or other CRC predisposing conditions,” the authors wrote in Gastroenterology.

With these parameters in mind, Dr. Issaka and colleagues issued nine best practice advice statements, noting that systematic reviews were not conducted, so statements are not rated based on quality of evidence or strength of presented considerations.

To begin, the investigators characterized two risk strata for CRC. Individuals with a first-degree relative who was diagnosed with CRC have an increased risk of CRC, particularly if that relative was diagnosed before age 50. In contrast, people with no such family history, or a personal history of CRC, hereditary CRC syndromes, inflammatory bowel disease, or other predisposing conditions, have average risk for CRC.

Those with average risk should start CRC screening at age 45, while those with high risk should start screening at age 40, or 10 years before the age of diagnosis of their youngest affected relative, whichever is sooner.

“The age to initiate screening according to family history of CRC could be optimized based on the number of affected family members, age at diagnosis of the affected relatives, as well as the 10-year cumulative incidence of CRC according to age within a specific source population (e.g., country),” the investigators wrote. “However, in the absence of widely available risk calculators developed for such risk-adapted screenings, a simplified approach to consider is initiating screening approximately 10 years before the age of diagnosis of the youngest affected relative or at age 40 years.”

The decision to screen and conduct postpolypectomy surveillance beyond age 75 should factor in risks, benefits, screening history, and comorbidities.

According to Dr. Issaka and colleagues, individuals with average risk can choose between several options for screening based on preference and availability, including fecal immunochemical test, colonoscopy, flexible sigmoidoscopy plus fecal immunochemical test, multitarget stool DNA fecal immunochemical test, and computed tomography colonography. Those with high risk, however, should undergo colonoscopy.

The final best practice advice statement offers a word of caution against widespread use of new risk-stratification tools for CRC and postpolypectomy surveillance that have yet to demonstrate real-world effectiveness and cost-effectiveness in diverse populations.

“Validation within diverse racial and ethnic populations is critical for models that include genetic factors, because genetic discovery studies have focused largely on individuals with European ancestry, and because risk-relevant genetic factors may vary according to individual’s origin of genetic ancestry,” the investigators wrote. “Although many studies differentiate individuals by race and ethnicity, which may capture some information about the likely presence of certain genetic variants, ancestry is a better predictor and should be captured in validation studies.”

The update was commissioned and approved by the AGA, and supported by the National Cancer Institute of the National Institutes of Health. The investigators disclosed relationships with Geneoscopy, CellMax Life, Universal Diagnostics, and others.

The American Gastroenterological Association has published a Clinical Practice Update with new best practice advice for colorectal cancer screening (CRC) and postpolypectomy surveillance.

Led by Rachel B. Issaka, MD, of Fred Hutchinson Cancer Center, Seattle, the Clinical Practice Update focuses primarily on time frames for surveillance based on known risk factors, plus a caution against widespread use of emerging risk-stratification tools that need more real-world evidence among diverse populations.

“Based on current evidence, risk stratification for initiating CRC screening or surveillance should be based on age, family history, predisposing hereditary CRC syndromes, prior screening, or other CRC predisposing conditions,” the authors wrote in Gastroenterology.

With these parameters in mind, Dr. Issaka and colleagues issued nine best practice advice statements, noting that systematic reviews were not conducted, so statements are not rated based on quality of evidence or strength of presented considerations.

To begin, the investigators characterized two risk strata for CRC. Individuals with a first-degree relative who was diagnosed with CRC have an increased risk of CRC, particularly if that relative was diagnosed before age 50. In contrast, people with no such family history, or a personal history of CRC, hereditary CRC syndromes, inflammatory bowel disease, or other predisposing conditions, have average risk for CRC.

Those with average risk should start CRC screening at age 45, while those with high risk should start screening at age 40, or 10 years before the age of diagnosis of their youngest affected relative, whichever is sooner.

“The age to initiate screening according to family history of CRC could be optimized based on the number of affected family members, age at diagnosis of the affected relatives, as well as the 10-year cumulative incidence of CRC according to age within a specific source population (e.g., country),” the investigators wrote. “However, in the absence of widely available risk calculators developed for such risk-adapted screenings, a simplified approach to consider is initiating screening approximately 10 years before the age of diagnosis of the youngest affected relative or at age 40 years.”

The decision to screen and conduct postpolypectomy surveillance beyond age 75 should factor in risks, benefits, screening history, and comorbidities.

According to Dr. Issaka and colleagues, individuals with average risk can choose between several options for screening based on preference and availability, including fecal immunochemical test, colonoscopy, flexible sigmoidoscopy plus fecal immunochemical test, multitarget stool DNA fecal immunochemical test, and computed tomography colonography. Those with high risk, however, should undergo colonoscopy.

The final best practice advice statement offers a word of caution against widespread use of new risk-stratification tools for CRC and postpolypectomy surveillance that have yet to demonstrate real-world effectiveness and cost-effectiveness in diverse populations.

“Validation within diverse racial and ethnic populations is critical for models that include genetic factors, because genetic discovery studies have focused largely on individuals with European ancestry, and because risk-relevant genetic factors may vary according to individual’s origin of genetic ancestry,” the investigators wrote. “Although many studies differentiate individuals by race and ethnicity, which may capture some information about the likely presence of certain genetic variants, ancestry is a better predictor and should be captured in validation studies.”

The update was commissioned and approved by the AGA, and supported by the National Cancer Institute of the National Institutes of Health. The investigators disclosed relationships with Geneoscopy, CellMax Life, Universal Diagnostics, and others.

The American Gastroenterological Association has published a Clinical Practice Update with new best practice advice for colorectal cancer screening (CRC) and postpolypectomy surveillance.

Led by Rachel B. Issaka, MD, of Fred Hutchinson Cancer Center, Seattle, the Clinical Practice Update focuses primarily on time frames for surveillance based on known risk factors, plus a caution against widespread use of emerging risk-stratification tools that need more real-world evidence among diverse populations.

“Based on current evidence, risk stratification for initiating CRC screening or surveillance should be based on age, family history, predisposing hereditary CRC syndromes, prior screening, or other CRC predisposing conditions,” the authors wrote in Gastroenterology.

With these parameters in mind, Dr. Issaka and colleagues issued nine best practice advice statements, noting that systematic reviews were not conducted, so statements are not rated based on quality of evidence or strength of presented considerations.

To begin, the investigators characterized two risk strata for CRC. Individuals with a first-degree relative who was diagnosed with CRC have an increased risk of CRC, particularly if that relative was diagnosed before age 50. In contrast, people with no such family history, or a personal history of CRC, hereditary CRC syndromes, inflammatory bowel disease, or other predisposing conditions, have average risk for CRC.

Those with average risk should start CRC screening at age 45, while those with high risk should start screening at age 40, or 10 years before the age of diagnosis of their youngest affected relative, whichever is sooner.

“The age to initiate screening according to family history of CRC could be optimized based on the number of affected family members, age at diagnosis of the affected relatives, as well as the 10-year cumulative incidence of CRC according to age within a specific source population (e.g., country),” the investigators wrote. “However, in the absence of widely available risk calculators developed for such risk-adapted screenings, a simplified approach to consider is initiating screening approximately 10 years before the age of diagnosis of the youngest affected relative or at age 40 years.”

The decision to screen and conduct postpolypectomy surveillance beyond age 75 should factor in risks, benefits, screening history, and comorbidities.

According to Dr. Issaka and colleagues, individuals with average risk can choose between several options for screening based on preference and availability, including fecal immunochemical test, colonoscopy, flexible sigmoidoscopy plus fecal immunochemical test, multitarget stool DNA fecal immunochemical test, and computed tomography colonography. Those with high risk, however, should undergo colonoscopy.

The final best practice advice statement offers a word of caution against widespread use of new risk-stratification tools for CRC and postpolypectomy surveillance that have yet to demonstrate real-world effectiveness and cost-effectiveness in diverse populations.

“Validation within diverse racial and ethnic populations is critical for models that include genetic factors, because genetic discovery studies have focused largely on individuals with European ancestry, and because risk-relevant genetic factors may vary according to individual’s origin of genetic ancestry,” the investigators wrote. “Although many studies differentiate individuals by race and ethnicity, which may capture some information about the likely presence of certain genetic variants, ancestry is a better predictor and should be captured in validation studies.”

The update was commissioned and approved by the AGA, and supported by the National Cancer Institute of the National Institutes of Health. The investigators disclosed relationships with Geneoscopy, CellMax Life, Universal Diagnostics, and others.