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Patch testing finds higher prevalence of ACD among children with AD
, 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. Yu and his colleagues utilized a database in which dermatologists and some allergists, all of whom had substantive experience in patch testing and in diagnosing and managing ACD in children, entered information about children who were referred to them for testing.
Of 912 children referred for patch testing between 2018 and 2022 from 14 geographically diverse centers in the United States (615 with AD and 297 without AD), those with AD were more likely to have more than one positive reaction (odds radio, 1.57; 95% confidence interval, 1.14-2.14; P = .005) and had a greater number of positive results overall (2.3 vs. 1.9; P = .012).
AD and ACD both present with red, itchy, eczema-like patches and plaques and can be “really hard to differentiate,” Dr. Yu said in an interview.
“Not everybody with AD needs patch testing,” he said, “but I do think some [patients] who have rashes in unusual locations or rashes that don’t seem to improve within an appropriate amount of time to topical medications ... are the children who probably should have patch testing.”
Candidates for patch testing include children with AD who present with isolated head or neck, hand or foot, or anal or genital dermatitis, Dr. Yu and his colleagues write in the study. In addition, Dr. Yu said in the interview, “if you have a child who has AD that involves the elbow and back of the knees but then they get new-onset facial dermatitis, say, or new-onset eyelid dermatitis ... there’s [significant] value in patch testing.”
Children with AD in the study had a more generalized distribution of dermatitis and were significantly less likely to have dermatitis affecting the anal or genital region, the authors note in the study.
Asked to comment on the results, Jennifer Perryman, MD, a dermatologist at UCHealth, Greeley, Colo., who performs patch testing in children and adults, said that ACD is indeed “often underdiagnosed” in children with AD, and the study “solidifies” the importance of considering ACD in this population.
“Clinicians should think about testing children when AD is [not well controlled or] is getting worse, is in an atypical distribution, or if they are considering systemic treatment,” she said in an e-mail.
“I tell my patients, ‘I know you have AD, but you could also have comorbid ACD, and if we can find and control that, we can make you better without adding more to your routine, medications, etc.’ ” said Dr. Perryman, who was not involved in the research.
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.
, 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. Yu and his colleagues utilized a database in which dermatologists and some allergists, all of whom had substantive experience in patch testing and in diagnosing and managing ACD in children, entered information about children who were referred to them for testing.
Of 912 children referred for patch testing between 2018 and 2022 from 14 geographically diverse centers in the United States (615 with AD and 297 without AD), those with AD were more likely to have more than one positive reaction (odds radio, 1.57; 95% confidence interval, 1.14-2.14; P = .005) and had a greater number of positive results overall (2.3 vs. 1.9; P = .012).
AD and ACD both present with red, itchy, eczema-like patches and plaques and can be “really hard to differentiate,” Dr. Yu said in an interview.
“Not everybody with AD needs patch testing,” he said, “but I do think some [patients] who have rashes in unusual locations or rashes that don’t seem to improve within an appropriate amount of time to topical medications ... are the children who probably should have patch testing.”
Candidates for patch testing include children with AD who present with isolated head or neck, hand or foot, or anal or genital dermatitis, Dr. Yu and his colleagues write in the study. In addition, Dr. Yu said in the interview, “if you have a child who has AD that involves the elbow and back of the knees but then they get new-onset facial dermatitis, say, or new-onset eyelid dermatitis ... there’s [significant] value in patch testing.”
Children with AD in the study had a more generalized distribution of dermatitis and were significantly less likely to have dermatitis affecting the anal or genital region, the authors note in the study.
Asked to comment on the results, Jennifer Perryman, MD, a dermatologist at UCHealth, Greeley, Colo., who performs patch testing in children and adults, said that ACD is indeed “often underdiagnosed” in children with AD, and the study “solidifies” the importance of considering ACD in this population.
“Clinicians should think about testing children when AD is [not well controlled or] is getting worse, is in an atypical distribution, or if they are considering systemic treatment,” she said in an e-mail.
“I tell my patients, ‘I know you have AD, but you could also have comorbid ACD, and if we can find and control that, we can make you better without adding more to your routine, medications, etc.’ ” said Dr. Perryman, who was not involved in the research.
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.
, 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. Yu and his colleagues utilized a database in which dermatologists and some allergists, all of whom had substantive experience in patch testing and in diagnosing and managing ACD in children, entered information about children who were referred to them for testing.
Of 912 children referred for patch testing between 2018 and 2022 from 14 geographically diverse centers in the United States (615 with AD and 297 without AD), those with AD were more likely to have more than one positive reaction (odds radio, 1.57; 95% confidence interval, 1.14-2.14; P = .005) and had a greater number of positive results overall (2.3 vs. 1.9; P = .012).
AD and ACD both present with red, itchy, eczema-like patches and plaques and can be “really hard to differentiate,” Dr. Yu said in an interview.
“Not everybody with AD needs patch testing,” he said, “but I do think some [patients] who have rashes in unusual locations or rashes that don’t seem to improve within an appropriate amount of time to topical medications ... are the children who probably should have patch testing.”
Candidates for patch testing include children with AD who present with isolated head or neck, hand or foot, or anal or genital dermatitis, Dr. Yu and his colleagues write in the study. In addition, Dr. Yu said in the interview, “if you have a child who has AD that involves the elbow and back of the knees but then they get new-onset facial dermatitis, say, or new-onset eyelid dermatitis ... there’s [significant] value in patch testing.”
Children with AD in the study had a more generalized distribution of dermatitis and were significantly less likely to have dermatitis affecting the anal or genital region, the authors note in the study.
Asked to comment on the results, Jennifer Perryman, MD, a dermatologist at UCHealth, Greeley, Colo., who performs patch testing in children and adults, said that ACD is indeed “often underdiagnosed” in children with AD, and the study “solidifies” the importance of considering ACD in this population.
“Clinicians should think about testing children when AD is [not well controlled or] is getting worse, is in an atypical distribution, or if they are considering systemic treatment,” she said in an e-mail.
“I tell my patients, ‘I know you have AD, but you could also have comorbid ACD, and if we can find and control that, we can make you better without adding more to your routine, medications, etc.’ ” said Dr. Perryman, who was not involved in the research.
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.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Zuranolone: FAQs for clinicians and patients
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.
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 GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA 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?
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?
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?
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?
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.
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 GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA 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?
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?
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?
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?
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.
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 GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA 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?
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?
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?
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?
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
Low-certainty evidence supports probiotics for IBS
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.
IBS patients frequently inquire about probiotics. As a clinician, this can be difficult to address. A search of the literature yields numerous small trials. Turning to the guidelines does not help, as the AGA Clinical Practice Guidelines on Probiotics offer no recommendations for IBS because of the low quality of evidence. Nevertheless, we have patients who want to try probiotics. Some of these patients have had inadequate responses to first-line therapies and/or prefer a nonpharmacologic approach.
For example, the strain with the most trials was Lactobacillus plantarum 299V. The dose used (10 billion CFU once daily) is commercially available (Jarrow Formulas Ideal Bowel Support® LP299V®). Bacillus strains were also promising for global symptoms, abdominal pain and bloating. Two trials used the same strain and dose, Bacillus coagulans MTCC 5856, 2 billion CFU once daily, also commercially available (LactoSpore). Both can be purchased via major online retailers for $10-$13 for a 30-day supply. I am glad to have something to recommend however conditionally.
Elizabeth (Beth) Videlock, MD, PhD is assistant professor of medicine in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles, and a staff physician in gastroenterology in the Greater Los Angeles Veterans Affairs Healthcare System. She is co-lead of the neurodevelopmental and neurodegenerative diseases research program of the Goodman-Luskin Microbiome Center at UCLA. She has no relevant disclosures.
IBS patients frequently inquire about probiotics. As a clinician, this can be difficult to address. A search of the literature yields numerous small trials. Turning to the guidelines does not help, as the AGA Clinical Practice Guidelines on Probiotics offer no recommendations for IBS because of the low quality of evidence. Nevertheless, we have patients who want to try probiotics. Some of these patients have had inadequate responses to first-line therapies and/or prefer a nonpharmacologic approach.
For example, the strain with the most trials was Lactobacillus plantarum 299V. The dose used (10 billion CFU once daily) is commercially available (Jarrow Formulas Ideal Bowel Support® LP299V®). Bacillus strains were also promising for global symptoms, abdominal pain and bloating. Two trials used the same strain and dose, Bacillus coagulans MTCC 5856, 2 billion CFU once daily, also commercially available (LactoSpore). Both can be purchased via major online retailers for $10-$13 for a 30-day supply. I am glad to have something to recommend however conditionally.
Elizabeth (Beth) Videlock, MD, PhD is assistant professor of medicine in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles, and a staff physician in gastroenterology in the Greater Los Angeles Veterans Affairs Healthcare System. She is co-lead of the neurodevelopmental and neurodegenerative diseases research program of the Goodman-Luskin Microbiome Center at UCLA. She has no relevant disclosures.
IBS patients frequently inquire about probiotics. As a clinician, this can be difficult to address. A search of the literature yields numerous small trials. Turning to the guidelines does not help, as the AGA Clinical Practice Guidelines on Probiotics offer no recommendations for IBS because of the low quality of evidence. Nevertheless, we have patients who want to try probiotics. Some of these patients have had inadequate responses to first-line therapies and/or prefer a nonpharmacologic approach.
For example, the strain with the most trials was Lactobacillus plantarum 299V. The dose used (10 billion CFU once daily) is commercially available (Jarrow Formulas Ideal Bowel Support® LP299V®). Bacillus strains were also promising for global symptoms, abdominal pain and bloating. Two trials used the same strain and dose, Bacillus coagulans MTCC 5856, 2 billion CFU once daily, also commercially available (LactoSpore). Both can be purchased via major online retailers for $10-$13 for a 30-day supply. I am glad to have something to recommend however conditionally.
Elizabeth (Beth) Videlock, MD, PhD is assistant professor of medicine in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles, and a staff physician in gastroenterology in the Greater Los Angeles Veterans Affairs Healthcare System. She is co-lead of the neurodevelopmental and neurodegenerative diseases research program of the Goodman-Luskin Microbiome Center at UCLA. She has no relevant disclosures.
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.
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.
FROM GASTROENTEROLOGY
Can these salt substitutes prevent complications of hypertension?
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.2 The 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
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.
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.
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.
1. Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart. 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
2. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. 2021;398:957-980. doi: 10.1016/S0140-6736(21)01330-1
3. USPSTF. Hypertension in adults: screening. Final recommendation statement. Published April 27, 2021. Accessed September 18, 2023. www.uspreventiveservicestaskforce.org/uspstf/recommendation/hypertension-in-adults-screening
4. Coles S, Fisher L, Lin KW, et al. Blood pressure targets in adults with hypertension: a clinical practice guideline from the AAFP. Published November 4, 2022. Accessed September 18, 2023. www.aafp.org/dam/AAFP/documents/journals/afp/AAFPHypertensionGuideline.pdf
5. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. doi: 10.1001/jama. 2013.284427
6. Unger T, Borgi C, Charchar F, et al. 2020 International Society of Hypertension global hypertension practice guidelines. Hypertension. 2020;75:1334-1357. doi: 10.1161/HYPERTENSIONAHA.120.15026
7. Mancia G, Kreutz R, Brunstrom M, et al; the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension. 2023 ESH Guidelines for the management of arterial hypertension. Endorsed by the European Renal Association (ERA) and the International Society of Hypertension (ISH). J Hypertens. 2023; Jun 21. doi: 10.1097/HJH.0000000000003480
8. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-e115. 10.1161/HYP.0000000000000065
9. National Center for Health Statistics. National Ambulatory Medical Care Survey: 2014 state and national summary tables. Accessed June 27, 2023. www.cdc.gov/nchs/data/ahcd/namcs_summary/2014_namcs_web_tables.pdf
10. Huang L, Trieu K, Yoshimura S, et al. Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials. BMJ. 2020;368:m315. doi: 10.1136/bmj.m315
11. Filippini T, Violi F, D’Amico R, et al. The effect of potassium supplementation on blood pressure in hypertensive subjects: a systematic review and meta-analysis. Int J Cardiol. 2017;230:127-135. doi: 10.1016/j.ijcard.2016.12.048
12. Brand A, Visser ME, Schoonees A, et al. Replacing salt with low-sodium salt substitutes (LSSS) for cardiovascular health in adults, children and pregnant women. Cochrane Database Syst Rev. 2022;8:CD015207. doi: 10.1002/14651858.CD015207
13. He FJ, Tan M, Ma Y, et al. Salt reduction to prevent hypertension and cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:632-647. doi: 10.1016/j.jacc.2019.11.055
14. Neal B, Wu Y, Feng X, et al. Effect of salt substitution on cardiovascular events and death. N Engl J Med. 2021;385:1067-1077. doi: 10.1056/NEJMoa2105675
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.2 The 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
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.
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.
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.2 The 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
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.
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.
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.
1. Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart. 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
2. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. 2021;398:957-980. doi: 10.1016/S0140-6736(21)01330-1
3. USPSTF. Hypertension in adults: screening. Final recommendation statement. Published April 27, 2021. Accessed September 18, 2023. www.uspreventiveservicestaskforce.org/uspstf/recommendation/hypertension-in-adults-screening
4. Coles S, Fisher L, Lin KW, et al. Blood pressure targets in adults with hypertension: a clinical practice guideline from the AAFP. Published November 4, 2022. Accessed September 18, 2023. www.aafp.org/dam/AAFP/documents/journals/afp/AAFPHypertensionGuideline.pdf
5. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. doi: 10.1001/jama. 2013.284427
6. Unger T, Borgi C, Charchar F, et al. 2020 International Society of Hypertension global hypertension practice guidelines. Hypertension. 2020;75:1334-1357. doi: 10.1161/HYPERTENSIONAHA.120.15026
7. Mancia G, Kreutz R, Brunstrom M, et al; the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension. 2023 ESH Guidelines for the management of arterial hypertension. Endorsed by the European Renal Association (ERA) and the International Society of Hypertension (ISH). J Hypertens. 2023; Jun 21. doi: 10.1097/HJH.0000000000003480
8. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-e115. 10.1161/HYP.0000000000000065
9. National Center for Health Statistics. National Ambulatory Medical Care Survey: 2014 state and national summary tables. Accessed June 27, 2023. www.cdc.gov/nchs/data/ahcd/namcs_summary/2014_namcs_web_tables.pdf
10. Huang L, Trieu K, Yoshimura S, et al. Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials. BMJ. 2020;368:m315. doi: 10.1136/bmj.m315
11. Filippini T, Violi F, D’Amico R, et al. The effect of potassium supplementation on blood pressure in hypertensive subjects: a systematic review and meta-analysis. Int J Cardiol. 2017;230:127-135. doi: 10.1016/j.ijcard.2016.12.048
12. Brand A, Visser ME, Schoonees A, et al. Replacing salt with low-sodium salt substitutes (LSSS) for cardiovascular health in adults, children and pregnant women. Cochrane Database Syst Rev. 2022;8:CD015207. doi: 10.1002/14651858.CD015207
13. He FJ, Tan M, Ma Y, et al. Salt reduction to prevent hypertension and cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:632-647. doi: 10.1016/j.jacc.2019.11.055
14. Neal B, Wu Y, Feng X, et al. Effect of salt substitution on cardiovascular events and death. N Engl J Med. 2021;385:1067-1077. doi: 10.1056/NEJMoa2105675
1. Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart. 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
2. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. 2021;398:957-980. doi: 10.1016/S0140-6736(21)01330-1
3. USPSTF. Hypertension in adults: screening. Final recommendation statement. Published April 27, 2021. Accessed September 18, 2023. www.uspreventiveservicestaskforce.org/uspstf/recommendation/hypertension-in-adults-screening
4. Coles S, Fisher L, Lin KW, et al. Blood pressure targets in adults with hypertension: a clinical practice guideline from the AAFP. Published November 4, 2022. Accessed September 18, 2023. www.aafp.org/dam/AAFP/documents/journals/afp/AAFPHypertensionGuideline.pdf
5. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. doi: 10.1001/jama. 2013.284427
6. Unger T, Borgi C, Charchar F, et al. 2020 International Society of Hypertension global hypertension practice guidelines. Hypertension. 2020;75:1334-1357. doi: 10.1161/HYPERTENSIONAHA.120.15026
7. Mancia G, Kreutz R, Brunstrom M, et al; the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension. 2023 ESH Guidelines for the management of arterial hypertension. Endorsed by the European Renal Association (ERA) and the International Society of Hypertension (ISH). J Hypertens. 2023; Jun 21. doi: 10.1097/HJH.0000000000003480
8. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-e115. 10.1161/HYP.0000000000000065
9. National Center for Health Statistics. National Ambulatory Medical Care Survey: 2014 state and national summary tables. Accessed June 27, 2023. www.cdc.gov/nchs/data/ahcd/namcs_summary/2014_namcs_web_tables.pdf
10. Huang L, Trieu K, Yoshimura S, et al. Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials. BMJ. 2020;368:m315. doi: 10.1136/bmj.m315
11. Filippini T, Violi F, D’Amico R, et al. The effect of potassium supplementation on blood pressure in hypertensive subjects: a systematic review and meta-analysis. Int J Cardiol. 2017;230:127-135. doi: 10.1016/j.ijcard.2016.12.048
12. Brand A, Visser ME, Schoonees A, et al. Replacing salt with low-sodium salt substitutes (LSSS) for cardiovascular health in adults, children and pregnant women. Cochrane Database Syst Rev. 2022;8:CD015207. doi: 10.1002/14651858.CD015207
13. He FJ, Tan M, Ma Y, et al. Salt reduction to prevent hypertension and cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:632-647. doi: 10.1016/j.jacc.2019.11.055
14. Neal B, Wu Y, Feng X, et al. Effect of salt substitution on cardiovascular events and death. N Engl J Med. 2021;385:1067-1077. doi: 10.1056/NEJMoa2105675
PRACTICE CHANGER
Consider recommending potassium-enriched salt substitutes for appropriate patients with hypertension to reduce blood pressure (BP) and risk for related cardiovascular (CV) events or mortality.
STRENGTH OF RECOMMENDATION
A: Based on a systematic review and meta-analysis of controlled trials. 1
Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart . 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
Feeling salty about our sodium intake
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
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.
1. World Health Organization. Global report on hypertension: the race against a silent killer. Published September 19, 2023. Accessed September 29, 2023. www.who.int/publications/i/item/9789240081062
2. Rose G. Sick individuals and sick populations. Int J Epidemiol. 2001;30:427-432. doi: 10.1093/ije/30.3.427
3. Chiavaroli L, Viguiliouk E, Nishi SK, et al. DASH dietary pattern and cardiometabolic outcomes: an umbrella review of systematic reviews and meta-analyses. Nutrients. 2019;11:338. doi: 10.3390/nu11020338
4. Saneei P, Salehi-Abargouei A, Esmaillzadeh A, et al. Influence of Dietary Approaches to Stop Hypertension (DASH) diet on blood pressure: a systematic review and meta-analysis on randomized controlled trials. Nutr Metab Cardiovasc Dis. 2014;24:1253-1261. doi: 10.1016/j.numecd.2014.06.008
5. Harnack LJ, Cogswell ME, Shikany JM, et al. Sources of sodium in US adults from 3 geographic regions. Circulation. 2017;135:1775-1783. doi: 10.1161/CIRCULATIONAHA.116.024446
6. Mellen PB, Gao SK, Vitolins MZ, et al. Deteriorating dietary habits among adults with hypertension: DASH dietary accordance, NHANES 1988-1994 and 1999-2004. Arch Intern Med. 2008;168:308-314. doi: 10.1001/archinternmed.2007.119
7. Chang ET, Powell R, Reese T. Can potassium-enriched salt substitutes prevent complications of hypertension? J Fam Pract. 2023;72:342-344. doi: 10.12788/jfp.0667
8. Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart. 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
9. Whelton PK, He J, Appel LJ, et al; National High Blood Pressure Education Program Coordinating Committee. Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program. JAMA. 2002;288:1882-1888. doi: 10.1001/jama.288.15.1882
10. Cogswell ME, Loria CM, Terry AL, et al. Estimated 24-Hour urinary sodium and potassium excretion in US adults. JAMA. 2018;319:1209-1220. doi: 1001/jama.2018.1156
11. FDA. Guidance for industry: voluntary sodium reduction goals. Published October 2021. Accessed September 28, 2023. www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-voluntary-sodium-reduction-goals
12. Nissaisorakarn V, Ormseth G, Earle W, et al. Less sodium, more potassium, or both: population-wide strategies to prevent hypertension. Am J Physiol Renal Physiol. 2023;325:F99-F104. doi: 10.1152/ajprenal.00007.202
13. Bernabe-Ortiz A, Sal Y Rosas VG, Ponce-Lucero V, et al. Effect of salt substitution on community-wide blood pressure and hypertension incidence. Nat Med. 2020;26:374-378. doi: 10.1038/s41591-020-0754-2
Editor-in-Chief
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Editor-in-Chief
[email protected]
Editor-in-Chief
[email protected]
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
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
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.
1. World Health Organization. Global report on hypertension: the race against a silent killer. Published September 19, 2023. Accessed September 29, 2023. www.who.int/publications/i/item/9789240081062
2. Rose G. Sick individuals and sick populations. Int J Epidemiol. 2001;30:427-432. doi: 10.1093/ije/30.3.427
3. Chiavaroli L, Viguiliouk E, Nishi SK, et al. DASH dietary pattern and cardiometabolic outcomes: an umbrella review of systematic reviews and meta-analyses. Nutrients. 2019;11:338. doi: 10.3390/nu11020338
4. Saneei P, Salehi-Abargouei A, Esmaillzadeh A, et al. Influence of Dietary Approaches to Stop Hypertension (DASH) diet on blood pressure: a systematic review and meta-analysis on randomized controlled trials. Nutr Metab Cardiovasc Dis. 2014;24:1253-1261. doi: 10.1016/j.numecd.2014.06.008
5. Harnack LJ, Cogswell ME, Shikany JM, et al. Sources of sodium in US adults from 3 geographic regions. Circulation. 2017;135:1775-1783. doi: 10.1161/CIRCULATIONAHA.116.024446
6. Mellen PB, Gao SK, Vitolins MZ, et al. Deteriorating dietary habits among adults with hypertension: DASH dietary accordance, NHANES 1988-1994 and 1999-2004. Arch Intern Med. 2008;168:308-314. doi: 10.1001/archinternmed.2007.119
7. Chang ET, Powell R, Reese T. Can potassium-enriched salt substitutes prevent complications of hypertension? J Fam Pract. 2023;72:342-344. doi: 10.12788/jfp.0667
8. Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart. 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
9. Whelton PK, He J, Appel LJ, et al; National High Blood Pressure Education Program Coordinating Committee. Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program. JAMA. 2002;288:1882-1888. doi: 10.1001/jama.288.15.1882
10. Cogswell ME, Loria CM, Terry AL, et al. Estimated 24-Hour urinary sodium and potassium excretion in US adults. JAMA. 2018;319:1209-1220. doi: 1001/jama.2018.1156
11. FDA. Guidance for industry: voluntary sodium reduction goals. Published October 2021. Accessed September 28, 2023. www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-voluntary-sodium-reduction-goals
12. Nissaisorakarn V, Ormseth G, Earle W, et al. Less sodium, more potassium, or both: population-wide strategies to prevent hypertension. Am J Physiol Renal Physiol. 2023;325:F99-F104. doi: 10.1152/ajprenal.00007.202
13. Bernabe-Ortiz A, Sal Y Rosas VG, Ponce-Lucero V, et al. Effect of salt substitution on community-wide blood pressure and hypertension incidence. Nat Med. 2020;26:374-378. doi: 10.1038/s41591-020-0754-2
1. World Health Organization. Global report on hypertension: the race against a silent killer. Published September 19, 2023. Accessed September 29, 2023. www.who.int/publications/i/item/9789240081062
2. Rose G. Sick individuals and sick populations. Int J Epidemiol. 2001;30:427-432. doi: 10.1093/ije/30.3.427
3. Chiavaroli L, Viguiliouk E, Nishi SK, et al. DASH dietary pattern and cardiometabolic outcomes: an umbrella review of systematic reviews and meta-analyses. Nutrients. 2019;11:338. doi: 10.3390/nu11020338
4. Saneei P, Salehi-Abargouei A, Esmaillzadeh A, et al. Influence of Dietary Approaches to Stop Hypertension (DASH) diet on blood pressure: a systematic review and meta-analysis on randomized controlled trials. Nutr Metab Cardiovasc Dis. 2014;24:1253-1261. doi: 10.1016/j.numecd.2014.06.008
5. Harnack LJ, Cogswell ME, Shikany JM, et al. Sources of sodium in US adults from 3 geographic regions. Circulation. 2017;135:1775-1783. doi: 10.1161/CIRCULATIONAHA.116.024446
6. Mellen PB, Gao SK, Vitolins MZ, et al. Deteriorating dietary habits among adults with hypertension: DASH dietary accordance, NHANES 1988-1994 and 1999-2004. Arch Intern Med. 2008;168:308-314. doi: 10.1001/archinternmed.2007.119
7. Chang ET, Powell R, Reese T. Can potassium-enriched salt substitutes prevent complications of hypertension? J Fam Pract. 2023;72:342-344. doi: 10.12788/jfp.0667
8. Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart. 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
9. Whelton PK, He J, Appel LJ, et al; National High Blood Pressure Education Program Coordinating Committee. Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program. JAMA. 2002;288:1882-1888. doi: 10.1001/jama.288.15.1882
10. Cogswell ME, Loria CM, Terry AL, et al. Estimated 24-Hour urinary sodium and potassium excretion in US adults. JAMA. 2018;319:1209-1220. doi: 1001/jama.2018.1156
11. FDA. Guidance for industry: voluntary sodium reduction goals. Published October 2021. Accessed September 28, 2023. www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-voluntary-sodium-reduction-goals
12. Nissaisorakarn V, Ormseth G, Earle W, et al. Less sodium, more potassium, or both: population-wide strategies to prevent hypertension. Am J Physiol Renal Physiol. 2023;325:F99-F104. doi: 10.1152/ajprenal.00007.202
13. Bernabe-Ortiz A, Sal Y Rosas VG, Ponce-Lucero V, et al. Effect of salt substitution on community-wide blood pressure and hypertension incidence. Nat Med. 2020;26:374-378. doi: 10.1038/s41591-020-0754-2
52-year-old man • intermittent fevers • recently received second dose of COVID-19 vaccine • tremors in all 4 extremities • Dx?
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
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
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]
1. Martino D, Chew N-K, Mir P, et al. Atypical movement disorders in antiphospholipid syndrome. 2006;21:944-949. doi: 10.1002/mds.20842
2. Vaccine Adverse Event Reporting System. Accessed February 9, 2022. vaers.hhs.gov
3. Duarte-García A, Pham MM, Crowson CS, et al. The epidemiology of antiphospholipid syndrome: a population-based Study. Arthritis Rheumatol. 2019;71:1545-1552. doi: 10.1002/art.40901
4. Baizabal-Carvallo JF, Jankovic J. Autoimmune and paraneoplastic movement disorders: an update. J Neurol Sci. 2018;385:175-184. doi: 10.1016/j.jns.2017.12.035
5. O’Leary RE, Hsiao JL, Worswick SD. Antiphospholipid syndrome in a patient with rheumatoid arthritis. Cutis. 2017;99:E21-E24.
6. Taha M, Samavati L. Antiphospholipid antibodies in COVID-19: a meta-analysis and systematic review. RMD Open. 2021;7:e001580. doi: 10.1136/rmdopen-2021-001580
7. Nakayama T, Akahoshi M, Irino K, et al. Transient antiphospholipid syndrome associated with primary cytomegalovirus infection: a case report and literature review. Case Rep Rheumatol. 2014;2014:27154. doi: 10.1155/2014/271548
8. Cruz-Tapias P, Blank M, Anaya J-M, et al. Infections and vaccines in the etiology of antiphospholipid syndrome. Curr Opin Rheumatol. 2012;24:389-393. doi: 10.1097/BOR.0b013e32835448b8
9. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384:2124-2130. doi: 10.1056/nejmoa2104882
10. Cimolai N. Untangling the intricacies of infection, thrombosis, vaccination, and antiphospholipid antibodies for COVID-19. SN Compr Clin Med. 2021;3:2093-2108. doi: 10.1007/s42399-021-00992-3
11. Jinno S, Naka I, Nakazawa T. Catastrophic antiphospholipid syndrome complicated with essential thrombocythaemia after COVID-19 vaccination: in search of the underlying mechanism. Rheumatol Adv Pract. 2021;5:rkab096. doi: 10.1093/rap/rkab096
12. Ricarte IF, Dutra LA, Abrantes FF, et al. Neurologic manifestations of antiphospholipid syndrome. Lupus. 2018;27:1404-1414. doi: 10.1177/0961203318776110
13. Gringeri M, Battini V, Cammarata G, et al. Herpes zoster and simplex reactivation following COVID-19 vaccination: new insights from a vaccine adverse event reporting system (VAERS) database analysis. Expert Rev Vaccines. 2022;21:675-684. doi: 10.1080/14760584.2022.2044799
14. Cirillo N, Doan R. The association between COVID-19 vaccination and Bell’s palsy. Lancet Infect Dis. 2022;22:5-6. doi: 10.1016/s1473-3099(21)00467-9
15. Poudel S, Nepali P, Baniya S, et al. Bell’s palsy as a possible complication of mRNA-1273 (Moderna) vaccine against COVID-19. Ann Med Surg (Lond). 2022;78:103897. doi: 10.1016/j.amsu.2022.103897
16. Furer V, Zisman D, Kibari A, et al. Herpes zoster following BNT162b2 mRNA COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series. Rheumatology (Oxford). 2021;60:SI90-SI95. doi: 10.1093/rheumatology/keab345
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
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
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
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
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]
1. Martino D, Chew N-K, Mir P, et al. Atypical movement disorders in antiphospholipid syndrome. 2006;21:944-949. doi: 10.1002/mds.20842
2. Vaccine Adverse Event Reporting System. Accessed February 9, 2022. vaers.hhs.gov
3. Duarte-García A, Pham MM, Crowson CS, et al. The epidemiology of antiphospholipid syndrome: a population-based Study. Arthritis Rheumatol. 2019;71:1545-1552. doi: 10.1002/art.40901
4. Baizabal-Carvallo JF, Jankovic J. Autoimmune and paraneoplastic movement disorders: an update. J Neurol Sci. 2018;385:175-184. doi: 10.1016/j.jns.2017.12.035
5. O’Leary RE, Hsiao JL, Worswick SD. Antiphospholipid syndrome in a patient with rheumatoid arthritis. Cutis. 2017;99:E21-E24.
6. Taha M, Samavati L. Antiphospholipid antibodies in COVID-19: a meta-analysis and systematic review. RMD Open. 2021;7:e001580. doi: 10.1136/rmdopen-2021-001580
7. Nakayama T, Akahoshi M, Irino K, et al. Transient antiphospholipid syndrome associated with primary cytomegalovirus infection: a case report and literature review. Case Rep Rheumatol. 2014;2014:27154. doi: 10.1155/2014/271548
8. Cruz-Tapias P, Blank M, Anaya J-M, et al. Infections and vaccines in the etiology of antiphospholipid syndrome. Curr Opin Rheumatol. 2012;24:389-393. doi: 10.1097/BOR.0b013e32835448b8
9. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384:2124-2130. doi: 10.1056/nejmoa2104882
10. Cimolai N. Untangling the intricacies of infection, thrombosis, vaccination, and antiphospholipid antibodies for COVID-19. SN Compr Clin Med. 2021;3:2093-2108. doi: 10.1007/s42399-021-00992-3
11. Jinno S, Naka I, Nakazawa T. Catastrophic antiphospholipid syndrome complicated with essential thrombocythaemia after COVID-19 vaccination: in search of the underlying mechanism. Rheumatol Adv Pract. 2021;5:rkab096. doi: 10.1093/rap/rkab096
12. Ricarte IF, Dutra LA, Abrantes FF, et al. Neurologic manifestations of antiphospholipid syndrome. Lupus. 2018;27:1404-1414. doi: 10.1177/0961203318776110
13. Gringeri M, Battini V, Cammarata G, et al. Herpes zoster and simplex reactivation following COVID-19 vaccination: new insights from a vaccine adverse event reporting system (VAERS) database analysis. Expert Rev Vaccines. 2022;21:675-684. doi: 10.1080/14760584.2022.2044799
14. Cirillo N, Doan R. The association between COVID-19 vaccination and Bell’s palsy. Lancet Infect Dis. 2022;22:5-6. doi: 10.1016/s1473-3099(21)00467-9
15. Poudel S, Nepali P, Baniya S, et al. Bell’s palsy as a possible complication of mRNA-1273 (Moderna) vaccine against COVID-19. Ann Med Surg (Lond). 2022;78:103897. doi: 10.1016/j.amsu.2022.103897
16. Furer V, Zisman D, Kibari A, et al. Herpes zoster following BNT162b2 mRNA COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series. Rheumatology (Oxford). 2021;60:SI90-SI95. doi: 10.1093/rheumatology/keab345
1. Martino D, Chew N-K, Mir P, et al. Atypical movement disorders in antiphospholipid syndrome. 2006;21:944-949. doi: 10.1002/mds.20842
2. Vaccine Adverse Event Reporting System. Accessed February 9, 2022. vaers.hhs.gov
3. Duarte-García A, Pham MM, Crowson CS, et al. The epidemiology of antiphospholipid syndrome: a population-based Study. Arthritis Rheumatol. 2019;71:1545-1552. doi: 10.1002/art.40901
4. Baizabal-Carvallo JF, Jankovic J. Autoimmune and paraneoplastic movement disorders: an update. J Neurol Sci. 2018;385:175-184. doi: 10.1016/j.jns.2017.12.035
5. O’Leary RE, Hsiao JL, Worswick SD. Antiphospholipid syndrome in a patient with rheumatoid arthritis. Cutis. 2017;99:E21-E24.
6. Taha M, Samavati L. Antiphospholipid antibodies in COVID-19: a meta-analysis and systematic review. RMD Open. 2021;7:e001580. doi: 10.1136/rmdopen-2021-001580
7. Nakayama T, Akahoshi M, Irino K, et al. Transient antiphospholipid syndrome associated with primary cytomegalovirus infection: a case report and literature review. Case Rep Rheumatol. 2014;2014:27154. doi: 10.1155/2014/271548
8. Cruz-Tapias P, Blank M, Anaya J-M, et al. Infections and vaccines in the etiology of antiphospholipid syndrome. Curr Opin Rheumatol. 2012;24:389-393. doi: 10.1097/BOR.0b013e32835448b8
9. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384:2124-2130. doi: 10.1056/nejmoa2104882
10. Cimolai N. Untangling the intricacies of infection, thrombosis, vaccination, and antiphospholipid antibodies for COVID-19. SN Compr Clin Med. 2021;3:2093-2108. doi: 10.1007/s42399-021-00992-3
11. Jinno S, Naka I, Nakazawa T. Catastrophic antiphospholipid syndrome complicated with essential thrombocythaemia after COVID-19 vaccination: in search of the underlying mechanism. Rheumatol Adv Pract. 2021;5:rkab096. doi: 10.1093/rap/rkab096
12. Ricarte IF, Dutra LA, Abrantes FF, et al. Neurologic manifestations of antiphospholipid syndrome. Lupus. 2018;27:1404-1414. doi: 10.1177/0961203318776110
13. Gringeri M, Battini V, Cammarata G, et al. Herpes zoster and simplex reactivation following COVID-19 vaccination: new insights from a vaccine adverse event reporting system (VAERS) database analysis. Expert Rev Vaccines. 2022;21:675-684. doi: 10.1080/14760584.2022.2044799
14. Cirillo N, Doan R. The association between COVID-19 vaccination and Bell’s palsy. Lancet Infect Dis. 2022;22:5-6. doi: 10.1016/s1473-3099(21)00467-9
15. Poudel S, Nepali P, Baniya S, et al. Bell’s palsy as a possible complication of mRNA-1273 (Moderna) vaccine against COVID-19. Ann Med Surg (Lond). 2022;78:103897. doi: 10.1016/j.amsu.2022.103897
16. Furer V, Zisman D, Kibari A, et al. Herpes zoster following BNT162b2 mRNA COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series. Rheumatology (Oxford). 2021;60:SI90-SI95. doi: 10.1093/rheumatology/keab345
► Intermittent fevers
► Recently received second dose of COVID-19 vaccine
► Tremors in all 4 extremities
AGA aims to increase awareness of exocrine pancreatic insufficiency
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 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 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.
FROM GASTROENTEROLOGY
ACIP updates recommendations for influenza vaccination
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.
1. Grohskopf LA, Blanton LH, Ferdinands JM, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2022–23 Influenza Season. MMWR Recomm Rep. 2022;71:1-28. doi: 10.15585/mmwr.rr7101a1
2. Grohskopf LA. Influenza vaccine safety update and proposed recommendations for the 2023-24 influenza season. Presented to the ACIP on June 21, 2023. Accessed September 20, 2023. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-06-21-23/03-influenza-grohskopf-508.pdf
3. Blanton LH, Grohskopf LA. Influenza vaccination of person with egg allergy: evidence to recommendations discussion and work group considerations. Presented to the ACIP on June 21, 2023. Accessed September 20, 2023. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-06-21-23/02-influenza-grohskopf-508.pdf
4. Kroger AT, Bahta L, Long S, et al. General best practice guidelines for immunization. Updated August 1, 2023. Accessed September 20, 2023. www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html
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.
1. Grohskopf LA, Blanton LH, Ferdinands JM, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2022–23 Influenza Season. MMWR Recomm Rep. 2022;71:1-28. doi: 10.15585/mmwr.rr7101a1
2. Grohskopf LA. Influenza vaccine safety update and proposed recommendations for the 2023-24 influenza season. Presented to the ACIP on June 21, 2023. Accessed September 20, 2023. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-06-21-23/03-influenza-grohskopf-508.pdf
3. Blanton LH, Grohskopf LA. Influenza vaccination of person with egg allergy: evidence to recommendations discussion and work group considerations. Presented to the ACIP on June 21, 2023. Accessed September 20, 2023. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-06-21-23/02-influenza-grohskopf-508.pdf
4. Kroger AT, Bahta L, Long S, et al. General best practice guidelines for immunization. Updated August 1, 2023. Accessed September 20, 2023. www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html
1. Grohskopf LA, Blanton LH, Ferdinands JM, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2022–23 Influenza Season. MMWR Recomm Rep. 2022;71:1-28. doi: 10.15585/mmwr.rr7101a1
2. Grohskopf LA. Influenza vaccine safety update and proposed recommendations for the 2023-24 influenza season. Presented to the ACIP on June 21, 2023. Accessed September 20, 2023. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-06-21-23/03-influenza-grohskopf-508.pdf
3. Blanton LH, Grohskopf LA. Influenza vaccination of person with egg allergy: evidence to recommendations discussion and work group considerations. Presented to the ACIP on June 21, 2023. Accessed September 20, 2023. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-06-21-23/02-influenza-grohskopf-508.pdf
4. Kroger AT, Bahta L, Long S, et al. General best practice guidelines for immunization. Updated August 1, 2023. Accessed September 20, 2023. www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html
AGA issues CPU for CRC screening, 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.
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.
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.
FROM GASTROENTEROLOGY
Inadequate sleep & obesity: Breaking the vicious cycle
Sleep is fundamental to overall health and longevity, with the average person spending about one-third of their life sleeping.1 Adequate sleep is critical for optimal cognition, memory consolidation, mood regulation, metabolism, appetite regulation, and immune and hormone functioning. According to the American Academy of Sleep Medicine and the Sleep Research Society, adults should sleep at least 7 hours per night on a regular basis “to promote optimal health.”2 Yet, between 2013 and 2020, only about 65% of adults in the United States were meeting this amount.3 Insufficient sleep is associated with an increased risk for chronic health conditions, including obesity, diabetes, cardiovascular diseases, and even premature death.4
In a population-based longitudinal study of sleep disorders, short sleep duration was associated with increased body mass index (BMI), low blood levels of leptin, and high ghrelin levels.5 In addition to physical impairments, poor sleep can impair cognitive performance and lead to vehicular accidents and increased accidents at work.4 The potential economic impact that this may have is significant, and includes increased costs and loss of productivity in the workplace.6
Many factors may contribute to short sleep duration: environment, mental and physical condition, and social influences such as occupation, family responsibilities, travel, group activities, and personal care. Furthermore, the rapidly evolving and developing media, communication, and entertainment industries are already strongly implicated in poor sleep quality and quantity, both contributing to excessive daytime sleepiness.7 Poor sleep quality is most notable in modern societies, and it correlates with the increasing prevalence of obesity, likely due to sleep’s effect on food consumption and physical activity.8 Optimizing a person’s sleep will improve overall health and longevity by inhibiting the development of chronic disease.
How insufficient sleep raises the risk for obesity
Not only is sleep beneficial for brain health, memory, learning, and growth, its effect on food consumption and physical activity likely correlates with the increased prevalence of obesity in modern society. Yet the optimal amount of sleep is controversial, and current recommendations of 7 or more hours of sleep per night for adults are derived from expert panels only.2 The recommended sleep duration for children is longer, and it varies by age.9 The quality of sleep and its impact on neuroendocrine hormones, not just the quantity of sleep, needs to be factored into these recommendations.
Sleep restriction activates the orexigenic system via the hormones leptin and ghrelin. These hormones control the food reward system, essentially increasing hunger and food intake. Leptin, created by white adipose tissue, is responsible for satiety and decreased food consumption.10 Ghrelin, made by oxyntic glands in the stomach, is responsible for the sensation of hunger.
In a 2004 study by Spiegel et al,11 leptin and ghrelin levels were measured during 2 days of sleep restriction (4 hours in bed) and sleep extension (10 hours in bed). Sleep restriction was associated with a decrease in leptin levels and an increase in ghrelin levels. The researchers reported that participants experienced an increase in hunger and appetite—especially for calorie-dense foods with high carbohydrate content.
Although research design has limitations with predominantly self-reported sleep data, studies have shown that short sleep time leads to increased food intake by increasing hunger signals and craving of unhealthy foods, and by providing more opportunities to eat while awake. It also may lead to decreased physical activity, creating a sedentary lifestyle that further encourages obesity.8 Reduced sleep is even correlated to decreased efficacy of weight-loss treatments.12
Continue to: Other sleep characteristics weakly correlated with obesity
Other sleep characteristics weakly correlated with obesity are sleep variability, timing, efficiency, quality, and daytime napping.8 Sleep variability causes dysregulation of eating patterns, leading to increased food intake. A shift to later sleep and waking times often results in higher consumption of calories after 8
Poor sleep efficiency and quality decreases N3-stage (deep non-REM) sleep, affects the autonomic nervous system, and has been associated with increased abdominal obesity. Daytime napping, which can cause irregular circadian rhythms and sleep schedules, is associated with increased obesity.15 Thus, each component of sleep needs to be assessed to promote optimal regulation of the orexigenic system.
Another study showed that inadequate sleep not only promotes unhealthy lifestyle habits that can lead to obesity but also decreases the ability to lose weight.16 This small study with 10 overweight patients provided its subjects with a controlled caloric intake over 2 weeks. Patients spent two 14-day periods 3 months apart in the laboratory, divided into 2 time-in-bed arms of 8.5 and 5.5 hours per night. Neuroendocrine changes caused by decreased sleep were associated with a significant lean body mass loss while conserving energy-dense fat.16 This study highlights the importance of sleep hygiene counseling when developing a weight-management plan with patients.
Sleep, and its many components, play an integral role in the prevention and treatment of obesity.17 Poor sleep will increase the risk for obesity and hinder its treatment. Therefore, sleep quality and duration are vital components of obesity management.
The sleep–obesity link in children and the elderly
Childhood obesity is linked to several chronic diseases in adulthood, including type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease, asthma, and obstructive sleep apnea (OSA).18 According to 2017-2018 NHANES (National Health and Nutrition Examination Surveys) data, obesity (BMI ≥ 95th percentile) prevalence among children and adolescents was reported at 19.3% and severe obesity (BMI ≥ 120% of the 95th percentile) at 6.1%. Pediatric overweight prevalence (≥ 85th percentile and < 95th percentile) was 16.1%.19
Continue to: Although poor sleep is associated...
Although poor sleep is associated with increased risk for obesity, there is no proven cause-effect relationship.20 Nutrition and physical activity have been identified as 2 critical factors in childhood obesity, but sleep health also needs to be investigated. Shorter sleep duration is strongly associated with the development of obesity. Furthermore, children with obesity are more likely to have shorter sleep duration.21 A short sleep duration alters plasma levels of insulin, low-density lipoprotein, and high-sensitivity C-reactive protein. It is associated with lower diet quality, an increased intake of nutrient-poor foods, and a lower intake of vegetables and fruits.22 Recent studies have shown that interventions to promote earlier bedtimes can improve sleep duration in children.
Older adults have many sleeping issues, including insomnia, circadian rhythm sleep-wake disorders, sleep-related movement disorders, and sleep-breathing disorders. Additionally, the older population has increased sleep latency, decreased sleep efficiency and total sleep time, decreased REM sleep, more frequent nighttime awakenings, and more daytime napping.23 The increased sleep disturbance with age is mainly related to higher risk factors for sleep disorders than the aging process itself. Sleeping 5 or fewer hours is associated with an increased risk for obesity and central abdominal fat compared with those who sleep 7 to 8 hours per night.24 Similar to children and youth, older adults also show a strong correlation between inadequate sleep and obesity.24
The consequence: A vicious cycle
Obesity in turn leads to shorter sleep duration and more disruptions. This negatively affects the orexigenic system, and the resulting hormonal derangement promotes worsening obesity. It is a cycle of poor sleep causing obesity and obesity causing poor sleep. Insomnia, in combination with shorter (and longer) sleep times, also has been linked with obesity.25 These patients experience more daytime sleepiness, fatigue, and nighttime sleep disturbances, all correlated with decreased quality of life and higher prevalence of medical comorbidities.8,26 Additional comorbidities secondary to obesity, including gastroesophageal reflux, depression, and asthma, also have been linked to sleep disturbances.8
OSA is a common sleep complication associated with obesity. With the increasing prevalence of obesity, the prevalence of OSA is rising.8,27 Factors that heighten the risk for OSA are male sex, age 40 to 70 years, postmenopausal status, elevated BMI, and craniofacial and upper airway abnormality.28 However, the US Preventive Services Task Force found insufficient evidence to screen for or treat OSA in asymptomatic adults.28 Signs and symptoms of OSA include nighttime awakenings with choking, loud snoring, and feeling unrefreshed after sleep.29
OSA is caused by the intermittent narrowing and obstruction of the pharyngeal airway due to anatomical and structural irregularities or neuromuscular impairments. Untreated OSA is associated with cardiovascular disease and cardiac arrhythmias such as atrial fibrillation. Even with this correlation between obesity and sleep, it is estimated that 80% of OSA remains undiagnosed.30 Approximately half of primary care clinicians do not screen at-risk patients for OSA, and 90% do not use validated OSA screening tools.31 Screening tools that have been validated are the STOP, STOP-BANG, Epworth Sleepiness Scale, and 4-Variable Screening Tool. However, the US Department of Veterans Affairs and the US Department of Defense have a more recent guideline recommending STOP as an easier-to-administer screen for OSA.32 A positive result with a screening tool should be confirmed with polysomnography.32
Continue to: Intervention for OSA
Intervention for OSA. The longest randomized controlled study to date, Sleep AHEAD, evaluated over a period of 10 years the effect of weight loss on OSA severity achieved with either an intensive lifestyle intervention (ILI) or with diabetes support and education (DSE).33 OSA severity is rated on an Apnea-Hypopnea Index (AHI), with scores reflecting the number of sleep apnea events per hour. This study demonstrated that weight loss was associated with decreased OSA severity. At 4-year follow-up, the greater the weight loss with ILI intervention, the lower the patients’ OSA severity scores. The study found an average decrease in AHI of 0.68 events per hour for every kilogram of weight loss in the ILI group (P < .0001).33,34 Over the follow-up visits, the ILI participants had 7.4 events per hour, a more significantly reduced AHI than the DSE participants (P < .0001).33,34
Additionally, a small cohort of study participants achieved OSA remission (ILI, 34.4%; DSE, 22.2%), indicated by a low AHI score (< 5 events per hour). At the conclusion of the study, OSA severity decreased to a greater degree with ILI intervention.33,34
Alcohol and drug use can negatively influence sleep patterns and obesity. Higher alcohol consumption is associated with poorer sleep quality and higher chances of developing short sleep duration and snoring.35 Alcohol, a muscle relaxant, causes upper airway narrowing and reduced tongue muscle tone, thereby increasing snoring and OSA as demonstrated by increased AHI on polysomnography after alcohol intake. Alcohol also changes sleep architecture by increasing slow-wave sleep, decreasing REM sleep duration, and increasing sleep arousal in the second half of the night.36 Disrupted circadian rhythm after alcohol consumption was correlated with increased adenosine neurotransmitters derived from ethanol metabolism.37 Alcohol dependence may be related to other psychiatric symptoms, and chronic alcohol use eventually alters sleep mechanisms leading to persistent insomnia, further perpetuating adverse outcomes such as suicidal ideation.36 There are positive associations between beer drinking and measures of abdominal adiposity in men, and “the combination of short sleep duration [and] disinhibited eating … is associated with greater alcohol intake and excess weight.”38
Therefore, counsel patients to avoid alcohol since it is a modifiable risk factor with pervasive adverse health effects.
Many drugs have a profound effect on sleep patterns. Illicit drug use in particular can affect the brain’s neurotransmitter serotonin system. For example, ecstasy users have an increased risk for OSA.39 People with cocaine and heroin use disorder tend to have more sleep-maintenance insomnia.40
Continue to: In contrast, those with alcohol...
In contrast, those with alcohol or cannabis use disorder tend to have more sleep-onset insomnia.40 Not only do illicit drugs interrupt sleep, but daily tobacco use also has been correlated with increased insomnia and shorter sleep duration since nicotine is a stimulant.41
Insomnia is commonly treated with sedative antidepressants and hypnotics—eg, mirtazapine and olanzapine—that contribute to weight gain.42 In addition, other common pharmaceuticals used for sleep disorders, such as diphenhydramine, have sedative properties and tend to lead to weight gain.43 Because so many medications affect sleep and weight, carefully review patients’ medication lists and switch offending agents to weight-neutral drugs if possible.
Treatment and tools to improve sleep in patients with obesity
Given the strong correlation between obesity and sleep disorders, validated screening tools should be used to assess sleep quality, including onset and potential symptoms associated with poor sleep (TABLE 144). For weight management to succeed in patients with obesity, it is crucial to address sleep in addition to nutrition and physical activity.17,45
Physical activity has many benefits to overall health, especially for chronic diseases such as type 2 diabetes and hypertension. The Centers for Disease Control and Prevention recommends at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic exercise per week in addition to muscle-strengthening activities 2 or more days per week.46 However, approximately 300 minutes of moderate-
Physical activity and diet in combination are vital, but diet restriction has a more substantial effect on weight loss than physical activity alone.48 Still, physical activity is essential in helping maintain and prevent weight regain.
Continue to: Nonpharmacologic interventions
Nonpharmacologic interventions include promoting greater sleep quality and quantity by emphasizing good sleep hygiene practices. Developing a practical and effective bedtime routine, creating a quiet sleep environment, and practicing healthy daily habits are essential components to sleep hygiene (TABLE 249,50). Relaxation techniques and cognitive behavioral therapy (CBT) also can help. CBT for insomnia (CBT-I) is the first-line intervention for chronic insomnia.51 Sleep restriction is a type of CBT used to treat insomnia, encouraging short-term sleep loss in the hopes of improving insomnia. A trial by Logue et al showed that patients with overweight and obesity randomized to undergo CBT with better sleep hygiene (nonpharmacologic) interventions had a greater mean weight loss percentage (5% vs 2%; P = .04) than did those who received CBT alone.52
Eastern medicine including herbal interventions lack evidence of efficacy and safety. Further studies need to be done on the effects that chamomile, kava, valerian root (Valeriana officinalis), tryptophan, and Wu Ling (from mycelia Xylaria nigripes) might have on sleep.53
Proceed cautiously with medication. The American College of Physicians recommends a shared decision-making approach when considering pharmacologic therapy for chronic insomnia and the American Academy of Sleep Medicine (AASM) offers guidance on options.51,54 However, the evidence behind AASM sleep pharmacologic recommendations is weak, implying a lesser degree of confidence in the outcome and, therefore, in its appropriateness. Thus, it falls upon the clinician and patient to weigh the benefits and burdens of the pharmacologic treatments of insomnia. If indicated, medications suggested to treat sleep onset and sleep maintenance insomnia are eszopiclone, zolpidem, and temazepam. Zaleplon, triazolam, and ramelteon may improve sleep initiation. Suvorexant and doxepin are used for sleep-maintenance insomnia.54 Exploring patient preferences, cost of treatment, health care options, and available resources should all be considered.
CORRESPONDENCE
Ecler Ercole Jaqua, MD, MBA, FAAFP, AGSF, FACLM, DipABOM, Loma Linda University Health, 25455 Barton Road, Suite 206A, Loma Linda, CA 92354; [email protected]
1. Aminoff MJ, Boller F, Swaab DF. We spend about one-third of our life either sleeping or attempting to do so. Handb Clin Neurol. 2011;98:vii. doi: 10.1016/B978-0-444-52006-7.00047-2
2. Watson NF, Badr MS, Belenky G, et al. Recommended amount of sleep for a healthy adult: a joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society. Sleep. 2015;38:843-844. doi: 10.5665/sleep.4716
3. CDC. Sleep and sleep disorders, adults. Accessed September 21, 2023. www.cdc.gov/sleep/data-and-statistics/adults.html
4. Chattu VK, Manzar MD, Kumary S. The global problem of insufficient sleep and its serious public health implications. Healthcare (Basel). 2019;7:1. doi: 10.3390/healthcare7010001
5. Taheri S, Lin L, Austin D, et al. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1:e62. doi: 10.1371/journal.pmed.0010062
6. Hafner M, Stepanek M, Taylor J, et al. Why sleep matters—the economic costs of insufficient sleep. Rand Health Q. 2017;6:11.
7. Hisler G, Twenge JM, Krizan Z. Associations between screen time and short sleep duration among adolescents varies by media type: evidence from a cohort study. Sleep Med. 2020;66:92-102. doi: 10.1016/j.sleep.2019.08.007
8. Ogilvie RP, Patel SR. The epidemiology of sleep and obesity. Sleep Health. 2017;3:383-388. doi: 10.1016/j.sleh.2017.07.013
9. CDC. Sleep and sleep disorders: How much sleep do I need? Accessed September 21, 2023. www.cdc.gov/sleep/about_sleep/how_much_sleep.html
10. van Egmond LT, Meth EMS, Engström J, et al. Effects of acute sleep loss on leptin, ghrelin, and adiponectin in adults with healthy weight and obesity: a laboratory study. Obesity (Silver Spring). 2023;31:635-641. doi: 10.1002/oby.23616
11. Spiegel K, Tasali E, Penev P, et al. Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141:846-850. doi: 10.7326/0003-4819-141-11-200412070-00008
12. Antza C, Kostopoulos G, Mostafa S, et al. The links between sleep duration, obesity and type 2 diabetes mellitus. J Endocrinol. 2021;252:125-141. doi: 10.1530/JOE-21-0155
13. Baron KG, Reid KJ, Kern AS, et al. Role of sleep timing in caloric intake and BMI. Obesity (Silver Spring). 2011;19:1374-1381. doi: 10.1038/oby.2011.100
14. Liu XY, Zheng CL, Xu C, et al. Nighttime snacking is associated with risk of obesity and hyperglycemia in adults: a cross-sectional survey from Chinese adult teachers J Biomed Res. 2017;31:541-547. doi: 10.7555/JBR.31.20160083
15. Cai Z, Yang Y, Zhang J, et al. The relationship between daytime napping and obesity: a systematic review and meta-analysis. Sci Rep. 2023.13:12124. doi: 10.1038/s41598-023-37883-7
16. Nedeltcheva AV, Kilkus JM, Imperial J, et al. Insufficient sleep undermines dietary efforts to reduce adiposity. Ann Intern Med. 2010;153:435-441. doi: 10.7326/0003-4819-153-7-201010050-00006
17. Chaput JP, Tremblay A. Adequate sleep to improve the treatment of obesity. CMAJ. 2012;184:1975-1976. doi: 10.1503/cmaj.120876
18. Kelsey MM, Zaepfel A, Bjornstad P, et al. Age-related consequences of childhood obesity. Gerontology. 2014;60:222-228. doi: 10.1159/000356023
19. Fryar CD, Carroll MD, Afful J. Prevalence of overweight, obesity, and severe obesity among children and adolescents aged 2-19 years: United States, 1963-1965 through 2017-2018. National Center for Health Statistics Health E-Stats. Updated January 29, 2021. Accessed September 21, 2021. www.cdc.gov/nchs/data/hestat/obesity-child-17-18/overweight-obesity-child-H.pdf
20. Fatima Y, Doi SAR, Mamun AA. Sleep quality and obesity in young subjects: a meta-analysis. Obes Rev. 2016;17:1154-1166. doi: 10.1111/obr.12444
21. Gohil A, Hannon TS. Poor sleep and obesity: concurrent epidemics in adolescent youth. Front Endocrinol. 2018;9:364. doi: 10.3389/fendo.2018.00364
22. Golley RK, Maher CA, Matricciani L, et al. Sleep duration or bedtime? Exploring the association between sleep timing behaviour, diet and BMI in children and adolescents. Int J Obes (Lond). 2013;37:546-551. doi: 10.1038/ijo.2012.212
23. Alessi CA. Sleep issues. In: Harper GM, Lyons WL, Potter JF, eds. Geriatrics Review Syllabus (GRS 10). Updated January 2021. Accessed August 29, 2023. http://geriatricscareonline.org
24. Patel SR, Blackwell T, Redline S, et al. The association between sleep duration and obesity in older adults. Int J Obes (Lond). 2008;32:1825-1834. doi: 10.1038/ijo.2008.198
25. Cai GH, Theorell-Haglöw J, Janson C, et al. Insomnia symptoms and sleep duration and their combined effects in relation to associations with obesity and central obesity. Sleep Med. 2018;46:81-87. doi: 10.1016/j.sleep.2018.03.009
26. Beccuti G, Pannain S. Sleep and obesity. Curr Opin Clin Nutr Metab Care. 2011;14:402-412. doi: 10.1097/MCO.0b013 e3283479109
27. Franklin KA, Lindberg E. Obstructive sleep apnea is a common disorder in the population–a review on the epidemiology of sleep apnea. J Thorac Dis. 2015;7:1311-1322. doi: 10.3978/j.issn.2072-1439.2015.06.11
28. USPSTF. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for obstructive sleep apnea in adults: US Preventive Services Task Force recommendation statement. JAMA. 2017;317:407-414. doi: 10.1001/jama.2016.20325
29. Goyal M, Johnson J. Obstructive sleep apnea diagnosis and management. Mo Med. 2017;114:120-124.
30. American Academy of Sleep Medicine. Hidden health crisis costing America billions: underdiagnosing and undertreating obstructive sleep apnea draining healthcare system. 2016. Accessed September 25, 2023. https://aasm.org/wp-content/uploads/2017/10/sleep-apnea-economic-crisis.pdf
31. Devaraj, NK. Knowledge, attitude, and practice regarding obstructive sleep apnea among primary care physicians. Sleep Breath. 2020;24:1581-1590. doi: 10.1007/s11325-020-02040-1
32. Mysliwiec V, Martin JL, Ulmer CS, et al. The management of chronic insomnia disorder and obstructive sleep apnea: synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guidelines. Ann Intern Med. 2020;172:325-336. doi: 10.7326/M19-3575
33. Kuna ST, Reboussin DM, Strotmeyer ES, et al. Effects of weight loss on obstructive sleep apnea severity. Ten-year results of the Sleep AHEAD study. Am J Respir Crit Care Med. 2021;203:221-229. doi: 10.1164/rccm.201912-2511OC
34. St-Onge MP, Tasali E. Weight loss is integral to obstructive sleep apnea management. Ten-year follow-up in Sleep AHEAD. Am J Respir Crit Care Med. 2021;203:161-162. doi: 10.1164/rccm.202007-2906ED
35. Zheng D, Yuan X, Ma C, et al. Alcohol consumption and sleep quality: a community-based study. Public Health Nutr. 2021;24:4851-4858. doi: 10.1017/S1368980020004553
36. Chakravorty S, Chaudhary NS, Brower KJ. Alcohol dependence and its relationship with insomnia and other sleep disorders. Alcohol Clin Exp Res. 2016;40:2271-2282. doi: 10.1111/acer.13217
37. Elmenhorst EM, Elmenhorst D, Benderoth S, et al. Cognitive impairments by alcohol and sleep deprivation indicate trait characteristics and a potential role for adenosine A1 receptors. Proc Natl Acad Sci U S A. 2018;115:8009-8014. doi: 10.1073/pnas.1803770115
38. Traversy G, Chaput JP. Alcohol consumption and obesity: an update. Curr Obes Rep. 2015;4:122-130. doi: 10.1007/s13679-014-0129-4
39. McCann UD, Sgambati FP, Schwartz AR, et al. Sleep apnea in young abstinent recreational MDMA (“ecstasy”) consumers. Neurology. 2009;73:2011-2017. doi: 10.1212/WNL.0b013e3181c51a62
40. Grau-López L, Grau-López L, Daigre C, et al. Insomnia symptoms in patients with substance use disorders during detoxification and associated clinical features. Front Psychiatry. 2020;11:540022. doi: 10.3389/fpsyt.2020.540022
41. Boehm MA, Lei QM, Lloyd RM, et al. Depression, anxiety, and tobacco use: overlapping impediments to sleep in a national sample of college students. J Am Coll Health. 2016;64:565-574. doi: 10.1080/07448481.2016.1205073
42. Gracious BL, Meyer AE. Psychotropic-induced weight gain and potential pharmacologic treatment strategies. Psychiatry (Edgmont). 2005;2:36-42.
43. Ratliff JC, Barber JA, Palmese LB, et al. Association of prescription H1 antihistamine use with obesity: results from the National Health and Nutrition Examination Survey. Obesity (Silver Spring). 2010;18:2398-2400. doi: 10.1038/oby.2010.176
44. Pataka A, Daskalopoulou E, Kalamaras G, et al. Evaluation of five different questionnaires for assessing sleep apnea syndrome in a sleep clinic. Sleep Med. 2014;15:776-781. doi: 10.1016/j.sleep.2014.03.012
45. Kline CE, Chasens ER, Bizhanova Z, et al. The association between sleep health and weight change during a 12-month behavioral weight loss intervention. Int J Obes (Lond). 2021;45:639-649. doi: 10.1038/s41366-020-00728-8
46. CDC. How much physical activity do adults need? Accessed August 23, 2023. www.cdc.gov/physicalactivity/basics/adults/index.htm
47. Flack KD, Hays HM, Moreland J, et al. Exercise for weight loss: further evaluating energy compensation with exercise. Med Sci Sports Exerc. 2020;52:2466-2475. doi: 10.1249/MSS.0000000000002376
48. Swift DL, Johannsen NM, Lavie CJ, et al. The role of exercise and physical activity in weight loss and maintenance. Prog Cardiovasc Dis. 2014;56:441-447. doi: 10.1016/j.pcad.2013.09.012
49. Irish LA, Kline CE, Gunn HE, et al. The role of sleep hygiene in promoting public health: a review of empirical evidence. Sleep Med Rev. 2015;22:23-36. doi: 10.1016/j.smrv.2014.10.001
50. CDC. Tips for better sleep. 2022. Accessed August 4, 2023. www.cdc.gov/sleep/about_sleep/sleep_hygiene.html
51. Qaseem A, Kansagara D, Forciea MA, et al. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165:125-133. doi: 10.7326/M15-2175
52. Logue EE, Bourguet CC, Palmieri PA, et al. The better weight-better sleep study: a pilot intervention in primary care. Am J Health Behav. 2012;36:319-334. doi: 10.5993/AJHB.36.3.4
53. Leach MJ, Page AT. Herbal medicine for insomnia: a systematic review and meta-analysis. Sleep Med Rev. 2015;24:1-12. doi: 10.1016/j.smrv.2014.12.003
54. Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13:307-349. doi: 10.5664/jcsm.6470
Sleep is fundamental to overall health and longevity, with the average person spending about one-third of their life sleeping.1 Adequate sleep is critical for optimal cognition, memory consolidation, mood regulation, metabolism, appetite regulation, and immune and hormone functioning. According to the American Academy of Sleep Medicine and the Sleep Research Society, adults should sleep at least 7 hours per night on a regular basis “to promote optimal health.”2 Yet, between 2013 and 2020, only about 65% of adults in the United States were meeting this amount.3 Insufficient sleep is associated with an increased risk for chronic health conditions, including obesity, diabetes, cardiovascular diseases, and even premature death.4
In a population-based longitudinal study of sleep disorders, short sleep duration was associated with increased body mass index (BMI), low blood levels of leptin, and high ghrelin levels.5 In addition to physical impairments, poor sleep can impair cognitive performance and lead to vehicular accidents and increased accidents at work.4 The potential economic impact that this may have is significant, and includes increased costs and loss of productivity in the workplace.6
Many factors may contribute to short sleep duration: environment, mental and physical condition, and social influences such as occupation, family responsibilities, travel, group activities, and personal care. Furthermore, the rapidly evolving and developing media, communication, and entertainment industries are already strongly implicated in poor sleep quality and quantity, both contributing to excessive daytime sleepiness.7 Poor sleep quality is most notable in modern societies, and it correlates with the increasing prevalence of obesity, likely due to sleep’s effect on food consumption and physical activity.8 Optimizing a person’s sleep will improve overall health and longevity by inhibiting the development of chronic disease.
How insufficient sleep raises the risk for obesity
Not only is sleep beneficial for brain health, memory, learning, and growth, its effect on food consumption and physical activity likely correlates with the increased prevalence of obesity in modern society. Yet the optimal amount of sleep is controversial, and current recommendations of 7 or more hours of sleep per night for adults are derived from expert panels only.2 The recommended sleep duration for children is longer, and it varies by age.9 The quality of sleep and its impact on neuroendocrine hormones, not just the quantity of sleep, needs to be factored into these recommendations.
Sleep restriction activates the orexigenic system via the hormones leptin and ghrelin. These hormones control the food reward system, essentially increasing hunger and food intake. Leptin, created by white adipose tissue, is responsible for satiety and decreased food consumption.10 Ghrelin, made by oxyntic glands in the stomach, is responsible for the sensation of hunger.
In a 2004 study by Spiegel et al,11 leptin and ghrelin levels were measured during 2 days of sleep restriction (4 hours in bed) and sleep extension (10 hours in bed). Sleep restriction was associated with a decrease in leptin levels and an increase in ghrelin levels. The researchers reported that participants experienced an increase in hunger and appetite—especially for calorie-dense foods with high carbohydrate content.
Although research design has limitations with predominantly self-reported sleep data, studies have shown that short sleep time leads to increased food intake by increasing hunger signals and craving of unhealthy foods, and by providing more opportunities to eat while awake. It also may lead to decreased physical activity, creating a sedentary lifestyle that further encourages obesity.8 Reduced sleep is even correlated to decreased efficacy of weight-loss treatments.12
Continue to: Other sleep characteristics weakly correlated with obesity
Other sleep characteristics weakly correlated with obesity are sleep variability, timing, efficiency, quality, and daytime napping.8 Sleep variability causes dysregulation of eating patterns, leading to increased food intake. A shift to later sleep and waking times often results in higher consumption of calories after 8
Poor sleep efficiency and quality decreases N3-stage (deep non-REM) sleep, affects the autonomic nervous system, and has been associated with increased abdominal obesity. Daytime napping, which can cause irregular circadian rhythms and sleep schedules, is associated with increased obesity.15 Thus, each component of sleep needs to be assessed to promote optimal regulation of the orexigenic system.
Another study showed that inadequate sleep not only promotes unhealthy lifestyle habits that can lead to obesity but also decreases the ability to lose weight.16 This small study with 10 overweight patients provided its subjects with a controlled caloric intake over 2 weeks. Patients spent two 14-day periods 3 months apart in the laboratory, divided into 2 time-in-bed arms of 8.5 and 5.5 hours per night. Neuroendocrine changes caused by decreased sleep were associated with a significant lean body mass loss while conserving energy-dense fat.16 This study highlights the importance of sleep hygiene counseling when developing a weight-management plan with patients.
Sleep, and its many components, play an integral role in the prevention and treatment of obesity.17 Poor sleep will increase the risk for obesity and hinder its treatment. Therefore, sleep quality and duration are vital components of obesity management.
The sleep–obesity link in children and the elderly
Childhood obesity is linked to several chronic diseases in adulthood, including type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease, asthma, and obstructive sleep apnea (OSA).18 According to 2017-2018 NHANES (National Health and Nutrition Examination Surveys) data, obesity (BMI ≥ 95th percentile) prevalence among children and adolescents was reported at 19.3% and severe obesity (BMI ≥ 120% of the 95th percentile) at 6.1%. Pediatric overweight prevalence (≥ 85th percentile and < 95th percentile) was 16.1%.19
Continue to: Although poor sleep is associated...
Although poor sleep is associated with increased risk for obesity, there is no proven cause-effect relationship.20 Nutrition and physical activity have been identified as 2 critical factors in childhood obesity, but sleep health also needs to be investigated. Shorter sleep duration is strongly associated with the development of obesity. Furthermore, children with obesity are more likely to have shorter sleep duration.21 A short sleep duration alters plasma levels of insulin, low-density lipoprotein, and high-sensitivity C-reactive protein. It is associated with lower diet quality, an increased intake of nutrient-poor foods, and a lower intake of vegetables and fruits.22 Recent studies have shown that interventions to promote earlier bedtimes can improve sleep duration in children.
Older adults have many sleeping issues, including insomnia, circadian rhythm sleep-wake disorders, sleep-related movement disorders, and sleep-breathing disorders. Additionally, the older population has increased sleep latency, decreased sleep efficiency and total sleep time, decreased REM sleep, more frequent nighttime awakenings, and more daytime napping.23 The increased sleep disturbance with age is mainly related to higher risk factors for sleep disorders than the aging process itself. Sleeping 5 or fewer hours is associated with an increased risk for obesity and central abdominal fat compared with those who sleep 7 to 8 hours per night.24 Similar to children and youth, older adults also show a strong correlation between inadequate sleep and obesity.24
The consequence: A vicious cycle
Obesity in turn leads to shorter sleep duration and more disruptions. This negatively affects the orexigenic system, and the resulting hormonal derangement promotes worsening obesity. It is a cycle of poor sleep causing obesity and obesity causing poor sleep. Insomnia, in combination with shorter (and longer) sleep times, also has been linked with obesity.25 These patients experience more daytime sleepiness, fatigue, and nighttime sleep disturbances, all correlated with decreased quality of life and higher prevalence of medical comorbidities.8,26 Additional comorbidities secondary to obesity, including gastroesophageal reflux, depression, and asthma, also have been linked to sleep disturbances.8
OSA is a common sleep complication associated with obesity. With the increasing prevalence of obesity, the prevalence of OSA is rising.8,27 Factors that heighten the risk for OSA are male sex, age 40 to 70 years, postmenopausal status, elevated BMI, and craniofacial and upper airway abnormality.28 However, the US Preventive Services Task Force found insufficient evidence to screen for or treat OSA in asymptomatic adults.28 Signs and symptoms of OSA include nighttime awakenings with choking, loud snoring, and feeling unrefreshed after sleep.29
OSA is caused by the intermittent narrowing and obstruction of the pharyngeal airway due to anatomical and structural irregularities or neuromuscular impairments. Untreated OSA is associated with cardiovascular disease and cardiac arrhythmias such as atrial fibrillation. Even with this correlation between obesity and sleep, it is estimated that 80% of OSA remains undiagnosed.30 Approximately half of primary care clinicians do not screen at-risk patients for OSA, and 90% do not use validated OSA screening tools.31 Screening tools that have been validated are the STOP, STOP-BANG, Epworth Sleepiness Scale, and 4-Variable Screening Tool. However, the US Department of Veterans Affairs and the US Department of Defense have a more recent guideline recommending STOP as an easier-to-administer screen for OSA.32 A positive result with a screening tool should be confirmed with polysomnography.32
Continue to: Intervention for OSA
Intervention for OSA. The longest randomized controlled study to date, Sleep AHEAD, evaluated over a period of 10 years the effect of weight loss on OSA severity achieved with either an intensive lifestyle intervention (ILI) or with diabetes support and education (DSE).33 OSA severity is rated on an Apnea-Hypopnea Index (AHI), with scores reflecting the number of sleep apnea events per hour. This study demonstrated that weight loss was associated with decreased OSA severity. At 4-year follow-up, the greater the weight loss with ILI intervention, the lower the patients’ OSA severity scores. The study found an average decrease in AHI of 0.68 events per hour for every kilogram of weight loss in the ILI group (P < .0001).33,34 Over the follow-up visits, the ILI participants had 7.4 events per hour, a more significantly reduced AHI than the DSE participants (P < .0001).33,34
Additionally, a small cohort of study participants achieved OSA remission (ILI, 34.4%; DSE, 22.2%), indicated by a low AHI score (< 5 events per hour). At the conclusion of the study, OSA severity decreased to a greater degree with ILI intervention.33,34
Alcohol and drug use can negatively influence sleep patterns and obesity. Higher alcohol consumption is associated with poorer sleep quality and higher chances of developing short sleep duration and snoring.35 Alcohol, a muscle relaxant, causes upper airway narrowing and reduced tongue muscle tone, thereby increasing snoring and OSA as demonstrated by increased AHI on polysomnography after alcohol intake. Alcohol also changes sleep architecture by increasing slow-wave sleep, decreasing REM sleep duration, and increasing sleep arousal in the second half of the night.36 Disrupted circadian rhythm after alcohol consumption was correlated with increased adenosine neurotransmitters derived from ethanol metabolism.37 Alcohol dependence may be related to other psychiatric symptoms, and chronic alcohol use eventually alters sleep mechanisms leading to persistent insomnia, further perpetuating adverse outcomes such as suicidal ideation.36 There are positive associations between beer drinking and measures of abdominal adiposity in men, and “the combination of short sleep duration [and] disinhibited eating … is associated with greater alcohol intake and excess weight.”38
Therefore, counsel patients to avoid alcohol since it is a modifiable risk factor with pervasive adverse health effects.
Many drugs have a profound effect on sleep patterns. Illicit drug use in particular can affect the brain’s neurotransmitter serotonin system. For example, ecstasy users have an increased risk for OSA.39 People with cocaine and heroin use disorder tend to have more sleep-maintenance insomnia.40
Continue to: In contrast, those with alcohol...
In contrast, those with alcohol or cannabis use disorder tend to have more sleep-onset insomnia.40 Not only do illicit drugs interrupt sleep, but daily tobacco use also has been correlated with increased insomnia and shorter sleep duration since nicotine is a stimulant.41
Insomnia is commonly treated with sedative antidepressants and hypnotics—eg, mirtazapine and olanzapine—that contribute to weight gain.42 In addition, other common pharmaceuticals used for sleep disorders, such as diphenhydramine, have sedative properties and tend to lead to weight gain.43 Because so many medications affect sleep and weight, carefully review patients’ medication lists and switch offending agents to weight-neutral drugs if possible.
Treatment and tools to improve sleep in patients with obesity
Given the strong correlation between obesity and sleep disorders, validated screening tools should be used to assess sleep quality, including onset and potential symptoms associated with poor sleep (TABLE 144). For weight management to succeed in patients with obesity, it is crucial to address sleep in addition to nutrition and physical activity.17,45
Physical activity has many benefits to overall health, especially for chronic diseases such as type 2 diabetes and hypertension. The Centers for Disease Control and Prevention recommends at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic exercise per week in addition to muscle-strengthening activities 2 or more days per week.46 However, approximately 300 minutes of moderate-
Physical activity and diet in combination are vital, but diet restriction has a more substantial effect on weight loss than physical activity alone.48 Still, physical activity is essential in helping maintain and prevent weight regain.
Continue to: Nonpharmacologic interventions
Nonpharmacologic interventions include promoting greater sleep quality and quantity by emphasizing good sleep hygiene practices. Developing a practical and effective bedtime routine, creating a quiet sleep environment, and practicing healthy daily habits are essential components to sleep hygiene (TABLE 249,50). Relaxation techniques and cognitive behavioral therapy (CBT) also can help. CBT for insomnia (CBT-I) is the first-line intervention for chronic insomnia.51 Sleep restriction is a type of CBT used to treat insomnia, encouraging short-term sleep loss in the hopes of improving insomnia. A trial by Logue et al showed that patients with overweight and obesity randomized to undergo CBT with better sleep hygiene (nonpharmacologic) interventions had a greater mean weight loss percentage (5% vs 2%; P = .04) than did those who received CBT alone.52
Eastern medicine including herbal interventions lack evidence of efficacy and safety. Further studies need to be done on the effects that chamomile, kava, valerian root (Valeriana officinalis), tryptophan, and Wu Ling (from mycelia Xylaria nigripes) might have on sleep.53
Proceed cautiously with medication. The American College of Physicians recommends a shared decision-making approach when considering pharmacologic therapy for chronic insomnia and the American Academy of Sleep Medicine (AASM) offers guidance on options.51,54 However, the evidence behind AASM sleep pharmacologic recommendations is weak, implying a lesser degree of confidence in the outcome and, therefore, in its appropriateness. Thus, it falls upon the clinician and patient to weigh the benefits and burdens of the pharmacologic treatments of insomnia. If indicated, medications suggested to treat sleep onset and sleep maintenance insomnia are eszopiclone, zolpidem, and temazepam. Zaleplon, triazolam, and ramelteon may improve sleep initiation. Suvorexant and doxepin are used for sleep-maintenance insomnia.54 Exploring patient preferences, cost of treatment, health care options, and available resources should all be considered.
CORRESPONDENCE
Ecler Ercole Jaqua, MD, MBA, FAAFP, AGSF, FACLM, DipABOM, Loma Linda University Health, 25455 Barton Road, Suite 206A, Loma Linda, CA 92354; [email protected]
Sleep is fundamental to overall health and longevity, with the average person spending about one-third of their life sleeping.1 Adequate sleep is critical for optimal cognition, memory consolidation, mood regulation, metabolism, appetite regulation, and immune and hormone functioning. According to the American Academy of Sleep Medicine and the Sleep Research Society, adults should sleep at least 7 hours per night on a regular basis “to promote optimal health.”2 Yet, between 2013 and 2020, only about 65% of adults in the United States were meeting this amount.3 Insufficient sleep is associated with an increased risk for chronic health conditions, including obesity, diabetes, cardiovascular diseases, and even premature death.4
In a population-based longitudinal study of sleep disorders, short sleep duration was associated with increased body mass index (BMI), low blood levels of leptin, and high ghrelin levels.5 In addition to physical impairments, poor sleep can impair cognitive performance and lead to vehicular accidents and increased accidents at work.4 The potential economic impact that this may have is significant, and includes increased costs and loss of productivity in the workplace.6
Many factors may contribute to short sleep duration: environment, mental and physical condition, and social influences such as occupation, family responsibilities, travel, group activities, and personal care. Furthermore, the rapidly evolving and developing media, communication, and entertainment industries are already strongly implicated in poor sleep quality and quantity, both contributing to excessive daytime sleepiness.7 Poor sleep quality is most notable in modern societies, and it correlates with the increasing prevalence of obesity, likely due to sleep’s effect on food consumption and physical activity.8 Optimizing a person’s sleep will improve overall health and longevity by inhibiting the development of chronic disease.
How insufficient sleep raises the risk for obesity
Not only is sleep beneficial for brain health, memory, learning, and growth, its effect on food consumption and physical activity likely correlates with the increased prevalence of obesity in modern society. Yet the optimal amount of sleep is controversial, and current recommendations of 7 or more hours of sleep per night for adults are derived from expert panels only.2 The recommended sleep duration for children is longer, and it varies by age.9 The quality of sleep and its impact on neuroendocrine hormones, not just the quantity of sleep, needs to be factored into these recommendations.
Sleep restriction activates the orexigenic system via the hormones leptin and ghrelin. These hormones control the food reward system, essentially increasing hunger and food intake. Leptin, created by white adipose tissue, is responsible for satiety and decreased food consumption.10 Ghrelin, made by oxyntic glands in the stomach, is responsible for the sensation of hunger.
In a 2004 study by Spiegel et al,11 leptin and ghrelin levels were measured during 2 days of sleep restriction (4 hours in bed) and sleep extension (10 hours in bed). Sleep restriction was associated with a decrease in leptin levels and an increase in ghrelin levels. The researchers reported that participants experienced an increase in hunger and appetite—especially for calorie-dense foods with high carbohydrate content.
Although research design has limitations with predominantly self-reported sleep data, studies have shown that short sleep time leads to increased food intake by increasing hunger signals and craving of unhealthy foods, and by providing more opportunities to eat while awake. It also may lead to decreased physical activity, creating a sedentary lifestyle that further encourages obesity.8 Reduced sleep is even correlated to decreased efficacy of weight-loss treatments.12
Continue to: Other sleep characteristics weakly correlated with obesity
Other sleep characteristics weakly correlated with obesity are sleep variability, timing, efficiency, quality, and daytime napping.8 Sleep variability causes dysregulation of eating patterns, leading to increased food intake. A shift to later sleep and waking times often results in higher consumption of calories after 8
Poor sleep efficiency and quality decreases N3-stage (deep non-REM) sleep, affects the autonomic nervous system, and has been associated with increased abdominal obesity. Daytime napping, which can cause irregular circadian rhythms and sleep schedules, is associated with increased obesity.15 Thus, each component of sleep needs to be assessed to promote optimal regulation of the orexigenic system.
Another study showed that inadequate sleep not only promotes unhealthy lifestyle habits that can lead to obesity but also decreases the ability to lose weight.16 This small study with 10 overweight patients provided its subjects with a controlled caloric intake over 2 weeks. Patients spent two 14-day periods 3 months apart in the laboratory, divided into 2 time-in-bed arms of 8.5 and 5.5 hours per night. Neuroendocrine changes caused by decreased sleep were associated with a significant lean body mass loss while conserving energy-dense fat.16 This study highlights the importance of sleep hygiene counseling when developing a weight-management plan with patients.
Sleep, and its many components, play an integral role in the prevention and treatment of obesity.17 Poor sleep will increase the risk for obesity and hinder its treatment. Therefore, sleep quality and duration are vital components of obesity management.
The sleep–obesity link in children and the elderly
Childhood obesity is linked to several chronic diseases in adulthood, including type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease, asthma, and obstructive sleep apnea (OSA).18 According to 2017-2018 NHANES (National Health and Nutrition Examination Surveys) data, obesity (BMI ≥ 95th percentile) prevalence among children and adolescents was reported at 19.3% and severe obesity (BMI ≥ 120% of the 95th percentile) at 6.1%. Pediatric overweight prevalence (≥ 85th percentile and < 95th percentile) was 16.1%.19
Continue to: Although poor sleep is associated...
Although poor sleep is associated with increased risk for obesity, there is no proven cause-effect relationship.20 Nutrition and physical activity have been identified as 2 critical factors in childhood obesity, but sleep health also needs to be investigated. Shorter sleep duration is strongly associated with the development of obesity. Furthermore, children with obesity are more likely to have shorter sleep duration.21 A short sleep duration alters plasma levels of insulin, low-density lipoprotein, and high-sensitivity C-reactive protein. It is associated with lower diet quality, an increased intake of nutrient-poor foods, and a lower intake of vegetables and fruits.22 Recent studies have shown that interventions to promote earlier bedtimes can improve sleep duration in children.
Older adults have many sleeping issues, including insomnia, circadian rhythm sleep-wake disorders, sleep-related movement disorders, and sleep-breathing disorders. Additionally, the older population has increased sleep latency, decreased sleep efficiency and total sleep time, decreased REM sleep, more frequent nighttime awakenings, and more daytime napping.23 The increased sleep disturbance with age is mainly related to higher risk factors for sleep disorders than the aging process itself. Sleeping 5 or fewer hours is associated with an increased risk for obesity and central abdominal fat compared with those who sleep 7 to 8 hours per night.24 Similar to children and youth, older adults also show a strong correlation between inadequate sleep and obesity.24
The consequence: A vicious cycle
Obesity in turn leads to shorter sleep duration and more disruptions. This negatively affects the orexigenic system, and the resulting hormonal derangement promotes worsening obesity. It is a cycle of poor sleep causing obesity and obesity causing poor sleep. Insomnia, in combination with shorter (and longer) sleep times, also has been linked with obesity.25 These patients experience more daytime sleepiness, fatigue, and nighttime sleep disturbances, all correlated with decreased quality of life and higher prevalence of medical comorbidities.8,26 Additional comorbidities secondary to obesity, including gastroesophageal reflux, depression, and asthma, also have been linked to sleep disturbances.8
OSA is a common sleep complication associated with obesity. With the increasing prevalence of obesity, the prevalence of OSA is rising.8,27 Factors that heighten the risk for OSA are male sex, age 40 to 70 years, postmenopausal status, elevated BMI, and craniofacial and upper airway abnormality.28 However, the US Preventive Services Task Force found insufficient evidence to screen for or treat OSA in asymptomatic adults.28 Signs and symptoms of OSA include nighttime awakenings with choking, loud snoring, and feeling unrefreshed after sleep.29
OSA is caused by the intermittent narrowing and obstruction of the pharyngeal airway due to anatomical and structural irregularities or neuromuscular impairments. Untreated OSA is associated with cardiovascular disease and cardiac arrhythmias such as atrial fibrillation. Even with this correlation between obesity and sleep, it is estimated that 80% of OSA remains undiagnosed.30 Approximately half of primary care clinicians do not screen at-risk patients for OSA, and 90% do not use validated OSA screening tools.31 Screening tools that have been validated are the STOP, STOP-BANG, Epworth Sleepiness Scale, and 4-Variable Screening Tool. However, the US Department of Veterans Affairs and the US Department of Defense have a more recent guideline recommending STOP as an easier-to-administer screen for OSA.32 A positive result with a screening tool should be confirmed with polysomnography.32
Continue to: Intervention for OSA
Intervention for OSA. The longest randomized controlled study to date, Sleep AHEAD, evaluated over a period of 10 years the effect of weight loss on OSA severity achieved with either an intensive lifestyle intervention (ILI) or with diabetes support and education (DSE).33 OSA severity is rated on an Apnea-Hypopnea Index (AHI), with scores reflecting the number of sleep apnea events per hour. This study demonstrated that weight loss was associated with decreased OSA severity. At 4-year follow-up, the greater the weight loss with ILI intervention, the lower the patients’ OSA severity scores. The study found an average decrease in AHI of 0.68 events per hour for every kilogram of weight loss in the ILI group (P < .0001).33,34 Over the follow-up visits, the ILI participants had 7.4 events per hour, a more significantly reduced AHI than the DSE participants (P < .0001).33,34
Additionally, a small cohort of study participants achieved OSA remission (ILI, 34.4%; DSE, 22.2%), indicated by a low AHI score (< 5 events per hour). At the conclusion of the study, OSA severity decreased to a greater degree with ILI intervention.33,34
Alcohol and drug use can negatively influence sleep patterns and obesity. Higher alcohol consumption is associated with poorer sleep quality and higher chances of developing short sleep duration and snoring.35 Alcohol, a muscle relaxant, causes upper airway narrowing and reduced tongue muscle tone, thereby increasing snoring and OSA as demonstrated by increased AHI on polysomnography after alcohol intake. Alcohol also changes sleep architecture by increasing slow-wave sleep, decreasing REM sleep duration, and increasing sleep arousal in the second half of the night.36 Disrupted circadian rhythm after alcohol consumption was correlated with increased adenosine neurotransmitters derived from ethanol metabolism.37 Alcohol dependence may be related to other psychiatric symptoms, and chronic alcohol use eventually alters sleep mechanisms leading to persistent insomnia, further perpetuating adverse outcomes such as suicidal ideation.36 There are positive associations between beer drinking and measures of abdominal adiposity in men, and “the combination of short sleep duration [and] disinhibited eating … is associated with greater alcohol intake and excess weight.”38
Therefore, counsel patients to avoid alcohol since it is a modifiable risk factor with pervasive adverse health effects.
Many drugs have a profound effect on sleep patterns. Illicit drug use in particular can affect the brain’s neurotransmitter serotonin system. For example, ecstasy users have an increased risk for OSA.39 People with cocaine and heroin use disorder tend to have more sleep-maintenance insomnia.40
Continue to: In contrast, those with alcohol...
In contrast, those with alcohol or cannabis use disorder tend to have more sleep-onset insomnia.40 Not only do illicit drugs interrupt sleep, but daily tobacco use also has been correlated with increased insomnia and shorter sleep duration since nicotine is a stimulant.41
Insomnia is commonly treated with sedative antidepressants and hypnotics—eg, mirtazapine and olanzapine—that contribute to weight gain.42 In addition, other common pharmaceuticals used for sleep disorders, such as diphenhydramine, have sedative properties and tend to lead to weight gain.43 Because so many medications affect sleep and weight, carefully review patients’ medication lists and switch offending agents to weight-neutral drugs if possible.
Treatment and tools to improve sleep in patients with obesity
Given the strong correlation between obesity and sleep disorders, validated screening tools should be used to assess sleep quality, including onset and potential symptoms associated with poor sleep (TABLE 144). For weight management to succeed in patients with obesity, it is crucial to address sleep in addition to nutrition and physical activity.17,45
Physical activity has many benefits to overall health, especially for chronic diseases such as type 2 diabetes and hypertension. The Centers for Disease Control and Prevention recommends at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic exercise per week in addition to muscle-strengthening activities 2 or more days per week.46 However, approximately 300 minutes of moderate-
Physical activity and diet in combination are vital, but diet restriction has a more substantial effect on weight loss than physical activity alone.48 Still, physical activity is essential in helping maintain and prevent weight regain.
Continue to: Nonpharmacologic interventions
Nonpharmacologic interventions include promoting greater sleep quality and quantity by emphasizing good sleep hygiene practices. Developing a practical and effective bedtime routine, creating a quiet sleep environment, and practicing healthy daily habits are essential components to sleep hygiene (TABLE 249,50). Relaxation techniques and cognitive behavioral therapy (CBT) also can help. CBT for insomnia (CBT-I) is the first-line intervention for chronic insomnia.51 Sleep restriction is a type of CBT used to treat insomnia, encouraging short-term sleep loss in the hopes of improving insomnia. A trial by Logue et al showed that patients with overweight and obesity randomized to undergo CBT with better sleep hygiene (nonpharmacologic) interventions had a greater mean weight loss percentage (5% vs 2%; P = .04) than did those who received CBT alone.52
Eastern medicine including herbal interventions lack evidence of efficacy and safety. Further studies need to be done on the effects that chamomile, kava, valerian root (Valeriana officinalis), tryptophan, and Wu Ling (from mycelia Xylaria nigripes) might have on sleep.53
Proceed cautiously with medication. The American College of Physicians recommends a shared decision-making approach when considering pharmacologic therapy for chronic insomnia and the American Academy of Sleep Medicine (AASM) offers guidance on options.51,54 However, the evidence behind AASM sleep pharmacologic recommendations is weak, implying a lesser degree of confidence in the outcome and, therefore, in its appropriateness. Thus, it falls upon the clinician and patient to weigh the benefits and burdens of the pharmacologic treatments of insomnia. If indicated, medications suggested to treat sleep onset and sleep maintenance insomnia are eszopiclone, zolpidem, and temazepam. Zaleplon, triazolam, and ramelteon may improve sleep initiation. Suvorexant and doxepin are used for sleep-maintenance insomnia.54 Exploring patient preferences, cost of treatment, health care options, and available resources should all be considered.
CORRESPONDENCE
Ecler Ercole Jaqua, MD, MBA, FAAFP, AGSF, FACLM, DipABOM, Loma Linda University Health, 25455 Barton Road, Suite 206A, Loma Linda, CA 92354; [email protected]
1. Aminoff MJ, Boller F, Swaab DF. We spend about one-third of our life either sleeping or attempting to do so. Handb Clin Neurol. 2011;98:vii. doi: 10.1016/B978-0-444-52006-7.00047-2
2. Watson NF, Badr MS, Belenky G, et al. Recommended amount of sleep for a healthy adult: a joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society. Sleep. 2015;38:843-844. doi: 10.5665/sleep.4716
3. CDC. Sleep and sleep disorders, adults. Accessed September 21, 2023. www.cdc.gov/sleep/data-and-statistics/adults.html
4. Chattu VK, Manzar MD, Kumary S. The global problem of insufficient sleep and its serious public health implications. Healthcare (Basel). 2019;7:1. doi: 10.3390/healthcare7010001
5. Taheri S, Lin L, Austin D, et al. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1:e62. doi: 10.1371/journal.pmed.0010062
6. Hafner M, Stepanek M, Taylor J, et al. Why sleep matters—the economic costs of insufficient sleep. Rand Health Q. 2017;6:11.
7. Hisler G, Twenge JM, Krizan Z. Associations between screen time and short sleep duration among adolescents varies by media type: evidence from a cohort study. Sleep Med. 2020;66:92-102. doi: 10.1016/j.sleep.2019.08.007
8. Ogilvie RP, Patel SR. The epidemiology of sleep and obesity. Sleep Health. 2017;3:383-388. doi: 10.1016/j.sleh.2017.07.013
9. CDC. Sleep and sleep disorders: How much sleep do I need? Accessed September 21, 2023. www.cdc.gov/sleep/about_sleep/how_much_sleep.html
10. van Egmond LT, Meth EMS, Engström J, et al. Effects of acute sleep loss on leptin, ghrelin, and adiponectin in adults with healthy weight and obesity: a laboratory study. Obesity (Silver Spring). 2023;31:635-641. doi: 10.1002/oby.23616
11. Spiegel K, Tasali E, Penev P, et al. Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141:846-850. doi: 10.7326/0003-4819-141-11-200412070-00008
12. Antza C, Kostopoulos G, Mostafa S, et al. The links between sleep duration, obesity and type 2 diabetes mellitus. J Endocrinol. 2021;252:125-141. doi: 10.1530/JOE-21-0155
13. Baron KG, Reid KJ, Kern AS, et al. Role of sleep timing in caloric intake and BMI. Obesity (Silver Spring). 2011;19:1374-1381. doi: 10.1038/oby.2011.100
14. Liu XY, Zheng CL, Xu C, et al. Nighttime snacking is associated with risk of obesity and hyperglycemia in adults: a cross-sectional survey from Chinese adult teachers J Biomed Res. 2017;31:541-547. doi: 10.7555/JBR.31.20160083
15. Cai Z, Yang Y, Zhang J, et al. The relationship between daytime napping and obesity: a systematic review and meta-analysis. Sci Rep. 2023.13:12124. doi: 10.1038/s41598-023-37883-7
16. Nedeltcheva AV, Kilkus JM, Imperial J, et al. Insufficient sleep undermines dietary efforts to reduce adiposity. Ann Intern Med. 2010;153:435-441. doi: 10.7326/0003-4819-153-7-201010050-00006
17. Chaput JP, Tremblay A. Adequate sleep to improve the treatment of obesity. CMAJ. 2012;184:1975-1976. doi: 10.1503/cmaj.120876
18. Kelsey MM, Zaepfel A, Bjornstad P, et al. Age-related consequences of childhood obesity. Gerontology. 2014;60:222-228. doi: 10.1159/000356023
19. Fryar CD, Carroll MD, Afful J. Prevalence of overweight, obesity, and severe obesity among children and adolescents aged 2-19 years: United States, 1963-1965 through 2017-2018. National Center for Health Statistics Health E-Stats. Updated January 29, 2021. Accessed September 21, 2021. www.cdc.gov/nchs/data/hestat/obesity-child-17-18/overweight-obesity-child-H.pdf
20. Fatima Y, Doi SAR, Mamun AA. Sleep quality and obesity in young subjects: a meta-analysis. Obes Rev. 2016;17:1154-1166. doi: 10.1111/obr.12444
21. Gohil A, Hannon TS. Poor sleep and obesity: concurrent epidemics in adolescent youth. Front Endocrinol. 2018;9:364. doi: 10.3389/fendo.2018.00364
22. Golley RK, Maher CA, Matricciani L, et al. Sleep duration or bedtime? Exploring the association between sleep timing behaviour, diet and BMI in children and adolescents. Int J Obes (Lond). 2013;37:546-551. doi: 10.1038/ijo.2012.212
23. Alessi CA. Sleep issues. In: Harper GM, Lyons WL, Potter JF, eds. Geriatrics Review Syllabus (GRS 10). Updated January 2021. Accessed August 29, 2023. http://geriatricscareonline.org
24. Patel SR, Blackwell T, Redline S, et al. The association between sleep duration and obesity in older adults. Int J Obes (Lond). 2008;32:1825-1834. doi: 10.1038/ijo.2008.198
25. Cai GH, Theorell-Haglöw J, Janson C, et al. Insomnia symptoms and sleep duration and their combined effects in relation to associations with obesity and central obesity. Sleep Med. 2018;46:81-87. doi: 10.1016/j.sleep.2018.03.009
26. Beccuti G, Pannain S. Sleep and obesity. Curr Opin Clin Nutr Metab Care. 2011;14:402-412. doi: 10.1097/MCO.0b013 e3283479109
27. Franklin KA, Lindberg E. Obstructive sleep apnea is a common disorder in the population–a review on the epidemiology of sleep apnea. J Thorac Dis. 2015;7:1311-1322. doi: 10.3978/j.issn.2072-1439.2015.06.11
28. USPSTF. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for obstructive sleep apnea in adults: US Preventive Services Task Force recommendation statement. JAMA. 2017;317:407-414. doi: 10.1001/jama.2016.20325
29. Goyal M, Johnson J. Obstructive sleep apnea diagnosis and management. Mo Med. 2017;114:120-124.
30. American Academy of Sleep Medicine. Hidden health crisis costing America billions: underdiagnosing and undertreating obstructive sleep apnea draining healthcare system. 2016. Accessed September 25, 2023. https://aasm.org/wp-content/uploads/2017/10/sleep-apnea-economic-crisis.pdf
31. Devaraj, NK. Knowledge, attitude, and practice regarding obstructive sleep apnea among primary care physicians. Sleep Breath. 2020;24:1581-1590. doi: 10.1007/s11325-020-02040-1
32. Mysliwiec V, Martin JL, Ulmer CS, et al. The management of chronic insomnia disorder and obstructive sleep apnea: synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guidelines. Ann Intern Med. 2020;172:325-336. doi: 10.7326/M19-3575
33. Kuna ST, Reboussin DM, Strotmeyer ES, et al. Effects of weight loss on obstructive sleep apnea severity. Ten-year results of the Sleep AHEAD study. Am J Respir Crit Care Med. 2021;203:221-229. doi: 10.1164/rccm.201912-2511OC
34. St-Onge MP, Tasali E. Weight loss is integral to obstructive sleep apnea management. Ten-year follow-up in Sleep AHEAD. Am J Respir Crit Care Med. 2021;203:161-162. doi: 10.1164/rccm.202007-2906ED
35. Zheng D, Yuan X, Ma C, et al. Alcohol consumption and sleep quality: a community-based study. Public Health Nutr. 2021;24:4851-4858. doi: 10.1017/S1368980020004553
36. Chakravorty S, Chaudhary NS, Brower KJ. Alcohol dependence and its relationship with insomnia and other sleep disorders. Alcohol Clin Exp Res. 2016;40:2271-2282. doi: 10.1111/acer.13217
37. Elmenhorst EM, Elmenhorst D, Benderoth S, et al. Cognitive impairments by alcohol and sleep deprivation indicate trait characteristics and a potential role for adenosine A1 receptors. Proc Natl Acad Sci U S A. 2018;115:8009-8014. doi: 10.1073/pnas.1803770115
38. Traversy G, Chaput JP. Alcohol consumption and obesity: an update. Curr Obes Rep. 2015;4:122-130. doi: 10.1007/s13679-014-0129-4
39. McCann UD, Sgambati FP, Schwartz AR, et al. Sleep apnea in young abstinent recreational MDMA (“ecstasy”) consumers. Neurology. 2009;73:2011-2017. doi: 10.1212/WNL.0b013e3181c51a62
40. Grau-López L, Grau-López L, Daigre C, et al. Insomnia symptoms in patients with substance use disorders during detoxification and associated clinical features. Front Psychiatry. 2020;11:540022. doi: 10.3389/fpsyt.2020.540022
41. Boehm MA, Lei QM, Lloyd RM, et al. Depression, anxiety, and tobacco use: overlapping impediments to sleep in a national sample of college students. J Am Coll Health. 2016;64:565-574. doi: 10.1080/07448481.2016.1205073
42. Gracious BL, Meyer AE. Psychotropic-induced weight gain and potential pharmacologic treatment strategies. Psychiatry (Edgmont). 2005;2:36-42.
43. Ratliff JC, Barber JA, Palmese LB, et al. Association of prescription H1 antihistamine use with obesity: results from the National Health and Nutrition Examination Survey. Obesity (Silver Spring). 2010;18:2398-2400. doi: 10.1038/oby.2010.176
44. Pataka A, Daskalopoulou E, Kalamaras G, et al. Evaluation of five different questionnaires for assessing sleep apnea syndrome in a sleep clinic. Sleep Med. 2014;15:776-781. doi: 10.1016/j.sleep.2014.03.012
45. Kline CE, Chasens ER, Bizhanova Z, et al. The association between sleep health and weight change during a 12-month behavioral weight loss intervention. Int J Obes (Lond). 2021;45:639-649. doi: 10.1038/s41366-020-00728-8
46. CDC. How much physical activity do adults need? Accessed August 23, 2023. www.cdc.gov/physicalactivity/basics/adults/index.htm
47. Flack KD, Hays HM, Moreland J, et al. Exercise for weight loss: further evaluating energy compensation with exercise. Med Sci Sports Exerc. 2020;52:2466-2475. doi: 10.1249/MSS.0000000000002376
48. Swift DL, Johannsen NM, Lavie CJ, et al. The role of exercise and physical activity in weight loss and maintenance. Prog Cardiovasc Dis. 2014;56:441-447. doi: 10.1016/j.pcad.2013.09.012
49. Irish LA, Kline CE, Gunn HE, et al. The role of sleep hygiene in promoting public health: a review of empirical evidence. Sleep Med Rev. 2015;22:23-36. doi: 10.1016/j.smrv.2014.10.001
50. CDC. Tips for better sleep. 2022. Accessed August 4, 2023. www.cdc.gov/sleep/about_sleep/sleep_hygiene.html
51. Qaseem A, Kansagara D, Forciea MA, et al. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165:125-133. doi: 10.7326/M15-2175
52. Logue EE, Bourguet CC, Palmieri PA, et al. The better weight-better sleep study: a pilot intervention in primary care. Am J Health Behav. 2012;36:319-334. doi: 10.5993/AJHB.36.3.4
53. Leach MJ, Page AT. Herbal medicine for insomnia: a systematic review and meta-analysis. Sleep Med Rev. 2015;24:1-12. doi: 10.1016/j.smrv.2014.12.003
54. Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13:307-349. doi: 10.5664/jcsm.6470
1. Aminoff MJ, Boller F, Swaab DF. We spend about one-third of our life either sleeping or attempting to do so. Handb Clin Neurol. 2011;98:vii. doi: 10.1016/B978-0-444-52006-7.00047-2
2. Watson NF, Badr MS, Belenky G, et al. Recommended amount of sleep for a healthy adult: a joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society. Sleep. 2015;38:843-844. doi: 10.5665/sleep.4716
3. CDC. Sleep and sleep disorders, adults. Accessed September 21, 2023. www.cdc.gov/sleep/data-and-statistics/adults.html
4. Chattu VK, Manzar MD, Kumary S. The global problem of insufficient sleep and its serious public health implications. Healthcare (Basel). 2019;7:1. doi: 10.3390/healthcare7010001
5. Taheri S, Lin L, Austin D, et al. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1:e62. doi: 10.1371/journal.pmed.0010062
6. Hafner M, Stepanek M, Taylor J, et al. Why sleep matters—the economic costs of insufficient sleep. Rand Health Q. 2017;6:11.
7. Hisler G, Twenge JM, Krizan Z. Associations between screen time and short sleep duration among adolescents varies by media type: evidence from a cohort study. Sleep Med. 2020;66:92-102. doi: 10.1016/j.sleep.2019.08.007
8. Ogilvie RP, Patel SR. The epidemiology of sleep and obesity. Sleep Health. 2017;3:383-388. doi: 10.1016/j.sleh.2017.07.013
9. CDC. Sleep and sleep disorders: How much sleep do I need? Accessed September 21, 2023. www.cdc.gov/sleep/about_sleep/how_much_sleep.html
10. van Egmond LT, Meth EMS, Engström J, et al. Effects of acute sleep loss on leptin, ghrelin, and adiponectin in adults with healthy weight and obesity: a laboratory study. Obesity (Silver Spring). 2023;31:635-641. doi: 10.1002/oby.23616
11. Spiegel K, Tasali E, Penev P, et al. Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141:846-850. doi: 10.7326/0003-4819-141-11-200412070-00008
12. Antza C, Kostopoulos G, Mostafa S, et al. The links between sleep duration, obesity and type 2 diabetes mellitus. J Endocrinol. 2021;252:125-141. doi: 10.1530/JOE-21-0155
13. Baron KG, Reid KJ, Kern AS, et al. Role of sleep timing in caloric intake and BMI. Obesity (Silver Spring). 2011;19:1374-1381. doi: 10.1038/oby.2011.100
14. Liu XY, Zheng CL, Xu C, et al. Nighttime snacking is associated with risk of obesity and hyperglycemia in adults: a cross-sectional survey from Chinese adult teachers J Biomed Res. 2017;31:541-547. doi: 10.7555/JBR.31.20160083
15. Cai Z, Yang Y, Zhang J, et al. The relationship between daytime napping and obesity: a systematic review and meta-analysis. Sci Rep. 2023.13:12124. doi: 10.1038/s41598-023-37883-7
16. Nedeltcheva AV, Kilkus JM, Imperial J, et al. Insufficient sleep undermines dietary efforts to reduce adiposity. Ann Intern Med. 2010;153:435-441. doi: 10.7326/0003-4819-153-7-201010050-00006
17. Chaput JP, Tremblay A. Adequate sleep to improve the treatment of obesity. CMAJ. 2012;184:1975-1976. doi: 10.1503/cmaj.120876
18. Kelsey MM, Zaepfel A, Bjornstad P, et al. Age-related consequences of childhood obesity. Gerontology. 2014;60:222-228. doi: 10.1159/000356023
19. Fryar CD, Carroll MD, Afful J. Prevalence of overweight, obesity, and severe obesity among children and adolescents aged 2-19 years: United States, 1963-1965 through 2017-2018. National Center for Health Statistics Health E-Stats. Updated January 29, 2021. Accessed September 21, 2021. www.cdc.gov/nchs/data/hestat/obesity-child-17-18/overweight-obesity-child-H.pdf
20. Fatima Y, Doi SAR, Mamun AA. Sleep quality and obesity in young subjects: a meta-analysis. Obes Rev. 2016;17:1154-1166. doi: 10.1111/obr.12444
21. Gohil A, Hannon TS. Poor sleep and obesity: concurrent epidemics in adolescent youth. Front Endocrinol. 2018;9:364. doi: 10.3389/fendo.2018.00364
22. Golley RK, Maher CA, Matricciani L, et al. Sleep duration or bedtime? Exploring the association between sleep timing behaviour, diet and BMI in children and adolescents. Int J Obes (Lond). 2013;37:546-551. doi: 10.1038/ijo.2012.212
23. Alessi CA. Sleep issues. In: Harper GM, Lyons WL, Potter JF, eds. Geriatrics Review Syllabus (GRS 10). Updated January 2021. Accessed August 29, 2023. http://geriatricscareonline.org
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PRACTICE RECOMMENDATIONS
› Consider cognitive behaviorial therapy for insomnia (CBT-I) first-line treatment for insomnia. A
› Carefully review patients’ medication lists, as many pharmaceuticals can affect weight and sleep. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
