Article

THE COMPARISON

A An 11-year-old Hispanic boy with allergic contact dermatitis (ACD) on the abdomen. The geometric nature of the eruption and proximity to the belt buckle were highly suggestive of ACD to nickel; patch testing was not needed.

B A Black woman with ACD on the neck. A punch biopsy demonstrated spongiotic dermatitis that was typical of ACD. The diagnosis was supported by the patient’s history of dermatitis that developed after new products were applied to the hair. The patient declined patch testing.

C A Hispanic man with ACD on hair-bearing areas of the face where hair dye was used. The patient’s history of dermatitis following the application of hair dye was highly suggestive of ACD; patch testing confirmed the allergen was paraphenylenediamine (PPD).

Allergic contact dermatitis (ACD) is an inflammatory condition of the skin caused by an immunologic response to 1 or more identifiable allergens. A delayed-type immune response (type IV hypersensitivity reaction) occurs after the skin is re-exposed to an offending allergen.¹ Severe pruritus is the main symptom of ACD in the early stages, accompanied by erythema, vesicles, and scaling in a distinct pattern corresponding to the allergen’s contact with the skin.² Delayed widespread dermatitis after exposure to an allergen—a phenomenon known as autoeczematization (id reaction)—also may occur.³

The gold-standard diagnostic tool for ACD is patch testing, in which the patient is re-exposed to the suspected contact allergen(s) and observed for the development of dermatitis.⁴ However, ACD can be diagnosed with a detailed patient history including occupation, hobbies, personal care practices, and possible triggers with subsequent rashes. Thorough clinical examination of the skin is paramount. Indicators of possible ACD include dermatitis that persists despite use of appropriate treatment, an unexplained flare of previously quiescent dermatitis, and a diagnosis of dermatitis without a clear cause.¹

Hairdressers, health care workers, and metal workers are at higher risk for ACD.⁵ Occupational ACD has notable socioeconomic implications, as it can result in frequent sick days, inability to perform tasks at work, and in some cases job loss.⁶

Patients with atopic dermatitis have impaired barrier function of the skin, permitting the entrance of allergens and subsequent sensitization.⁷ ACD is a challenge to manage, as complete avoidance of the allergen may not be possible.⁸

Continue to: The underrepresentation of patients...

The underrepresentation of patients with skin of color (SOC) in educational materials as well as socioeconomic health disparities may contribute to the lower rates of diagnosis, patch testing, and treatment of ACD in this patient population.

Epidemiology

An ACD prevalence of 15.2% was reported in a study of 793 Danish patients who underwent skin prick and patch testing.⁹ Alinaghi et al¹⁰ conducted a meta-analysis of 20,107 patients across 28 studies who were patch tested to determine the prevalence of ACD in the general population. The researchers concluded that 20.1% (95% CI, 16.8%-23.7%) of the general population experienced ACD. They analyzed 22 studies to determine the prevalence of ACD based on specific geographic area, including 18,709 individuals from Europe with a prevalence of 19.5% (95% CI, 15.8%-23.4%), 1639 individuals from North America with a prevalence of 20.6% (95% CI, 9.2%-35.2%), and 2 studies from China (no other studies from Asia found) with a prevalence of 20.6% (95% CI, 17.4%-23.9%). Researchers did not find data from studies conducted in Africa or South America.¹⁰

The current available epidemiologic data on ACD are not representative of SOC populations. DeLeo et al¹¹ looked at patch test reaction patterns in association with race and ethnicity in a large sample size (N = 19,457); 92.9% of these patients were White and only 7.1% were Black. Large-scale, inclusive studies are needed, which can only be achieved with increased suspicion for ACD and increased access to patch testing.

ACD is more common in women, with nickel being the most frequently identified allergen (FIGURE A).¹⁰ Personal care products often are linked to ACD (FIGURE B). An analysis of data from the North American Contact Dermatitis Group revealed that the top 5 personal care product allergens were methylisothiazolinone (a preservative), fragrance mix I, balsam of Peru, quaternium-15 (a preservative), and paraphenylenediamine (PPD; a common component of hair dye) (FIGURE C).¹²

There is a paucity of epidemiologic data among various ethnic groups; however, a few studies have suggested that there is no difference in the frequency rates of positive patch test results in Black vs White populations.^11,13,14 One study of patch test results from 114 Black patients and 877 White patients at the Cleveland Clinic Foundation in Ohio demonstrated a similar allergy frequency of 43.0% and 43.6%, respectively.13 However, there were differences in the types of allergen sensitization. Black patients had higher positive patch test rates for PPD than White patients (10.6% vs 4.5%). Black men had a higher frequency of sensitivity to PPD (21.2% vs 4.2%) and imidazolidinyl urea (a formaldehyde-releasing preservative; 9.1% vs 2.6%) compared to White men.¹³

Continue to: Ethnicity and cultural practices...

Ethnicity and cultural practices influence epidemiologic patterns of ACD. Darker hair dyes used in Black patients¹⁴ and deeply pigmented PPD dye found in henna tattoos used in Indian and Black patients¹⁵ may lead to increased sensitization to PPD. ACD due to formaldehyde is more common in White patients, possibly due to more frequent use of formaldehyde-containing moisturizers, shampoos, and creams.¹⁵

Key clinical features in people with darker skin tones

In patients with SOC, the clinical features of ACD vary, posing a diagnostic challenge. Hyperpigmentation, lichenification, and induration are more likely to be seen than the papules, vesicles, and erythematous dermatitis often described in lighter skin tones or acute ACD. Erythema can be difficult to assess on darker skin and may appear violaceous or very faint pink.16

Worth noting

A high index of suspicion is necessary when interpreting patch tests in patients with SOC, as patch test kits use a reading plate with graduated intensities of erythema, papulation, and vesicular reactions to determine the likelihood of ACD. The potential contact allergens are placed on the skin on Day 1 and covered. Then, on Day 3 the allergens are removed. The skin is clinically evaluated using visual assessment and skin palpation. The reactions are graded as negative, irritant reaction, equivocal, weak positive, strong positive, or extreme reaction at around Days 3 and 5 to capture both early and delayed reactions.¹⁷ A patch test may be positive even if obvious signs of erythema are not appreciated as expected.

ACD is more common in women, with nickel being the most frequently identified allergen.

Adjusting the lighting in the examination room, including side lighting, or using a blue background can be helpful in identifying erythema in darker skin tones.^15,16,18 Palpation of the skin also is useful, as even slight texture changes and induration are indicators of a possible skin reaction to the test allergen.¹⁵

Health disparity highlight

Clinical photographs of ACD and patch test results in patients with SOC are not commonplace in the literature. Positive patch test results in patients with darker skin tones vary from those of patients with lighter skin tones, and if the clinician reading the patch test result is not familiar with the findings in darker skin tones, the diagnosis may be delayed or missed.¹⁵

Continue to: Furthermore, Scott et al...

Furthermore, Scott et al¹⁵ highlighted that many dermatology residency training programs have a paucity of SOC education in their curriculum. This lack of representation may contribute to the diagnostic challenges encountered by health care providers.

The lower rates of patch testing in Black patients are likely due to the impact of social determinants of health.

Timely access to health care and education as well as economic stability are essential for the successful management of patients with ACD. Some individuals with SOC have been disproportionately affected by social determinants of health. Rodriguez-Homs et al¹⁹ demonstrated that the distance needed to travel to a clinic and the poverty rate of the county the patient lives in play a role in referral to a clinician specializing in contact dermatitis.

A retrospective registry review of 2310 patients undergoing patch testing at the Massachusetts General Hospital in Boston revealed that 2.5% were Black, 5.5% were Latinx, 8.3% were Asian, and the remaining 83.7% were White.²⁰ Qian et al²¹ also looked at patch testing patterns among various sociodemographic groups (N = 1,107,530) and found that 69% of patients were White and 59% were female. Rates of patch testing among patients who were Black, lesser educated, male, lower income, and younger (children ages 0-12 years) were significantly lower than for other groups when ACD was suspected (P < .0001).²¹ The lower rates of patch testing in patients with SOC may be due to low suspicion of diagnosis, low referral rates due to limited medical insurance, and financial instability, as well as other socioeconomic factors.²⁰

Tamazian et al¹⁶ reviewed pediatric populations at 13 US centers and found that Black children received patch testing less frequently than White and Hispanic children. Another review of pediatric patch testing in patients with SOC found that a less comprehensive panel of allergens was used in this population.²²

The key to resolution of ACD is removal of the offending antigen, and if patients are not being tested, then they risk having a prolonged and complicated course of ACD with a poor prognosis. Patients with SOC also experience greater negative psychosocial impact due to ACD disease burden.^21,23 The lower rates of patch testing in Black patients cannot solely be attributed to difficulty diagnosing ACD in darker skin tones; it is likely due to the impact of social determinants of health. Alleviating health disparities will improve patient outcomes and quality of life.

THE COMPARISON

A An 11-year-old Hispanic boy with allergic contact dermatitis (ACD) on the abdomen. The geometric nature of the eruption and proximity to the belt buckle were highly suggestive of ACD to nickel; patch testing was not needed.

B A Black woman with ACD on the neck. A punch biopsy demonstrated spongiotic dermatitis that was typical of ACD. The diagnosis was supported by the patient’s history of dermatitis that developed after new products were applied to the hair. The patient declined patch testing.

C A Hispanic man with ACD on hair-bearing areas of the face where hair dye was used. The patient’s history of dermatitis following the application of hair dye was highly suggestive of ACD; patch testing confirmed the allergen was paraphenylenediamine (PPD).

Allergic contact dermatitis (ACD) is an inflammatory condition of the skin caused by an immunologic response to 1 or more identifiable allergens. A delayed-type immune response (type IV hypersensitivity reaction) occurs after the skin is re-exposed to an offending allergen.¹ Severe pruritus is the main symptom of ACD in the early stages, accompanied by erythema, vesicles, and scaling in a distinct pattern corresponding to the allergen’s contact with the skin.² Delayed widespread dermatitis after exposure to an allergen—a phenomenon known as autoeczematization (id reaction)—also may occur.³

The gold-standard diagnostic tool for ACD is patch testing, in which the patient is re-exposed to the suspected contact allergen(s) and observed for the development of dermatitis.⁴ However, ACD can be diagnosed with a detailed patient history including occupation, hobbies, personal care practices, and possible triggers with subsequent rashes. Thorough clinical examination of the skin is paramount. Indicators of possible ACD include dermatitis that persists despite use of appropriate treatment, an unexplained flare of previously quiescent dermatitis, and a diagnosis of dermatitis without a clear cause.¹

Hairdressers, health care workers, and metal workers are at higher risk for ACD.⁵ Occupational ACD has notable socioeconomic implications, as it can result in frequent sick days, inability to perform tasks at work, and in some cases job loss.⁶

Patients with atopic dermatitis have impaired barrier function of the skin, permitting the entrance of allergens and subsequent sensitization.⁷ ACD is a challenge to manage, as complete avoidance of the allergen may not be possible.⁸

Continue to: The underrepresentation of patients...

The underrepresentation of patients with skin of color (SOC) in educational materials as well as socioeconomic health disparities may contribute to the lower rates of diagnosis, patch testing, and treatment of ACD in this patient population.

Epidemiology

An ACD prevalence of 15.2% was reported in a study of 793 Danish patients who underwent skin prick and patch testing.⁹ Alinaghi et al¹⁰ conducted a meta-analysis of 20,107 patients across 28 studies who were patch tested to determine the prevalence of ACD in the general population. The researchers concluded that 20.1% (95% CI, 16.8%-23.7%) of the general population experienced ACD. They analyzed 22 studies to determine the prevalence of ACD based on specific geographic area, including 18,709 individuals from Europe with a prevalence of 19.5% (95% CI, 15.8%-23.4%), 1639 individuals from North America with a prevalence of 20.6% (95% CI, 9.2%-35.2%), and 2 studies from China (no other studies from Asia found) with a prevalence of 20.6% (95% CI, 17.4%-23.9%). Researchers did not find data from studies conducted in Africa or South America.¹⁰

The current available epidemiologic data on ACD are not representative of SOC populations. DeLeo et al¹¹ looked at patch test reaction patterns in association with race and ethnicity in a large sample size (N = 19,457); 92.9% of these patients were White and only 7.1% were Black. Large-scale, inclusive studies are needed, which can only be achieved with increased suspicion for ACD and increased access to patch testing.

ACD is more common in women, with nickel being the most frequently identified allergen (FIGURE A).¹⁰ Personal care products often are linked to ACD (FIGURE B). An analysis of data from the North American Contact Dermatitis Group revealed that the top 5 personal care product allergens were methylisothiazolinone (a preservative), fragrance mix I, balsam of Peru, quaternium-15 (a preservative), and paraphenylenediamine (PPD; a common component of hair dye) (FIGURE C).¹²

There is a paucity of epidemiologic data among various ethnic groups; however, a few studies have suggested that there is no difference in the frequency rates of positive patch test results in Black vs White populations.^11,13,14 One study of patch test results from 114 Black patients and 877 White patients at the Cleveland Clinic Foundation in Ohio demonstrated a similar allergy frequency of 43.0% and 43.6%, respectively.13 However, there were differences in the types of allergen sensitization. Black patients had higher positive patch test rates for PPD than White patients (10.6% vs 4.5%). Black men had a higher frequency of sensitivity to PPD (21.2% vs 4.2%) and imidazolidinyl urea (a formaldehyde-releasing preservative; 9.1% vs 2.6%) compared to White men.¹³

Continue to: Ethnicity and cultural practices...

Ethnicity and cultural practices influence epidemiologic patterns of ACD. Darker hair dyes used in Black patients¹⁴ and deeply pigmented PPD dye found in henna tattoos used in Indian and Black patients¹⁵ may lead to increased sensitization to PPD. ACD due to formaldehyde is more common in White patients, possibly due to more frequent use of formaldehyde-containing moisturizers, shampoos, and creams.¹⁵

Key clinical features in people with darker skin tones

In patients with SOC, the clinical features of ACD vary, posing a diagnostic challenge. Hyperpigmentation, lichenification, and induration are more likely to be seen than the papules, vesicles, and erythematous dermatitis often described in lighter skin tones or acute ACD. Erythema can be difficult to assess on darker skin and may appear violaceous or very faint pink.16

Worth noting

A high index of suspicion is necessary when interpreting patch tests in patients with SOC, as patch test kits use a reading plate with graduated intensities of erythema, papulation, and vesicular reactions to determine the likelihood of ACD. The potential contact allergens are placed on the skin on Day 1 and covered. Then, on Day 3 the allergens are removed. The skin is clinically evaluated using visual assessment and skin palpation. The reactions are graded as negative, irritant reaction, equivocal, weak positive, strong positive, or extreme reaction at around Days 3 and 5 to capture both early and delayed reactions.¹⁷ A patch test may be positive even if obvious signs of erythema are not appreciated as expected.

ACD is more common in women, with nickel being the most frequently identified allergen.

Adjusting the lighting in the examination room, including side lighting, or using a blue background can be helpful in identifying erythema in darker skin tones.^15,16,18 Palpation of the skin also is useful, as even slight texture changes and induration are indicators of a possible skin reaction to the test allergen.¹⁵

Health disparity highlight

Clinical photographs of ACD and patch test results in patients with SOC are not commonplace in the literature. Positive patch test results in patients with darker skin tones vary from those of patients with lighter skin tones, and if the clinician reading the patch test result is not familiar with the findings in darker skin tones, the diagnosis may be delayed or missed.¹⁵

Continue to: Furthermore, Scott et al...

Furthermore, Scott et al¹⁵ highlighted that many dermatology residency training programs have a paucity of SOC education in their curriculum. This lack of representation may contribute to the diagnostic challenges encountered by health care providers.

The lower rates of patch testing in Black patients are likely due to the impact of social determinants of health.

Timely access to health care and education as well as economic stability are essential for the successful management of patients with ACD. Some individuals with SOC have been disproportionately affected by social determinants of health. Rodriguez-Homs et al¹⁹ demonstrated that the distance needed to travel to a clinic and the poverty rate of the county the patient lives in play a role in referral to a clinician specializing in contact dermatitis.

A retrospective registry review of 2310 patients undergoing patch testing at the Massachusetts General Hospital in Boston revealed that 2.5% were Black, 5.5% were Latinx, 8.3% were Asian, and the remaining 83.7% were White.²⁰ Qian et al²¹ also looked at patch testing patterns among various sociodemographic groups (N = 1,107,530) and found that 69% of patients were White and 59% were female. Rates of patch testing among patients who were Black, lesser educated, male, lower income, and younger (children ages 0-12 years) were significantly lower than for other groups when ACD was suspected (P < .0001).²¹ The lower rates of patch testing in patients with SOC may be due to low suspicion of diagnosis, low referral rates due to limited medical insurance, and financial instability, as well as other socioeconomic factors.²⁰

Tamazian et al¹⁶ reviewed pediatric populations at 13 US centers and found that Black children received patch testing less frequently than White and Hispanic children. Another review of pediatric patch testing in patients with SOC found that a less comprehensive panel of allergens was used in this population.²²

The key to resolution of ACD is removal of the offending antigen, and if patients are not being tested, then they risk having a prolonged and complicated course of ACD with a poor prognosis. Patients with SOC also experience greater negative psychosocial impact due to ACD disease burden.^21,23 The lower rates of patch testing in Black patients cannot solely be attributed to difficulty diagnosing ACD in darker skin tones; it is likely due to the impact of social determinants of health. Alleviating health disparities will improve patient outcomes and quality of life.

THE COMPARISON

A An 11-year-old Hispanic boy with allergic contact dermatitis (ACD) on the abdomen. The geometric nature of the eruption and proximity to the belt buckle were highly suggestive of ACD to nickel; patch testing was not needed.

B A Black woman with ACD on the neck. A punch biopsy demonstrated spongiotic dermatitis that was typical of ACD. The diagnosis was supported by the patient’s history of dermatitis that developed after new products were applied to the hair. The patient declined patch testing.

C A Hispanic man with ACD on hair-bearing areas of the face where hair dye was used. The patient’s history of dermatitis following the application of hair dye was highly suggestive of ACD; patch testing confirmed the allergen was paraphenylenediamine (PPD).

Allergic contact dermatitis (ACD) is an inflammatory condition of the skin caused by an immunologic response to 1 or more identifiable allergens. A delayed-type immune response (type IV hypersensitivity reaction) occurs after the skin is re-exposed to an offending allergen.¹ Severe pruritus is the main symptom of ACD in the early stages, accompanied by erythema, vesicles, and scaling in a distinct pattern corresponding to the allergen’s contact with the skin.² Delayed widespread dermatitis after exposure to an allergen—a phenomenon known as autoeczematization (id reaction)—also may occur.³

The gold-standard diagnostic tool for ACD is patch testing, in which the patient is re-exposed to the suspected contact allergen(s) and observed for the development of dermatitis.⁴ However, ACD can be diagnosed with a detailed patient history including occupation, hobbies, personal care practices, and possible triggers with subsequent rashes. Thorough clinical examination of the skin is paramount. Indicators of possible ACD include dermatitis that persists despite use of appropriate treatment, an unexplained flare of previously quiescent dermatitis, and a diagnosis of dermatitis without a clear cause.¹

Hairdressers, health care workers, and metal workers are at higher risk for ACD.⁵ Occupational ACD has notable socioeconomic implications, as it can result in frequent sick days, inability to perform tasks at work, and in some cases job loss.⁶

Patients with atopic dermatitis have impaired barrier function of the skin, permitting the entrance of allergens and subsequent sensitization.⁷ ACD is a challenge to manage, as complete avoidance of the allergen may not be possible.⁸

Continue to: The underrepresentation of patients...

The underrepresentation of patients with skin of color (SOC) in educational materials as well as socioeconomic health disparities may contribute to the lower rates of diagnosis, patch testing, and treatment of ACD in this patient population.

Epidemiology

An ACD prevalence of 15.2% was reported in a study of 793 Danish patients who underwent skin prick and patch testing.⁹ Alinaghi et al¹⁰ conducted a meta-analysis of 20,107 patients across 28 studies who were patch tested to determine the prevalence of ACD in the general population. The researchers concluded that 20.1% (95% CI, 16.8%-23.7%) of the general population experienced ACD. They analyzed 22 studies to determine the prevalence of ACD based on specific geographic area, including 18,709 individuals from Europe with a prevalence of 19.5% (95% CI, 15.8%-23.4%), 1639 individuals from North America with a prevalence of 20.6% (95% CI, 9.2%-35.2%), and 2 studies from China (no other studies from Asia found) with a prevalence of 20.6% (95% CI, 17.4%-23.9%). Researchers did not find data from studies conducted in Africa or South America.¹⁰

The current available epidemiologic data on ACD are not representative of SOC populations. DeLeo et al¹¹ looked at patch test reaction patterns in association with race and ethnicity in a large sample size (N = 19,457); 92.9% of these patients were White and only 7.1% were Black. Large-scale, inclusive studies are needed, which can only be achieved with increased suspicion for ACD and increased access to patch testing.

ACD is more common in women, with nickel being the most frequently identified allergen (FIGURE A).¹⁰ Personal care products often are linked to ACD (FIGURE B). An analysis of data from the North American Contact Dermatitis Group revealed that the top 5 personal care product allergens were methylisothiazolinone (a preservative), fragrance mix I, balsam of Peru, quaternium-15 (a preservative), and paraphenylenediamine (PPD; a common component of hair dye) (FIGURE C).¹²

There is a paucity of epidemiologic data among various ethnic groups; however, a few studies have suggested that there is no difference in the frequency rates of positive patch test results in Black vs White populations.^11,13,14 One study of patch test results from 114 Black patients and 877 White patients at the Cleveland Clinic Foundation in Ohio demonstrated a similar allergy frequency of 43.0% and 43.6%, respectively.13 However, there were differences in the types of allergen sensitization. Black patients had higher positive patch test rates for PPD than White patients (10.6% vs 4.5%). Black men had a higher frequency of sensitivity to PPD (21.2% vs 4.2%) and imidazolidinyl urea (a formaldehyde-releasing preservative; 9.1% vs 2.6%) compared to White men.¹³

Continue to: Ethnicity and cultural practices...

Ethnicity and cultural practices influence epidemiologic patterns of ACD. Darker hair dyes used in Black patients¹⁴ and deeply pigmented PPD dye found in henna tattoos used in Indian and Black patients¹⁵ may lead to increased sensitization to PPD. ACD due to formaldehyde is more common in White patients, possibly due to more frequent use of formaldehyde-containing moisturizers, shampoos, and creams.¹⁵

Key clinical features in people with darker skin tones

In patients with SOC, the clinical features of ACD vary, posing a diagnostic challenge. Hyperpigmentation, lichenification, and induration are more likely to be seen than the papules, vesicles, and erythematous dermatitis often described in lighter skin tones or acute ACD. Erythema can be difficult to assess on darker skin and may appear violaceous or very faint pink.16

Worth noting

A high index of suspicion is necessary when interpreting patch tests in patients with SOC, as patch test kits use a reading plate with graduated intensities of erythema, papulation, and vesicular reactions to determine the likelihood of ACD. The potential contact allergens are placed on the skin on Day 1 and covered. Then, on Day 3 the allergens are removed. The skin is clinically evaluated using visual assessment and skin palpation. The reactions are graded as negative, irritant reaction, equivocal, weak positive, strong positive, or extreme reaction at around Days 3 and 5 to capture both early and delayed reactions.¹⁷ A patch test may be positive even if obvious signs of erythema are not appreciated as expected.

ACD is more common in women, with nickel being the most frequently identified allergen.

Adjusting the lighting in the examination room, including side lighting, or using a blue background can be helpful in identifying erythema in darker skin tones.^15,16,18 Palpation of the skin also is useful, as even slight texture changes and induration are indicators of a possible skin reaction to the test allergen.¹⁵

Health disparity highlight

Clinical photographs of ACD and patch test results in patients with SOC are not commonplace in the literature. Positive patch test results in patients with darker skin tones vary from those of patients with lighter skin tones, and if the clinician reading the patch test result is not familiar with the findings in darker skin tones, the diagnosis may be delayed or missed.¹⁵

Continue to: Furthermore, Scott et al...

Furthermore, Scott et al¹⁵ highlighted that many dermatology residency training programs have a paucity of SOC education in their curriculum. This lack of representation may contribute to the diagnostic challenges encountered by health care providers.

The lower rates of patch testing in Black patients are likely due to the impact of social determinants of health.

Timely access to health care and education as well as economic stability are essential for the successful management of patients with ACD. Some individuals with SOC have been disproportionately affected by social determinants of health. Rodriguez-Homs et al¹⁹ demonstrated that the distance needed to travel to a clinic and the poverty rate of the county the patient lives in play a role in referral to a clinician specializing in contact dermatitis.

A retrospective registry review of 2310 patients undergoing patch testing at the Massachusetts General Hospital in Boston revealed that 2.5% were Black, 5.5% were Latinx, 8.3% were Asian, and the remaining 83.7% were White.²⁰ Qian et al²¹ also looked at patch testing patterns among various sociodemographic groups (N = 1,107,530) and found that 69% of patients were White and 59% were female. Rates of patch testing among patients who were Black, lesser educated, male, lower income, and younger (children ages 0-12 years) were significantly lower than for other groups when ACD was suspected (P < .0001).²¹ The lower rates of patch testing in patients with SOC may be due to low suspicion of diagnosis, low referral rates due to limited medical insurance, and financial instability, as well as other socioeconomic factors.²⁰

Tamazian et al¹⁶ reviewed pediatric populations at 13 US centers and found that Black children received patch testing less frequently than White and Hispanic children. Another review of pediatric patch testing in patients with SOC found that a less comprehensive panel of allergens was used in this population.²²

The key to resolution of ACD is removal of the offending antigen, and if patients are not being tested, then they risk having a prolonged and complicated course of ACD with a poor prognosis. Patients with SOC also experience greater negative psychosocial impact due to ACD disease burden.^21,23 The lower rates of patch testing in Black patients cannot solely be attributed to difficulty diagnosing ACD in darker skin tones; it is likely due to the impact of social determinants of health. Alleviating health disparities will improve patient outcomes and quality of life.

Question: What doubles every 2 months and takes more than a decade and a half to reach its ultimate destination?

Answer: Medical knowledge. 

In 2011, researchers projected that by 2020, medical knowledge would double every 73 days. Also in 2011, investigators estimated that clinical research takes 17 years to translate from bench to bedside. 

This “fast-slow” paradox became more relevant than ever in 2020, when the coronavirus pandemic brought the world to a near standstill. Stakeholders in undergraduate, postgraduate, and continuing medical education (CME) were suddenly faced with choices that had been discussed theoretically but not yet applied on a wide scale: How do we deliver education if in-person instruction is not an option? 

Organized medicine and the clinical community made choices based on groundwork that had been laid prior to the pandemic. The medical community acted quickly out of necessity, implementing novel learning methods that are now being utilized and that need to be assessed in an ongoing manner. 

The Backdrop

Medical education has long been dominated by an in-person, didactic model anchored in teacher-centered, classroom-based learning. This design has been firmly entrenched for more than 100 years, since the publication of the Flexner report in 1910, which established the standard of 4 years of medical education. Prior to 2020, many experts acknowledged that alternative practices and emerging technologies should play a role in medical education, but indecision abounded, perhaps because there was no real-world catalyst for reform. Thus, despite various attempts, the adoption of alternative forms of teaching moved slowly. 

Pre-pandemic efforts

In 2017, the American Medication Association issued a report calling for “one of the most complete curricular reforms since the Flexner Report.” It urged leaders to “rethink nearly every facet of physician training,” including “greater emphasis on new technology.” The report also suggested a 14-month pre-rotation program focused on the core medical knowledge necessary to practice in a hospital setting, along with work in a primary care setting once every other week. 

Before the pandemic, “blended learning” (digital and live) and “flipped classroom” approaches were assessed. A meta-analysis comparing a blended learning format to traditional classroom model programs found that blended learning resulted in better knowledge outcomes. In the flipped classroom approach, non-classroom individual or group activities replace in-class instruction after pre-class self-preparation with provided resources. A meta-analysis of 28 comparative studies showed that the flipped classroom approach resulted in improved learning compared to traditional methods. Additionally, bite-sized learning approaches have been implemented and evaluated, showing improvement in immediate knowledge recall. 

Barriers to widespread implementation

Despite the need to increase medical knowledge dissemination and implement approaches proven to do so effectively, barriers to adoption are well documented. Obstacles include time limitations, inadequate technical skills, insufficient infrastructure, and a wide variety in and range of expertise of both learners and institutional strategies. There are also differences in effective techniques for teaching various topics based on the content. Some topics require knowledge-based training, whereas others fall more easily into skills-based training. 

Additionally, when it comes to new evidence that needs to be translated to clinical evaluation and delivery, there is ongoing debate about the established peer-review process, which is rigorous but time-consuming vs the open-access publication process, which can disseminate information more quickly but is prone to error. 

Proposed solutions

Proposed solutions to these barriers include improving educator skills, offering incentives for innovative content development, cultivating better institutional strategies, and achieving buy-in from all stakeholders. Also important is thoughtful adaptation of content to various electronic formats, such as audiovisual presentation of educational material, social media content, and gamification of content, as well as ongoing assessment of both education delivery and consumption—followed by rapid pivoting when necessary. 

Despite these clearly identified challenges and thoughtful solutions, change was relatively slow until March 2020. 

The Trigger

With medical knowledge expanding so rapidly, imagine if medical education moved slowly or came to a complete halt when a worldwide pandemic was declared, the effects would have been catastrophic. COVID pushed organized medicine and the healthcare community to accelerate the adoption of novel technological approaches to keep the medical knowledge pipeline flowing at a relatively reasonable— if not ideal—rate. 

Challenges the pandemic produced, along with potential mitigation strategies, are outlined below.      

Economic consequences: The pandemic resulted in lost income for training programs and decreased funding for graduate medical education.

Possible solution: Creating budget allowances to adopt new technologies

Impact on diversity, equity, and inclusion: COVID-19 amplified existing implicit and explicit biases in society, particularly in the field of medicine. Women trainees and individuals from disadvantaged backgrounds were disproportionately impacted.

Possible solution: Creating programs that increase awareness of the subtle nature of implicit bias and the outsized impact it can have on certain segments of the population, and offering resources to mitigate stressors such as childcare and access to technology solutions

Impact on mental health and wellness: Working through the pandemic was challenging professionally, and the pandemic also exposed individuals to stigma, loneliness, and behavioral health issues (eg, mood and sleeping disorders), which created challenges in personal lives as well. These challenges lasted well over 2 years and have a clear ongoing impact.  

Possible solution: Providing accessible behavioral health resources, regularly assessing and addressing burnout, and regularly cycling trainees off of high-intensity rotations

Education delivery challenges: The sudden cancellation of in-person classes and training, from medical school lectures to rotations, created uncertainty. In-person rounds and bedside learning were significantly restricted. Moreover, as the need to perform clinical duties during the pandemic increased, time for teaching decreased. Some areas were more heavily impacted than others (eg, instruction around elective surgeries, outpatient medicine, and non-critical care training). 

Possible solution: Digitizing education delivery and developing other innovative methods to compensate for a lack of face-to-face instruction

Sudden need for rapid information dissemination: The limits of traditional peer review were tested during the pandemic. Managing individuals infected with the novel coronavirus created a situation where the clinical community needed scientific information quickly, increasing the risk of misinformation. 

Possible solution: Disseminating information as quickly as possible by leveraging public-private partnerships and government investment in high-quality science while maintaining peer review integrity to ensure rigorous evaluation

The Evidence

Early evidence is emerging about efforts undertaken during the pandemic to maintain adequate levels of preclinical learning, clinical training, and CME. 

Preclinical learning: Virtual formats are generally accepted, and interactive discussion is preferred. But be aware of potential stressors.

A cross-sectional study involving 173 histology and pathology students at European University Cyprus found that preclinical medical education is possible via virtual learning. The pandemic forced respondents to adapt immediately to emergency remote teaching. Survey results found the concept was generally well accepted, though some stressors (eg, poor internet connection) impacted perception. Most histology and pathology students (58% and 68%, respectively) said they would prefer blended learning in the future, compared with all-live (39% and 28%, respectively), or all-virtual (4% and 5%, respectively) classrooms. 

In a systematic review of 13 studies that compared digital learning with live classroom education for medical and nursing students, investigators from China found that standalone digital models are as effective as conventional modalities for improving knowledge and practice. Moreover, students preferred interactive discussion to a straight lecture format when participating online. 

Clinical training: Virtual clerkships work, but a blended approach seems preferable.

In a study involving 16 third-year medical students in the general surgery clerkship at Cleveland Clinic, respondents reported their experience before and after participating in a case-based virtual surgery clerkship program. Students were significantly more confident that they could independently assess a surgical consult after taking the course. Average scores of curriculum-based surgical knowledge increased as well. 

In an assessment of alternative approaches to clinical clerkships involving 42 students, investigators from China evaluated the impact of using simulated electronic health records (EHRs) for inpatient training and electronic problem-based learning and virtual interviews for outpatient training. Students using simulated EHRs felt it improved their ability to write in and summarize the record. Those who participated in electronic problem-based learning and virtual interviewing said their interviewing and counseling skills improved. However, students also noted traditional clinical clerkships are better for certain types of learning, suggesting that a blended approach is preferred. 

CME: Virtual CME is accepted and improves performance, but barriers remain, including a preference for face-to-face networking.

Researchers reviewed 2,007 post-activity responses from clinicians who participated in online CME at a South Korean hospital. Of the 1332 participants who reported their satisfaction level, 85% reported being satisfied with the format and content. Among all respondents, nearly 9 in 10 said that the content would influence the way they practice. Of the 611 participants who responded to a follow-up survey 3 months later, 78% said they made changes in their clinical practice based on what they learned. 

However, many clinicians prefer in-person CME. A Canadian-based memory clinic held 5 interprofessional education sessions and reported on participant experience; 3 of the sessions occurred live before March 2020 and 2 were held via videoconference once the pandemic was declared. Ratings of satisfaction, relevance, knowledge acquisition, and knowledge application were similar in both groups, but the virtual sessions were rated as less enjoyable and lacking in networking opportunities. In-person learning was preferred. 

Primary care clinicians in Portugal evaluated a CME digital platform and reported several barriers, including time constraints, perceived excessive work, lack of digital competence, lack of motivation, and emotional factors.      

The Future
Although challenges remain, changes due to the pandemic have been implemented in medical training and have shown preliminary success in certain domains. Medical education is rapidly evolving, and as we move further from the pandemic, diligent ongoing evaluation is needed to assess the best use of technology and various innovative teaching modalities. Keeping medical education learner-centered and instituting timely course correction if certain modalities of knowledge/skill delivery are found to be ineffective will be key to ensuring the robustness of training for future generations.   

Question: What doubles every 2 months and takes more than a decade and a half to reach its ultimate destination?

Answer: Medical knowledge. 

In 2011, researchers projected that by 2020, medical knowledge would double every 73 days. Also in 2011, investigators estimated that clinical research takes 17 years to translate from bench to bedside. 

This “fast-slow” paradox became more relevant than ever in 2020, when the coronavirus pandemic brought the world to a near standstill. Stakeholders in undergraduate, postgraduate, and continuing medical education (CME) were suddenly faced with choices that had been discussed theoretically but not yet applied on a wide scale: How do we deliver education if in-person instruction is not an option? 

Organized medicine and the clinical community made choices based on groundwork that had been laid prior to the pandemic. The medical community acted quickly out of necessity, implementing novel learning methods that are now being utilized and that need to be assessed in an ongoing manner. 

The Backdrop

Medical education has long been dominated by an in-person, didactic model anchored in teacher-centered, classroom-based learning. This design has been firmly entrenched for more than 100 years, since the publication of the Flexner report in 1910, which established the standard of 4 years of medical education. Prior to 2020, many experts acknowledged that alternative practices and emerging technologies should play a role in medical education, but indecision abounded, perhaps because there was no real-world catalyst for reform. Thus, despite various attempts, the adoption of alternative forms of teaching moved slowly. 

Pre-pandemic efforts

In 2017, the American Medication Association issued a report calling for “one of the most complete curricular reforms since the Flexner Report.” It urged leaders to “rethink nearly every facet of physician training,” including “greater emphasis on new technology.” The report also suggested a 14-month pre-rotation program focused on the core medical knowledge necessary to practice in a hospital setting, along with work in a primary care setting once every other week. 

Before the pandemic, “blended learning” (digital and live) and “flipped classroom” approaches were assessed. A meta-analysis comparing a blended learning format to traditional classroom model programs found that blended learning resulted in better knowledge outcomes. In the flipped classroom approach, non-classroom individual or group activities replace in-class instruction after pre-class self-preparation with provided resources. A meta-analysis of 28 comparative studies showed that the flipped classroom approach resulted in improved learning compared to traditional methods. Additionally, bite-sized learning approaches have been implemented and evaluated, showing improvement in immediate knowledge recall. 

Barriers to widespread implementation

Despite the need to increase medical knowledge dissemination and implement approaches proven to do so effectively, barriers to adoption are well documented. Obstacles include time limitations, inadequate technical skills, insufficient infrastructure, and a wide variety in and range of expertise of both learners and institutional strategies. There are also differences in effective techniques for teaching various topics based on the content. Some topics require knowledge-based training, whereas others fall more easily into skills-based training. 

Additionally, when it comes to new evidence that needs to be translated to clinical evaluation and delivery, there is ongoing debate about the established peer-review process, which is rigorous but time-consuming vs the open-access publication process, which can disseminate information more quickly but is prone to error. 

Proposed solutions

Proposed solutions to these barriers include improving educator skills, offering incentives for innovative content development, cultivating better institutional strategies, and achieving buy-in from all stakeholders. Also important is thoughtful adaptation of content to various electronic formats, such as audiovisual presentation of educational material, social media content, and gamification of content, as well as ongoing assessment of both education delivery and consumption—followed by rapid pivoting when necessary. 

Despite these clearly identified challenges and thoughtful solutions, change was relatively slow until March 2020. 

The Trigger

With medical knowledge expanding so rapidly, imagine if medical education moved slowly or came to a complete halt when a worldwide pandemic was declared, the effects would have been catastrophic. COVID pushed organized medicine and the healthcare community to accelerate the adoption of novel technological approaches to keep the medical knowledge pipeline flowing at a relatively reasonable— if not ideal—rate. 

Challenges the pandemic produced, along with potential mitigation strategies, are outlined below.      

Economic consequences: The pandemic resulted in lost income for training programs and decreased funding for graduate medical education.

Possible solution: Creating budget allowances to adopt new technologies

Impact on diversity, equity, and inclusion: COVID-19 amplified existing implicit and explicit biases in society, particularly in the field of medicine. Women trainees and individuals from disadvantaged backgrounds were disproportionately impacted.

Possible solution: Creating programs that increase awareness of the subtle nature of implicit bias and the outsized impact it can have on certain segments of the population, and offering resources to mitigate stressors such as childcare and access to technology solutions

Impact on mental health and wellness: Working through the pandemic was challenging professionally, and the pandemic also exposed individuals to stigma, loneliness, and behavioral health issues (eg, mood and sleeping disorders), which created challenges in personal lives as well. These challenges lasted well over 2 years and have a clear ongoing impact.  

Possible solution: Providing accessible behavioral health resources, regularly assessing and addressing burnout, and regularly cycling trainees off of high-intensity rotations

Education delivery challenges: The sudden cancellation of in-person classes and training, from medical school lectures to rotations, created uncertainty. In-person rounds and bedside learning were significantly restricted. Moreover, as the need to perform clinical duties during the pandemic increased, time for teaching decreased. Some areas were more heavily impacted than others (eg, instruction around elective surgeries, outpatient medicine, and non-critical care training). 

Possible solution: Digitizing education delivery and developing other innovative methods to compensate for a lack of face-to-face instruction

Sudden need for rapid information dissemination: The limits of traditional peer review were tested during the pandemic. Managing individuals infected with the novel coronavirus created a situation where the clinical community needed scientific information quickly, increasing the risk of misinformation. 

Possible solution: Disseminating information as quickly as possible by leveraging public-private partnerships and government investment in high-quality science while maintaining peer review integrity to ensure rigorous evaluation

The Evidence

Early evidence is emerging about efforts undertaken during the pandemic to maintain adequate levels of preclinical learning, clinical training, and CME. 

Preclinical learning: Virtual formats are generally accepted, and interactive discussion is preferred. But be aware of potential stressors.

A cross-sectional study involving 173 histology and pathology students at European University Cyprus found that preclinical medical education is possible via virtual learning. The pandemic forced respondents to adapt immediately to emergency remote teaching. Survey results found the concept was generally well accepted, though some stressors (eg, poor internet connection) impacted perception. Most histology and pathology students (58% and 68%, respectively) said they would prefer blended learning in the future, compared with all-live (39% and 28%, respectively), or all-virtual (4% and 5%, respectively) classrooms. 

In a systematic review of 13 studies that compared digital learning with live classroom education for medical and nursing students, investigators from China found that standalone digital models are as effective as conventional modalities for improving knowledge and practice. Moreover, students preferred interactive discussion to a straight lecture format when participating online. 

Clinical training: Virtual clerkships work, but a blended approach seems preferable.

In a study involving 16 third-year medical students in the general surgery clerkship at Cleveland Clinic, respondents reported their experience before and after participating in a case-based virtual surgery clerkship program. Students were significantly more confident that they could independently assess a surgical consult after taking the course. Average scores of curriculum-based surgical knowledge increased as well. 

In an assessment of alternative approaches to clinical clerkships involving 42 students, investigators from China evaluated the impact of using simulated electronic health records (EHRs) for inpatient training and electronic problem-based learning and virtual interviews for outpatient training. Students using simulated EHRs felt it improved their ability to write in and summarize the record. Those who participated in electronic problem-based learning and virtual interviewing said their interviewing and counseling skills improved. However, students also noted traditional clinical clerkships are better for certain types of learning, suggesting that a blended approach is preferred. 

CME: Virtual CME is accepted and improves performance, but barriers remain, including a preference for face-to-face networking.

Researchers reviewed 2,007 post-activity responses from clinicians who participated in online CME at a South Korean hospital. Of the 1332 participants who reported their satisfaction level, 85% reported being satisfied with the format and content. Among all respondents, nearly 9 in 10 said that the content would influence the way they practice. Of the 611 participants who responded to a follow-up survey 3 months later, 78% said they made changes in their clinical practice based on what they learned. 

However, many clinicians prefer in-person CME. A Canadian-based memory clinic held 5 interprofessional education sessions and reported on participant experience; 3 of the sessions occurred live before March 2020 and 2 were held via videoconference once the pandemic was declared. Ratings of satisfaction, relevance, knowledge acquisition, and knowledge application were similar in both groups, but the virtual sessions were rated as less enjoyable and lacking in networking opportunities. In-person learning was preferred. 

Primary care clinicians in Portugal evaluated a CME digital platform and reported several barriers, including time constraints, perceived excessive work, lack of digital competence, lack of motivation, and emotional factors.      

The Future
Although challenges remain, changes due to the pandemic have been implemented in medical training and have shown preliminary success in certain domains. Medical education is rapidly evolving, and as we move further from the pandemic, diligent ongoing evaluation is needed to assess the best use of technology and various innovative teaching modalities. Keeping medical education learner-centered and instituting timely course correction if certain modalities of knowledge/skill delivery are found to be ineffective will be key to ensuring the robustness of training for future generations.   

Question: What doubles every 2 months and takes more than a decade and a half to reach its ultimate destination?

Answer: Medical knowledge. 

In 2011, researchers projected that by 2020, medical knowledge would double every 73 days. Also in 2011, investigators estimated that clinical research takes 17 years to translate from bench to bedside. 

This “fast-slow” paradox became more relevant than ever in 2020, when the coronavirus pandemic brought the world to a near standstill. Stakeholders in undergraduate, postgraduate, and continuing medical education (CME) were suddenly faced with choices that had been discussed theoretically but not yet applied on a wide scale: How do we deliver education if in-person instruction is not an option? 

Organized medicine and the clinical community made choices based on groundwork that had been laid prior to the pandemic. The medical community acted quickly out of necessity, implementing novel learning methods that are now being utilized and that need to be assessed in an ongoing manner. 

The Backdrop

Medical education has long been dominated by an in-person, didactic model anchored in teacher-centered, classroom-based learning. This design has been firmly entrenched for more than 100 years, since the publication of the Flexner report in 1910, which established the standard of 4 years of medical education. Prior to 2020, many experts acknowledged that alternative practices and emerging technologies should play a role in medical education, but indecision abounded, perhaps because there was no real-world catalyst for reform. Thus, despite various attempts, the adoption of alternative forms of teaching moved slowly. 

Pre-pandemic efforts

In 2017, the American Medication Association issued a report calling for “one of the most complete curricular reforms since the Flexner Report.” It urged leaders to “rethink nearly every facet of physician training,” including “greater emphasis on new technology.” The report also suggested a 14-month pre-rotation program focused on the core medical knowledge necessary to practice in a hospital setting, along with work in a primary care setting once every other week. 

Before the pandemic, “blended learning” (digital and live) and “flipped classroom” approaches were assessed. A meta-analysis comparing a blended learning format to traditional classroom model programs found that blended learning resulted in better knowledge outcomes. In the flipped classroom approach, non-classroom individual or group activities replace in-class instruction after pre-class self-preparation with provided resources. A meta-analysis of 28 comparative studies showed that the flipped classroom approach resulted in improved learning compared to traditional methods. Additionally, bite-sized learning approaches have been implemented and evaluated, showing improvement in immediate knowledge recall. 

Barriers to widespread implementation

Despite the need to increase medical knowledge dissemination and implement approaches proven to do so effectively, barriers to adoption are well documented. Obstacles include time limitations, inadequate technical skills, insufficient infrastructure, and a wide variety in and range of expertise of both learners and institutional strategies. There are also differences in effective techniques for teaching various topics based on the content. Some topics require knowledge-based training, whereas others fall more easily into skills-based training. 

Additionally, when it comes to new evidence that needs to be translated to clinical evaluation and delivery, there is ongoing debate about the established peer-review process, which is rigorous but time-consuming vs the open-access publication process, which can disseminate information more quickly but is prone to error. 

Proposed solutions

Proposed solutions to these barriers include improving educator skills, offering incentives for innovative content development, cultivating better institutional strategies, and achieving buy-in from all stakeholders. Also important is thoughtful adaptation of content to various electronic formats, such as audiovisual presentation of educational material, social media content, and gamification of content, as well as ongoing assessment of both education delivery and consumption—followed by rapid pivoting when necessary. 

Despite these clearly identified challenges and thoughtful solutions, change was relatively slow until March 2020. 

The Trigger

With medical knowledge expanding so rapidly, imagine if medical education moved slowly or came to a complete halt when a worldwide pandemic was declared, the effects would have been catastrophic. COVID pushed organized medicine and the healthcare community to accelerate the adoption of novel technological approaches to keep the medical knowledge pipeline flowing at a relatively reasonable— if not ideal—rate. 

Challenges the pandemic produced, along with potential mitigation strategies, are outlined below.      

Economic consequences: The pandemic resulted in lost income for training programs and decreased funding for graduate medical education.

Possible solution: Creating budget allowances to adopt new technologies

Impact on diversity, equity, and inclusion: COVID-19 amplified existing implicit and explicit biases in society, particularly in the field of medicine. Women trainees and individuals from disadvantaged backgrounds were disproportionately impacted.

Possible solution: Creating programs that increase awareness of the subtle nature of implicit bias and the outsized impact it can have on certain segments of the population, and offering resources to mitigate stressors such as childcare and access to technology solutions

Impact on mental health and wellness: Working through the pandemic was challenging professionally, and the pandemic also exposed individuals to stigma, loneliness, and behavioral health issues (eg, mood and sleeping disorders), which created challenges in personal lives as well. These challenges lasted well over 2 years and have a clear ongoing impact.  

Possible solution: Providing accessible behavioral health resources, regularly assessing and addressing burnout, and regularly cycling trainees off of high-intensity rotations

Education delivery challenges: The sudden cancellation of in-person classes and training, from medical school lectures to rotations, created uncertainty. In-person rounds and bedside learning were significantly restricted. Moreover, as the need to perform clinical duties during the pandemic increased, time for teaching decreased. Some areas were more heavily impacted than others (eg, instruction around elective surgeries, outpatient medicine, and non-critical care training). 

Possible solution: Digitizing education delivery and developing other innovative methods to compensate for a lack of face-to-face instruction

Sudden need for rapid information dissemination: The limits of traditional peer review were tested during the pandemic. Managing individuals infected with the novel coronavirus created a situation where the clinical community needed scientific information quickly, increasing the risk of misinformation. 

Possible solution: Disseminating information as quickly as possible by leveraging public-private partnerships and government investment in high-quality science while maintaining peer review integrity to ensure rigorous evaluation

The Evidence

Early evidence is emerging about efforts undertaken during the pandemic to maintain adequate levels of preclinical learning, clinical training, and CME. 

Preclinical learning: Virtual formats are generally accepted, and interactive discussion is preferred. But be aware of potential stressors.

A cross-sectional study involving 173 histology and pathology students at European University Cyprus found that preclinical medical education is possible via virtual learning. The pandemic forced respondents to adapt immediately to emergency remote teaching. Survey results found the concept was generally well accepted, though some stressors (eg, poor internet connection) impacted perception. Most histology and pathology students (58% and 68%, respectively) said they would prefer blended learning in the future, compared with all-live (39% and 28%, respectively), or all-virtual (4% and 5%, respectively) classrooms. 

In a systematic review of 13 studies that compared digital learning with live classroom education for medical and nursing students, investigators from China found that standalone digital models are as effective as conventional modalities for improving knowledge and practice. Moreover, students preferred interactive discussion to a straight lecture format when participating online. 

Clinical training: Virtual clerkships work, but a blended approach seems preferable.

In a study involving 16 third-year medical students in the general surgery clerkship at Cleveland Clinic, respondents reported their experience before and after participating in a case-based virtual surgery clerkship program. Students were significantly more confident that they could independently assess a surgical consult after taking the course. Average scores of curriculum-based surgical knowledge increased as well. 

In an assessment of alternative approaches to clinical clerkships involving 42 students, investigators from China evaluated the impact of using simulated electronic health records (EHRs) for inpatient training and electronic problem-based learning and virtual interviews for outpatient training. Students using simulated EHRs felt it improved their ability to write in and summarize the record. Those who participated in electronic problem-based learning and virtual interviewing said their interviewing and counseling skills improved. However, students also noted traditional clinical clerkships are better for certain types of learning, suggesting that a blended approach is preferred. 

CME: Virtual CME is accepted and improves performance, but barriers remain, including a preference for face-to-face networking.

Researchers reviewed 2,007 post-activity responses from clinicians who participated in online CME at a South Korean hospital. Of the 1332 participants who reported their satisfaction level, 85% reported being satisfied with the format and content. Among all respondents, nearly 9 in 10 said that the content would influence the way they practice. Of the 611 participants who responded to a follow-up survey 3 months later, 78% said they made changes in their clinical practice based on what they learned. 

However, many clinicians prefer in-person CME. A Canadian-based memory clinic held 5 interprofessional education sessions and reported on participant experience; 3 of the sessions occurred live before March 2020 and 2 were held via videoconference once the pandemic was declared. Ratings of satisfaction, relevance, knowledge acquisition, and knowledge application were similar in both groups, but the virtual sessions were rated as less enjoyable and lacking in networking opportunities. In-person learning was preferred. 

Primary care clinicians in Portugal evaluated a CME digital platform and reported several barriers, including time constraints, perceived excessive work, lack of digital competence, lack of motivation, and emotional factors.      

The Future
Although challenges remain, changes due to the pandemic have been implemented in medical training and have shown preliminary success in certain domains. Medical education is rapidly evolving, and as we move further from the pandemic, diligent ongoing evaluation is needed to assess the best use of technology and various innovative teaching modalities. Keeping medical education learner-centered and instituting timely course correction if certain modalities of knowledge/skill delivery are found to be ineffective will be key to ensuring the robustness of training for future generations.   

VMS, also known as hot flashes, night sweats, or cold sweats, occur for the majority of perimenopausal and menopausal women.¹ In one study, the mean duration of clinically significant VMS was 5 years, and one-third of participants continued to have bothersome hot flashes 10 or more years after the onset of menopause.² VMS may contribute to disrupted sleep patterns and depressed mood.³

All obstetrician-gynecologists know that estradiol and other estrogens are highly effective in the treatment of bothersome VMS. A meta-analysis reported that the frequency of VMS was reduced by 60% to 80% with oral estradiol (1 mg/day), transdermal estradiol(0.05 mg/day), and conjugated estrogen (0.625 mg).⁴ Breast tenderness and irregular uterine bleeding are common side effects of estrogen treatment of VMS. Estrogen treatment is contraindicated in patients with estrogen-responsive cancers, coronary heart disease, myocardial infarction, stroke, venous thromboembolism, and some cases of inherited thrombophilia. For these patients, an important option is the nonhormonal treatment of VMS, and several nonhormonal medications have been demonstrated to be effective therapy (TABLE 1). In this editorial I will review the medication treatment of VMS with escitalopram, paroxetine, gabapentin, and fezolinetant.

Escitalopram and paroxetine

Escitalopram and paroxetine have been shown to reduce VMS more than placebo in multiple clinical trials.^5-10 In addition, escitalopram and paroxetine, at the doses tested, may be more effective for the treatment of VMS than sertraline, citalopram, or fluoxetine.¹¹ In one trial assessing the efficacy of escitalopram to treat VMS, 205 patients with VMS were randomly assigned to 8 weeks of treatment with placebo or escitalopram.⁵ The initial escitalopram dose was 10 mg daily. At week 4:

• if VMS frequency was reduced by ≥ 50%, the patient remained on the 10-mg dose
• if VMS frequency was reduced by < 50%, the escitalopram dose was increased to 20 mg daily.

Following 8 weeks of treatment, the frequency of VMS decreased for patients in the placebo and escitalopram groups by 33% and 47%, respectively. Similar results have been reported in other studies.⁶

Paroxetine at a dose of 7.5 mg/day administered at bedtime is approved by the US Food and Drug Administration (FDA) for the treatment of VMS. In a pivotal study, 1,112 patients with VMS were randomly assigned to receive a placebo or paroxetine 7.5 mg at bedtime.⁹ In the 12-week study the reported decrease in mean weekly frequency of VMS for patients in the placebo and paroxetine groups were -37 and -44, respectively.⁹ Paroxetine 7.5 mg also reduced awakenings per night attributed to VMS and increased nighttime sleep duration.¹⁰

Depressed mood is prevalent among perimenopausal and postmenopausal patients.¹² Prescribing escitalopram or paroxetine for VMS also may improve mood. Venlafaxine and desvenlafaxine are effective for the treatment of VMS;^13,14 however, I seldom prescribe these medications for VMS because in my experience they are associated with more bothersome side effects, including dry mouth, decreased appetite, nausea, and insomnia than escitalopram or low-dose paroxetine.

Continue to: Gabapentin...

Gabapentin

Numerous randomized clinical trials have reported that gabapentin is superior to placebo for the treatment of VMS.¹⁵ In one trial, 420 patients with breast cancer and VMS were randomly assigned to 8 weeks of treatment with placebo, gabapentin 300 mg/day (G300), or gabapentin 900 mg/day (G900) in 3 divided doses.¹⁶ Following 8 weeks of treatment, reduction in hot-flash severity score among patients receiving placebo, G300, or G900 was 15%, 31%, and 46%, respectively. Fatigue and somnolence were reported more frequently among patients taking gabapentin 900 mg/day. In a small trial, 60 patients with VMS were randomized to receive placebo, conjugated estrogen (0.2625 mg/day),or gabapentin (target dose of 2,400 mg/day in 3 divided doses).¹⁷ Following 12 weeks of treatment, the patient-reported decrease in VMS for those taking placebo, estrogen, or gabapentin was 54%, 72%, and 71%, respectively.

High-dose gabapentin treatment was associated with side effects of headache and dizziness more often than placebo or estrogen. Although gabapentin is not a treatment for insomnia, in my practice if a menopausal patient has prominent and bothersome symptoms of sleep disturbance and mild VMS symptoms, I will consider a trial of low-dose gabapentin. Some experts recommend initiating gabapentin at a dose of 100 mgdaily before bedtime to assess the effectiveness of a low dose that seldom causes significant side effects.

ILLUSTRATION: ZONDA/ZAZA STUDIO/SHUTTERSTOCK

Fezolinetant

In a study of genetic variation associated with VMS, investigators discovered that nucleic acid variation in the neurokinin 3 (NK3) receptor was strongly associated with the prevalence of VMS, suggesting that this receptor is in the causal pathway to menopausal VMS.¹⁸ Additional research demonstrated that the kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which are involved in the control of hypothalamic thermoregulation, are stimulated by neurokinin B, acting through the NK3 receptor, and suppressed by estradiol. A reduction in hypothalamic estrogen results in unopposed neurokinin B activity, which stimulates KNDy neurons, destabilizing the hypothalamic thermoregulatory center, causing vasodilation, which is perceived as hot flashes and sweating followed by chills.¹⁹

Fezolinetant is a high-affinity NK3 receptor antagonist that blocks the activity of neurokinin B, stabilizing the hypothalamic thermoregulatory center, thereby suppressing hot flashes. It is approved by the FDA for the treatment of moderate to severe VMS due to menopause using a fixed dose of 45 mg daily.²⁰ In one clinical trial, 500 menopausal patients with bothersome VMS were randomly assigned to 12 weeks of treatment with placebo, fezolinetant 30 mg/day, or fezolinetant 45 mg/day. Following 12 weeks of treatment, the reported frequency rates of VMS among patients in the placebo, F30, and F45 groups were reduced by 43%, 61%, and 64%, respectively.²¹ In addition, following 12 weeks of treatment, the severity of VMS rates among patients in the placebo, F30, and F45 groups were reduced by 20%, 26%, and 32%, respectively.

Fezolinetant improved the quality of sleep and was associated with an improvement in patient-reported quality of life. Following 12 weeks of treatment, sleep quality among patients in the placebo, F30, and F45 groups was reported to be “much or moderately better” in 34%, 45%, and 54% of the patients, respectively.²¹ Similar results were reported in a companion study.²²

Fezolinetant is contraindicated for patients with liver cirrhosis or severe renal impairment (estimated glomerular filtration rate of < 30 mL/min/1.73 m2). Before initiating treatment, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin (total and direct). Fezolinetant should not be prescribed if any of these tests are greater than twice the upper limit of normal. These tests should be repeated at 3, 6, and 9 months, and if the patient reports symptoms or signs of liver injury (nausea, vomiting, jaundice). Fezolinetant is metabolized by CYP1A2 and should not be prescribed to patients taking strong CYP1A2 inhibitors. The most common side effects associated with fezolinetant treatment are abdominal pain (4.3%), diarrhea (3.9%), insomnia (3.9%), back pain (3.0%), and hepatic transaminase elevation (2.3%). Fezolinetant has not been thoroughly evaluated in patients older than age 65. Following an oral dose of the medication, the median maximum concentration is reached in 1.5 hours, and the half-life is estimated to be 10 hours.²⁰ Of all the medications discussed in this editorial, fezolinetant is the most expensive.

Effective VMS treatment improves overall health

Estrogen therapy is the gold standard treatment of VMS. However, many menopausal patients with bothersome VMS prefer not to take estrogen, and some have a medical condition that is a contraindication to estrogen treatment. The nonhormonal medication options for the treatment of VMS include escitalopram, paroxetine, gabapentin, and fezolinetant. Patients value the ability to choose the treatment they prefer, among all available hormonal and nonhormonal medication options. For mid-life women, effectively treating bothersome VMS is only one of many interventions that improves health. Optimal health is best achieved with²³:

• high-quality diet
• daily physical activity
• appropriate body mass index
• nicotine avoidance
• a healthy sleep schedule
• normal blood pressure, lipid, and glucose levels.

Women who have a high-quality diet; daily physical activity; an appropriate body mass index; and normal blood pressure, cholesterol, and glucose levels are estimated to live 9 disease-free years longer than other women.²⁴ ●

VMS, also known as hot flashes, night sweats, or cold sweats, occur for the majority of perimenopausal and menopausal women.¹ In one study, the mean duration of clinically significant VMS was 5 years, and one-third of participants continued to have bothersome hot flashes 10 or more years after the onset of menopause.² VMS may contribute to disrupted sleep patterns and depressed mood.³

All obstetrician-gynecologists know that estradiol and other estrogens are highly effective in the treatment of bothersome VMS. A meta-analysis reported that the frequency of VMS was reduced by 60% to 80% with oral estradiol (1 mg/day), transdermal estradiol(0.05 mg/day), and conjugated estrogen (0.625 mg).⁴ Breast tenderness and irregular uterine bleeding are common side effects of estrogen treatment of VMS. Estrogen treatment is contraindicated in patients with estrogen-responsive cancers, coronary heart disease, myocardial infarction, stroke, venous thromboembolism, and some cases of inherited thrombophilia. For these patients, an important option is the nonhormonal treatment of VMS, and several nonhormonal medications have been demonstrated to be effective therapy (TABLE 1). In this editorial I will review the medication treatment of VMS with escitalopram, paroxetine, gabapentin, and fezolinetant.

Escitalopram and paroxetine

Escitalopram and paroxetine have been shown to reduce VMS more than placebo in multiple clinical trials.^5-10 In addition, escitalopram and paroxetine, at the doses tested, may be more effective for the treatment of VMS than sertraline, citalopram, or fluoxetine.¹¹ In one trial assessing the efficacy of escitalopram to treat VMS, 205 patients with VMS were randomly assigned to 8 weeks of treatment with placebo or escitalopram.⁵ The initial escitalopram dose was 10 mg daily. At week 4:

• if VMS frequency was reduced by ≥ 50%, the patient remained on the 10-mg dose
• if VMS frequency was reduced by < 50%, the escitalopram dose was increased to 20 mg daily.

Following 8 weeks of treatment, the frequency of VMS decreased for patients in the placebo and escitalopram groups by 33% and 47%, respectively. Similar results have been reported in other studies.⁶

Paroxetine at a dose of 7.5 mg/day administered at bedtime is approved by the US Food and Drug Administration (FDA) for the treatment of VMS. In a pivotal study, 1,112 patients with VMS were randomly assigned to receive a placebo or paroxetine 7.5 mg at bedtime.⁹ In the 12-week study the reported decrease in mean weekly frequency of VMS for patients in the placebo and paroxetine groups were -37 and -44, respectively.⁹ Paroxetine 7.5 mg also reduced awakenings per night attributed to VMS and increased nighttime sleep duration.¹⁰

Depressed mood is prevalent among perimenopausal and postmenopausal patients.¹² Prescribing escitalopram or paroxetine for VMS also may improve mood. Venlafaxine and desvenlafaxine are effective for the treatment of VMS;^13,14 however, I seldom prescribe these medications for VMS because in my experience they are associated with more bothersome side effects, including dry mouth, decreased appetite, nausea, and insomnia than escitalopram or low-dose paroxetine.

Continue to: Gabapentin...

Gabapentin

Numerous randomized clinical trials have reported that gabapentin is superior to placebo for the treatment of VMS.¹⁵ In one trial, 420 patients with breast cancer and VMS were randomly assigned to 8 weeks of treatment with placebo, gabapentin 300 mg/day (G300), or gabapentin 900 mg/day (G900) in 3 divided doses.¹⁶ Following 8 weeks of treatment, reduction in hot-flash severity score among patients receiving placebo, G300, or G900 was 15%, 31%, and 46%, respectively. Fatigue and somnolence were reported more frequently among patients taking gabapentin 900 mg/day. In a small trial, 60 patients with VMS were randomized to receive placebo, conjugated estrogen (0.2625 mg/day),or gabapentin (target dose of 2,400 mg/day in 3 divided doses).¹⁷ Following 12 weeks of treatment, the patient-reported decrease in VMS for those taking placebo, estrogen, or gabapentin was 54%, 72%, and 71%, respectively.

High-dose gabapentin treatment was associated with side effects of headache and dizziness more often than placebo or estrogen. Although gabapentin is not a treatment for insomnia, in my practice if a menopausal patient has prominent and bothersome symptoms of sleep disturbance and mild VMS symptoms, I will consider a trial of low-dose gabapentin. Some experts recommend initiating gabapentin at a dose of 100 mgdaily before bedtime to assess the effectiveness of a low dose that seldom causes significant side effects.

ILLUSTRATION: ZONDA/ZAZA STUDIO/SHUTTERSTOCK

Fezolinetant

In a study of genetic variation associated with VMS, investigators discovered that nucleic acid variation in the neurokinin 3 (NK3) receptor was strongly associated with the prevalence of VMS, suggesting that this receptor is in the causal pathway to menopausal VMS.¹⁸ Additional research demonstrated that the kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which are involved in the control of hypothalamic thermoregulation, are stimulated by neurokinin B, acting through the NK3 receptor, and suppressed by estradiol. A reduction in hypothalamic estrogen results in unopposed neurokinin B activity, which stimulates KNDy neurons, destabilizing the hypothalamic thermoregulatory center, causing vasodilation, which is perceived as hot flashes and sweating followed by chills.¹⁹

Fezolinetant is a high-affinity NK3 receptor antagonist that blocks the activity of neurokinin B, stabilizing the hypothalamic thermoregulatory center, thereby suppressing hot flashes. It is approved by the FDA for the treatment of moderate to severe VMS due to menopause using a fixed dose of 45 mg daily.²⁰ In one clinical trial, 500 menopausal patients with bothersome VMS were randomly assigned to 12 weeks of treatment with placebo, fezolinetant 30 mg/day, or fezolinetant 45 mg/day. Following 12 weeks of treatment, the reported frequency rates of VMS among patients in the placebo, F30, and F45 groups were reduced by 43%, 61%, and 64%, respectively.²¹ In addition, following 12 weeks of treatment, the severity of VMS rates among patients in the placebo, F30, and F45 groups were reduced by 20%, 26%, and 32%, respectively.

Fezolinetant improved the quality of sleep and was associated with an improvement in patient-reported quality of life. Following 12 weeks of treatment, sleep quality among patients in the placebo, F30, and F45 groups was reported to be “much or moderately better” in 34%, 45%, and 54% of the patients, respectively.²¹ Similar results were reported in a companion study.²²

Fezolinetant is contraindicated for patients with liver cirrhosis or severe renal impairment (estimated glomerular filtration rate of < 30 mL/min/1.73 m2). Before initiating treatment, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin (total and direct). Fezolinetant should not be prescribed if any of these tests are greater than twice the upper limit of normal. These tests should be repeated at 3, 6, and 9 months, and if the patient reports symptoms or signs of liver injury (nausea, vomiting, jaundice). Fezolinetant is metabolized by CYP1A2 and should not be prescribed to patients taking strong CYP1A2 inhibitors. The most common side effects associated with fezolinetant treatment are abdominal pain (4.3%), diarrhea (3.9%), insomnia (3.9%), back pain (3.0%), and hepatic transaminase elevation (2.3%). Fezolinetant has not been thoroughly evaluated in patients older than age 65. Following an oral dose of the medication, the median maximum concentration is reached in 1.5 hours, and the half-life is estimated to be 10 hours.²⁰ Of all the medications discussed in this editorial, fezolinetant is the most expensive.

Effective VMS treatment improves overall health

Estrogen therapy is the gold standard treatment of VMS. However, many menopausal patients with bothersome VMS prefer not to take estrogen, and some have a medical condition that is a contraindication to estrogen treatment. The nonhormonal medication options for the treatment of VMS include escitalopram, paroxetine, gabapentin, and fezolinetant. Patients value the ability to choose the treatment they prefer, among all available hormonal and nonhormonal medication options. For mid-life women, effectively treating bothersome VMS is only one of many interventions that improves health. Optimal health is best achieved with²³:

• high-quality diet
• daily physical activity
• appropriate body mass index
• nicotine avoidance
• a healthy sleep schedule
• normal blood pressure, lipid, and glucose levels.

Women who have a high-quality diet; daily physical activity; an appropriate body mass index; and normal blood pressure, cholesterol, and glucose levels are estimated to live 9 disease-free years longer than other women.²⁴ ●

VMS, also known as hot flashes, night sweats, or cold sweats, occur for the majority of perimenopausal and menopausal women.¹ In one study, the mean duration of clinically significant VMS was 5 years, and one-third of participants continued to have bothersome hot flashes 10 or more years after the onset of menopause.² VMS may contribute to disrupted sleep patterns and depressed mood.³

All obstetrician-gynecologists know that estradiol and other estrogens are highly effective in the treatment of bothersome VMS. A meta-analysis reported that the frequency of VMS was reduced by 60% to 80% with oral estradiol (1 mg/day), transdermal estradiol(0.05 mg/day), and conjugated estrogen (0.625 mg).⁴ Breast tenderness and irregular uterine bleeding are common side effects of estrogen treatment of VMS. Estrogen treatment is contraindicated in patients with estrogen-responsive cancers, coronary heart disease, myocardial infarction, stroke, venous thromboembolism, and some cases of inherited thrombophilia. For these patients, an important option is the nonhormonal treatment of VMS, and several nonhormonal medications have been demonstrated to be effective therapy (TABLE 1). In this editorial I will review the medication treatment of VMS with escitalopram, paroxetine, gabapentin, and fezolinetant.

Escitalopram and paroxetine

Escitalopram and paroxetine have been shown to reduce VMS more than placebo in multiple clinical trials.^5-10 In addition, escitalopram and paroxetine, at the doses tested, may be more effective for the treatment of VMS than sertraline, citalopram, or fluoxetine.¹¹ In one trial assessing the efficacy of escitalopram to treat VMS, 205 patients with VMS were randomly assigned to 8 weeks of treatment with placebo or escitalopram.⁵ The initial escitalopram dose was 10 mg daily. At week 4:

• if VMS frequency was reduced by ≥ 50%, the patient remained on the 10-mg dose
• if VMS frequency was reduced by < 50%, the escitalopram dose was increased to 20 mg daily.

Following 8 weeks of treatment, the frequency of VMS decreased for patients in the placebo and escitalopram groups by 33% and 47%, respectively. Similar results have been reported in other studies.⁶

Paroxetine at a dose of 7.5 mg/day administered at bedtime is approved by the US Food and Drug Administration (FDA) for the treatment of VMS. In a pivotal study, 1,112 patients with VMS were randomly assigned to receive a placebo or paroxetine 7.5 mg at bedtime.⁹ In the 12-week study the reported decrease in mean weekly frequency of VMS for patients in the placebo and paroxetine groups were -37 and -44, respectively.⁹ Paroxetine 7.5 mg also reduced awakenings per night attributed to VMS and increased nighttime sleep duration.¹⁰

Depressed mood is prevalent among perimenopausal and postmenopausal patients.¹² Prescribing escitalopram or paroxetine for VMS also may improve mood. Venlafaxine and desvenlafaxine are effective for the treatment of VMS;^13,14 however, I seldom prescribe these medications for VMS because in my experience they are associated with more bothersome side effects, including dry mouth, decreased appetite, nausea, and insomnia than escitalopram or low-dose paroxetine.

Continue to: Gabapentin...

Gabapentin

Numerous randomized clinical trials have reported that gabapentin is superior to placebo for the treatment of VMS.¹⁵ In one trial, 420 patients with breast cancer and VMS were randomly assigned to 8 weeks of treatment with placebo, gabapentin 300 mg/day (G300), or gabapentin 900 mg/day (G900) in 3 divided doses.¹⁶ Following 8 weeks of treatment, reduction in hot-flash severity score among patients receiving placebo, G300, or G900 was 15%, 31%, and 46%, respectively. Fatigue and somnolence were reported more frequently among patients taking gabapentin 900 mg/day. In a small trial, 60 patients with VMS were randomized to receive placebo, conjugated estrogen (0.2625 mg/day),or gabapentin (target dose of 2,400 mg/day in 3 divided doses).¹⁷ Following 12 weeks of treatment, the patient-reported decrease in VMS for those taking placebo, estrogen, or gabapentin was 54%, 72%, and 71%, respectively.

High-dose gabapentin treatment was associated with side effects of headache and dizziness more often than placebo or estrogen. Although gabapentin is not a treatment for insomnia, in my practice if a menopausal patient has prominent and bothersome symptoms of sleep disturbance and mild VMS symptoms, I will consider a trial of low-dose gabapentin. Some experts recommend initiating gabapentin at a dose of 100 mgdaily before bedtime to assess the effectiveness of a low dose that seldom causes significant side effects.

ILLUSTRATION: ZONDA/ZAZA STUDIO/SHUTTERSTOCK

Fezolinetant

In a study of genetic variation associated with VMS, investigators discovered that nucleic acid variation in the neurokinin 3 (NK3) receptor was strongly associated with the prevalence of VMS, suggesting that this receptor is in the causal pathway to menopausal VMS.¹⁸ Additional research demonstrated that the kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which are involved in the control of hypothalamic thermoregulation, are stimulated by neurokinin B, acting through the NK3 receptor, and suppressed by estradiol. A reduction in hypothalamic estrogen results in unopposed neurokinin B activity, which stimulates KNDy neurons, destabilizing the hypothalamic thermoregulatory center, causing vasodilation, which is perceived as hot flashes and sweating followed by chills.¹⁹

Fezolinetant is a high-affinity NK3 receptor antagonist that blocks the activity of neurokinin B, stabilizing the hypothalamic thermoregulatory center, thereby suppressing hot flashes. It is approved by the FDA for the treatment of moderate to severe VMS due to menopause using a fixed dose of 45 mg daily.²⁰ In one clinical trial, 500 menopausal patients with bothersome VMS were randomly assigned to 12 weeks of treatment with placebo, fezolinetant 30 mg/day, or fezolinetant 45 mg/day. Following 12 weeks of treatment, the reported frequency rates of VMS among patients in the placebo, F30, and F45 groups were reduced by 43%, 61%, and 64%, respectively.²¹ In addition, following 12 weeks of treatment, the severity of VMS rates among patients in the placebo, F30, and F45 groups were reduced by 20%, 26%, and 32%, respectively.

Fezolinetant improved the quality of sleep and was associated with an improvement in patient-reported quality of life. Following 12 weeks of treatment, sleep quality among patients in the placebo, F30, and F45 groups was reported to be “much or moderately better” in 34%, 45%, and 54% of the patients, respectively.²¹ Similar results were reported in a companion study.²²

Fezolinetant is contraindicated for patients with liver cirrhosis or severe renal impairment (estimated glomerular filtration rate of < 30 mL/min/1.73 m2). Before initiating treatment, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin (total and direct). Fezolinetant should not be prescribed if any of these tests are greater than twice the upper limit of normal. These tests should be repeated at 3, 6, and 9 months, and if the patient reports symptoms or signs of liver injury (nausea, vomiting, jaundice). Fezolinetant is metabolized by CYP1A2 and should not be prescribed to patients taking strong CYP1A2 inhibitors. The most common side effects associated with fezolinetant treatment are abdominal pain (4.3%), diarrhea (3.9%), insomnia (3.9%), back pain (3.0%), and hepatic transaminase elevation (2.3%). Fezolinetant has not been thoroughly evaluated in patients older than age 65. Following an oral dose of the medication, the median maximum concentration is reached in 1.5 hours, and the half-life is estimated to be 10 hours.²⁰ Of all the medications discussed in this editorial, fezolinetant is the most expensive.

Effective VMS treatment improves overall health

Estrogen therapy is the gold standard treatment of VMS. However, many menopausal patients with bothersome VMS prefer not to take estrogen, and some have a medical condition that is a contraindication to estrogen treatment. The nonhormonal medication options for the treatment of VMS include escitalopram, paroxetine, gabapentin, and fezolinetant. Patients value the ability to choose the treatment they prefer, among all available hormonal and nonhormonal medication options. For mid-life women, effectively treating bothersome VMS is only one of many interventions that improves health. Optimal health is best achieved with²³:

• high-quality diet
• daily physical activity
• appropriate body mass index
• nicotine avoidance
• a healthy sleep schedule
• normal blood pressure, lipid, and glucose levels.

Women who have a high-quality diet; daily physical activity; an appropriate body mass index; and normal blood pressure, cholesterol, and glucose levels are estimated to live 9 disease-free years longer than other women.²⁴ ●

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

ILLUSTRATIVE CASE

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

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

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

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

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

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

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

Continue to: In this 2022 systematic review...

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

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

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

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

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

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

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

Continue to: Only 2 of the studes...

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

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

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

CAVEATS

Some patient populations, comorbidities excluded from study

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

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

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

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

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

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

ILLUSTRATIVE CASE

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

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

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

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

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

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

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

Continue to: In this 2022 systematic review...

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

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

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

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

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

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

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

Continue to: Only 2 of the studes...

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

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

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

CAVEATS

Some patient populations, comorbidities excluded from study

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

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

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

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

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

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

ILLUSTRATIVE CASE

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

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

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

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

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

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

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

Continue to: In this 2022 systematic review...

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

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

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

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

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

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

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

Continue to: Only 2 of the studes...

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

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

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

CAVEATS

Some patient populations, comorbidities excluded from study

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

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

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

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

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

THE CASE

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

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

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

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

THE DIAGNOSIS

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

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

DISCUSSION

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

Continue to: The development of antiphospholipid antibodies...

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

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

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

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

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

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

Continue to: Treatment is focused on resolved the autoimmune condition

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

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

THE TAKEAWAY

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

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

THE CASE

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

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

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

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

THE DIAGNOSIS

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

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

DISCUSSION

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

Continue to: The development of antiphospholipid antibodies...

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

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

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

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

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

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

Continue to: Treatment is focused on resolved the autoimmune condition

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

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

THE TAKEAWAY

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

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

THE CASE

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

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

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

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

THE DIAGNOSIS

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

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

DISCUSSION

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

Continue to: The development of antiphospholipid antibodies...

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

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

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

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

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

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

Continue to: Treatment is focused on resolved the autoimmune condition

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

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

THE TAKEAWAY

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

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

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

When should flu vaccine be administered?

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

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

What’s in this year’s vaccines?

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

Should you take special precautions with egg allergy?

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

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

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

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

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

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

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

When should flu vaccine be administered?

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

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

What’s in this year’s vaccines?

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

Should you take special precautions with egg allergy?

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

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

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

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

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

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

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

When should flu vaccine be administered?

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

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

What’s in this year’s vaccines?

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

Should you take special precautions with egg allergy?

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

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

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

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

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

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

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.

Poor sleep will increase the risk for obesity and hinder its treatment. Therefore, sleep quality and duration are vital components of obesity management.

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 pm¹³; late-night snacks are a part of this sleep–obesity equation.¹⁴

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.

It is a cycle of poor sleep causing obesity and obesity causing poor sleep.

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

Approximately half of primary care clinicians do not screen at-risk patients for OSA, and 90% do not use validated OSA screening tools.

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

It falls upon the clinician and patient to weigh the benefits and burdens of the pharmacologic treatments of insomnia.

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-intensity activity per week is suggested for successful weight loss with exercise alone.⁴⁷

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 2^49,50). 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.

Poor sleep will increase the risk for obesity and hinder its treatment. Therefore, sleep quality and duration are vital components of obesity management.

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 pm¹³; late-night snacks are a part of this sleep–obesity equation.¹⁴

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.

It is a cycle of poor sleep causing obesity and obesity causing poor sleep.

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

Approximately half of primary care clinicians do not screen at-risk patients for OSA, and 90% do not use validated OSA screening tools.

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

It falls upon the clinician and patient to weigh the benefits and burdens of the pharmacologic treatments of insomnia.

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-intensity activity per week is suggested for successful weight loss with exercise alone.⁴⁷

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 2^49,50). 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.

Poor sleep will increase the risk for obesity and hinder its treatment. Therefore, sleep quality and duration are vital components of obesity management.

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 pm¹³; late-night snacks are a part of this sleep–obesity equation.¹⁴

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.

It is a cycle of poor sleep causing obesity and obesity causing poor sleep.

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

Approximately half of primary care clinicians do not screen at-risk patients for OSA, and 90% do not use validated OSA screening tools.

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

It falls upon the clinician and patient to weigh the benefits and burdens of the pharmacologic treatments of insomnia.

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-intensity activity per week is suggested for successful weight loss with exercise alone.⁴⁷

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 2^49,50). 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]

The Diagnosis: Mycobacterium abscessus Infection

Upon further testing, cultures were positive for Mycobacterium abscessus. Our patient was referred to infectious disease for co-management, and his treatment plan consisted of intravenous amikacin 885 mg 3 times weekly, intravenous imipenem 1 g twice daily, azithromycin 500 mg/d, and omadacycline 150 mg/d for at least 3 months. Magnetic resonance imaging findings were consistent with a combination of cellulitis and osteomyelitis, and our patient was referred to plastic surgery for debridement. He subsequently was lost to follow-up.

Mycobacterium abscessus is classified as both a nontuberculous and rapidly growing mycobacterium. Mycobacterium abscessus recently has emerged as a pathogen of increasing public health concern, especially due to its high rate of antibiotic resistance.^1-5 It is highly prevalent in the environment, and infection has been reported from a wide variety of environmental sources.^6-8 Immunocompromised individuals, such as our patient, undergoing anti–tumor necrosis factor therapy are at increased risk for infection from all Mycobacterium species.^9-11 Recognizing these infections quickly is a priority for patient care, as M abscessus can lead to disseminated infection and high mortality rates.¹

Histopathology of M abscessus consists of granulomatous inflammation with mixed granulomas¹²; however, these findings are not always appreciable, and staining does not always reveal visible organisms. In our patient, histopathology revealed patchy plasmalymphocytic infiltrates of the dermis and subcutaneous tissue, which are signs of generalized inflammation (Figure). Therefore, cultures positive for M abscessus are the gold standard for diagnosis and established the diagnosis in this case.

The differential diagnoses for our patient’s ulceration included squamous cell carcinoma, pyoderma gangrenosum, aseptic abscess ulcer, and pyodermatitispyostomatitis vegetans. Immunosuppressive therapy is a risk factor for squamous cell carcinoma^13,14; however, ulcerated squamous cell carcinoma typically presents with prominent everted edges with a necrotic tumor base.¹⁵ Biopsy reveals cells with abundant eosinophilic cytoplasm, large nuclei, and variable keratin pearls.¹⁶ Pyoderma gangrenosum is an inflammatory skin condition associated with Crohn disease and often is a diagnosis of exclusion characterized by neutrophilic infiltrates on biopsy.^17-19 Aseptic abscess ulcers are characterized by neutrophil-filled lesions that respond to corticosteroids but not antibiotics.²⁰ Pyodermatitis-pyostomatitis vegetans is a rare skin manifestation of inflammatory bowel disease associated with a pustular eruption of the skin and/or mouth. Histopathology reveals pustules within or below the epidermis with many eosinophils or neutrophils. Granulomas do not occur as in M abscessus.²¹

Treatment of M abscessus infection requires the coadministration of several antibiotics across multiple classes to ensure complete disease resolution. High rates of antibiotic resistance are characterized by at least partial resistance to almost every antibiotic; clarithromycin has near-complete efficacy, but resistant strains have started to emerge. Amikacin and cefoxitin are other antibiotics that have reported a resistance rate of less than 50%, but they are only effective 90% and 70% of the time, respectively.^1,22 The antibiotic omadacycline, which is approved by the US Food and Drug Administration to treat acute bacterial skin and soft-tissue infections, also may have utility in treating M abscessus infections.^23,24 Finally, phage therapy may offer a potential mode of treatment for this bacterium and was used to treat pulmonary infection in a patient with cystic fibrosis.²⁵ Despite these newer innovations, the current standard of care involves clarithromycin or azithromycin in combination with a parenteral antibiotic such as cefoxitin, amikacin, or imipenem for at least 4 months.¹

The Diagnosis: Mycobacterium abscessus Infection

Upon further testing, cultures were positive for Mycobacterium abscessus. Our patient was referred to infectious disease for co-management, and his treatment plan consisted of intravenous amikacin 885 mg 3 times weekly, intravenous imipenem 1 g twice daily, azithromycin 500 mg/d, and omadacycline 150 mg/d for at least 3 months. Magnetic resonance imaging findings were consistent with a combination of cellulitis and osteomyelitis, and our patient was referred to plastic surgery for debridement. He subsequently was lost to follow-up.

Mycobacterium abscessus is classified as both a nontuberculous and rapidly growing mycobacterium. Mycobacterium abscessus recently has emerged as a pathogen of increasing public health concern, especially due to its high rate of antibiotic resistance.^1-5 It is highly prevalent in the environment, and infection has been reported from a wide variety of environmental sources.^6-8 Immunocompromised individuals, such as our patient, undergoing anti–tumor necrosis factor therapy are at increased risk for infection from all Mycobacterium species.^9-11 Recognizing these infections quickly is a priority for patient care, as M abscessus can lead to disseminated infection and high mortality rates.¹

Histopathology of M abscessus consists of granulomatous inflammation with mixed granulomas¹²; however, these findings are not always appreciable, and staining does not always reveal visible organisms. In our patient, histopathology revealed patchy plasmalymphocytic infiltrates of the dermis and subcutaneous tissue, which are signs of generalized inflammation (Figure). Therefore, cultures positive for M abscessus are the gold standard for diagnosis and established the diagnosis in this case.

The differential diagnoses for our patient’s ulceration included squamous cell carcinoma, pyoderma gangrenosum, aseptic abscess ulcer, and pyodermatitispyostomatitis vegetans. Immunosuppressive therapy is a risk factor for squamous cell carcinoma^13,14; however, ulcerated squamous cell carcinoma typically presents with prominent everted edges with a necrotic tumor base.¹⁵ Biopsy reveals cells with abundant eosinophilic cytoplasm, large nuclei, and variable keratin pearls.¹⁶ Pyoderma gangrenosum is an inflammatory skin condition associated with Crohn disease and often is a diagnosis of exclusion characterized by neutrophilic infiltrates on biopsy.^17-19 Aseptic abscess ulcers are characterized by neutrophil-filled lesions that respond to corticosteroids but not antibiotics.²⁰ Pyodermatitis-pyostomatitis vegetans is a rare skin manifestation of inflammatory bowel disease associated with a pustular eruption of the skin and/or mouth. Histopathology reveals pustules within or below the epidermis with many eosinophils or neutrophils. Granulomas do not occur as in M abscessus.²¹

Treatment of M abscessus infection requires the coadministration of several antibiotics across multiple classes to ensure complete disease resolution. High rates of antibiotic resistance are characterized by at least partial resistance to almost every antibiotic; clarithromycin has near-complete efficacy, but resistant strains have started to emerge. Amikacin and cefoxitin are other antibiotics that have reported a resistance rate of less than 50%, but they are only effective 90% and 70% of the time, respectively.^1,22 The antibiotic omadacycline, which is approved by the US Food and Drug Administration to treat acute bacterial skin and soft-tissue infections, also may have utility in treating M abscessus infections.^23,24 Finally, phage therapy may offer a potential mode of treatment for this bacterium and was used to treat pulmonary infection in a patient with cystic fibrosis.²⁵ Despite these newer innovations, the current standard of care involves clarithromycin or azithromycin in combination with a parenteral antibiotic such as cefoxitin, amikacin, or imipenem for at least 4 months.¹

The Diagnosis: Mycobacterium abscessus Infection

Upon further testing, cultures were positive for Mycobacterium abscessus. Our patient was referred to infectious disease for co-management, and his treatment plan consisted of intravenous amikacin 885 mg 3 times weekly, intravenous imipenem 1 g twice daily, azithromycin 500 mg/d, and omadacycline 150 mg/d for at least 3 months. Magnetic resonance imaging findings were consistent with a combination of cellulitis and osteomyelitis, and our patient was referred to plastic surgery for debridement. He subsequently was lost to follow-up.

Mycobacterium abscessus is classified as both a nontuberculous and rapidly growing mycobacterium. Mycobacterium abscessus recently has emerged as a pathogen of increasing public health concern, especially due to its high rate of antibiotic resistance.^1-5 It is highly prevalent in the environment, and infection has been reported from a wide variety of environmental sources.^6-8 Immunocompromised individuals, such as our patient, undergoing anti–tumor necrosis factor therapy are at increased risk for infection from all Mycobacterium species.^9-11 Recognizing these infections quickly is a priority for patient care, as M abscessus can lead to disseminated infection and high mortality rates.¹

Histopathology of M abscessus consists of granulomatous inflammation with mixed granulomas¹²; however, these findings are not always appreciable, and staining does not always reveal visible organisms. In our patient, histopathology revealed patchy plasmalymphocytic infiltrates of the dermis and subcutaneous tissue, which are signs of generalized inflammation (Figure). Therefore, cultures positive for M abscessus are the gold standard for diagnosis and established the diagnosis in this case.

The differential diagnoses for our patient’s ulceration included squamous cell carcinoma, pyoderma gangrenosum, aseptic abscess ulcer, and pyodermatitispyostomatitis vegetans. Immunosuppressive therapy is a risk factor for squamous cell carcinoma^13,14; however, ulcerated squamous cell carcinoma typically presents with prominent everted edges with a necrotic tumor base.¹⁵ Biopsy reveals cells with abundant eosinophilic cytoplasm, large nuclei, and variable keratin pearls.¹⁶ Pyoderma gangrenosum is an inflammatory skin condition associated with Crohn disease and often is a diagnosis of exclusion characterized by neutrophilic infiltrates on biopsy.^17-19 Aseptic abscess ulcers are characterized by neutrophil-filled lesions that respond to corticosteroids but not antibiotics.²⁰ Pyodermatitis-pyostomatitis vegetans is a rare skin manifestation of inflammatory bowel disease associated with a pustular eruption of the skin and/or mouth. Histopathology reveals pustules within or below the epidermis with many eosinophils or neutrophils. Granulomas do not occur as in M abscessus.²¹

Treatment of M abscessus infection requires the coadministration of several antibiotics across multiple classes to ensure complete disease resolution. High rates of antibiotic resistance are characterized by at least partial resistance to almost every antibiotic; clarithromycin has near-complete efficacy, but resistant strains have started to emerge. Amikacin and cefoxitin are other antibiotics that have reported a resistance rate of less than 50%, but they are only effective 90% and 70% of the time, respectively.^1,22 The antibiotic omadacycline, which is approved by the US Food and Drug Administration to treat acute bacterial skin and soft-tissue infections, also may have utility in treating M abscessus infections.^23,24 Finally, phage therapy may offer a potential mode of treatment for this bacterium and was used to treat pulmonary infection in a patient with cystic fibrosis.²⁵ Despite these newer innovations, the current standard of care involves clarithromycin or azithromycin in combination with a parenteral antibiotic such as cefoxitin, amikacin, or imipenem for at least 4 months.¹