Sometimes more is more.

Elderly individuals who socialize almost daily may live significantly longer than those who socialize less, a large Chinese study suggests.

Correlations between socializing and survival were detected regardless of baseline health status, suggesting that physicians should be recommending daily socialization for all elderly patients, lead author Ziqiong Wang, MD, of Sichuan University West China Hospital, Chengdu, China, and colleagues reported.

These findings align with an array of prior studies reporting physical and mental health benefits from socialization, and negative impacts from isolation, the investigators wrote in the Journal of Epidemiology & Community Health. Not all studies have yielded the same picture, however, and most research has been conducted in Western countries, leading to uncertainty about whether different outcomes would be seen in populations in other parts of the world. Furthermore, the authors added that few studies have explored the amount of socialization needed to derive a positive benefit.

To address this knowledge gap, the investigators analyzed survival data from 28,563 participants in the Chinese Longitudinal Healthy Longevity Survey with a median age of 89 years at baseline.

Columbia University

“[This analysis] is from a highly respected ongoing longitudinal study of aging in China, which includes a large number of subjects and employs very strong research design and statistical analytical methods, so it has credibility,” John W. Rowe, MD, Julius B. Richmond Professor of Health Policy and Aging at Columbia University, New York, said in a written comment.

The investigators stratified frequency of socialization into five tiers: never, not monthly but sometimes, not weekly but at least once per month, not daily but at least once per week, and almost every day.

Survival proportions were calculated using the Kaplan-Meier method after accounting for a range of individual characteristics, including age, sex, household income, smoking status, diabetes, self-rated health, and others. Comparative findings were described in terms of time ratios using multivariable parametric accelerated failure time (AFT) models.

“The AFT model estimates the time ratio (TR), which is interpreted as the expected time to events in one category relative to the reference group,” the investigators wrote. “Unlike the interpretation of proportional hazard model results where hazard ratios larger than 1 are equal to higher risk, a TR of greater than 1 is considered to have a longer time to events, compared with the reference group.”

From baseline to 5 years, each socialization tier was significantly associated with prolonged survival, suggesting a general benefit. Compared with no socialization, socializing sometimes but not monthly was associated with 42% longer survival, at least monthly socialization was associated with 48% longer survival, at least weekly was associated with 110% longer survival, and socializing almost every day was associated with 87% longer survival.

The outsized benefit of daily socialization became clear in a long-term survival analysis, which spanned 5 years through the end of follow-up. Compared with no socialization, daily socialization tripled survival (TR, 3.04; P < .001), compared with prolongations ranging from 5% to 64% for less socialization, with just one of these lower tiers achieving statistical significance (P = .046).

Of note, the benefit of daily socialization was detected regardless of a person’s health status at baseline.

“No matter if elderly participants had chronic diseases or not, [and] no matter if older people had good self-rated health or not, the survival benefits of frequently participating in social activity were the same,” said principal author Sen He, MD, of Sichuan University, in a written comment.

“Socializing almost every day seems to be the most beneficial for a long life,” Dr. Sen added, noting that more research is needed to determine if there is an optimal type of social activity.

Dr. Rowe pointed out two key findings from the study. The first was that it confirmed “prior studies that have identified a beneficial effect of social activity on life expectancy.

“We have known that engagement is essential for successful aging and that isolation is toxic. While this finding is not novel, it is nice to see this confirmation of what we thought we knew,” he wrote.

Secondly, the study has identified “a threshold effect”, which is that “the long-term benefit on life expectancy was only seen in the presence of fairly intense social interactions, essentially daily,” he said.

University of Michigan

According to Preeti Malani, MD, professor of medicine and geriatrician at the University of Michigan, Ann Arbor, the findings are also helpful because they offer data from another part of the world, adding confidence in findings from Western countries.

“This [study] happens to focus on older adults in China, which is helpful since aging is not the same everywhere in the world,” Dr. Malani said. “While the numbers here may not be precise, it’s fair to say that socialization is good for your health – for everyone but especially for older adults.”

Considering the body of evidence now spanning a range of populations, Dr. Malani said physicians should be screening for, and recommending, socialization for all elderly patients, particularly because many aren’t getting enough of it.

“Work that my colleagues and I have done (with the National Poll on Healthy Aging) suggests that there is a portion of older adults that have very little to no social contact,” Dr. Malani said. “A physician may not know this unless they are asking routinely about socialization the way we might ask about diet and exercise. How much is enough? No one knows, but anything is better than nothing and likely more is better.”

She also suggested that personalization is key.

“Physical and emotional health may limit the ability to socialize, so not everyone can engage all the time,” Dr. Malani said. “Also, socialization can look different for different people. Technology allows for socialization even if an individual has trouble leaving their home. I especially worry about this issue for older adults that are also caregivers. Those individuals also need time for themselves” and on way to fulfill that need is by socializing with others.

The study was supported by Sichuan (China) Science and Technology Program, the National Key R&D Program of China, and the National Natural Science Foundation of China. The investigators, Dr. Rowe, and Dr. Malani disclosed no relevant conflicts of interest.

Sometimes more is more.

Elderly individuals who socialize almost daily may live significantly longer than those who socialize less, a large Chinese study suggests.

Correlations between socializing and survival were detected regardless of baseline health status, suggesting that physicians should be recommending daily socialization for all elderly patients, lead author Ziqiong Wang, MD, of Sichuan University West China Hospital, Chengdu, China, and colleagues reported.

These findings align with an array of prior studies reporting physical and mental health benefits from socialization, and negative impacts from isolation, the investigators wrote in the Journal of Epidemiology & Community Health. Not all studies have yielded the same picture, however, and most research has been conducted in Western countries, leading to uncertainty about whether different outcomes would be seen in populations in other parts of the world. Furthermore, the authors added that few studies have explored the amount of socialization needed to derive a positive benefit.

To address this knowledge gap, the investigators analyzed survival data from 28,563 participants in the Chinese Longitudinal Healthy Longevity Survey with a median age of 89 years at baseline.

Columbia University

“[This analysis] is from a highly respected ongoing longitudinal study of aging in China, which includes a large number of subjects and employs very strong research design and statistical analytical methods, so it has credibility,” John W. Rowe, MD, Julius B. Richmond Professor of Health Policy and Aging at Columbia University, New York, said in a written comment.

The investigators stratified frequency of socialization into five tiers: never, not monthly but sometimes, not weekly but at least once per month, not daily but at least once per week, and almost every day.

Survival proportions were calculated using the Kaplan-Meier method after accounting for a range of individual characteristics, including age, sex, household income, smoking status, diabetes, self-rated health, and others. Comparative findings were described in terms of time ratios using multivariable parametric accelerated failure time (AFT) models.

“The AFT model estimates the time ratio (TR), which is interpreted as the expected time to events in one category relative to the reference group,” the investigators wrote. “Unlike the interpretation of proportional hazard model results where hazard ratios larger than 1 are equal to higher risk, a TR of greater than 1 is considered to have a longer time to events, compared with the reference group.”

From baseline to 5 years, each socialization tier was significantly associated with prolonged survival, suggesting a general benefit. Compared with no socialization, socializing sometimes but not monthly was associated with 42% longer survival, at least monthly socialization was associated with 48% longer survival, at least weekly was associated with 110% longer survival, and socializing almost every day was associated with 87% longer survival.

The outsized benefit of daily socialization became clear in a long-term survival analysis, which spanned 5 years through the end of follow-up. Compared with no socialization, daily socialization tripled survival (TR, 3.04; P < .001), compared with prolongations ranging from 5% to 64% for less socialization, with just one of these lower tiers achieving statistical significance (P = .046).

Of note, the benefit of daily socialization was detected regardless of a person’s health status at baseline.

“No matter if elderly participants had chronic diseases or not, [and] no matter if older people had good self-rated health or not, the survival benefits of frequently participating in social activity were the same,” said principal author Sen He, MD, of Sichuan University, in a written comment.

“Socializing almost every day seems to be the most beneficial for a long life,” Dr. Sen added, noting that more research is needed to determine if there is an optimal type of social activity.

Dr. Rowe pointed out two key findings from the study. The first was that it confirmed “prior studies that have identified a beneficial effect of social activity on life expectancy.

“We have known that engagement is essential for successful aging and that isolation is toxic. While this finding is not novel, it is nice to see this confirmation of what we thought we knew,” he wrote.

Secondly, the study has identified “a threshold effect”, which is that “the long-term benefit on life expectancy was only seen in the presence of fairly intense social interactions, essentially daily,” he said.

University of Michigan

According to Preeti Malani, MD, professor of medicine and geriatrician at the University of Michigan, Ann Arbor, the findings are also helpful because they offer data from another part of the world, adding confidence in findings from Western countries.

“This [study] happens to focus on older adults in China, which is helpful since aging is not the same everywhere in the world,” Dr. Malani said. “While the numbers here may not be precise, it’s fair to say that socialization is good for your health – for everyone but especially for older adults.”

Considering the body of evidence now spanning a range of populations, Dr. Malani said physicians should be screening for, and recommending, socialization for all elderly patients, particularly because many aren’t getting enough of it.

“Work that my colleagues and I have done (with the National Poll on Healthy Aging) suggests that there is a portion of older adults that have very little to no social contact,” Dr. Malani said. “A physician may not know this unless they are asking routinely about socialization the way we might ask about diet and exercise. How much is enough? No one knows, but anything is better than nothing and likely more is better.”

She also suggested that personalization is key.

“Physical and emotional health may limit the ability to socialize, so not everyone can engage all the time,” Dr. Malani said. “Also, socialization can look different for different people. Technology allows for socialization even if an individual has trouble leaving their home. I especially worry about this issue for older adults that are also caregivers. Those individuals also need time for themselves” and on way to fulfill that need is by socializing with others.

The study was supported by Sichuan (China) Science and Technology Program, the National Key R&D Program of China, and the National Natural Science Foundation of China. The investigators, Dr. Rowe, and Dr. Malani disclosed no relevant conflicts of interest.

Sometimes more is more.

Elderly individuals who socialize almost daily may live significantly longer than those who socialize less, a large Chinese study suggests.

Correlations between socializing and survival were detected regardless of baseline health status, suggesting that physicians should be recommending daily socialization for all elderly patients, lead author Ziqiong Wang, MD, of Sichuan University West China Hospital, Chengdu, China, and colleagues reported.

These findings align with an array of prior studies reporting physical and mental health benefits from socialization, and negative impacts from isolation, the investigators wrote in the Journal of Epidemiology & Community Health. Not all studies have yielded the same picture, however, and most research has been conducted in Western countries, leading to uncertainty about whether different outcomes would be seen in populations in other parts of the world. Furthermore, the authors added that few studies have explored the amount of socialization needed to derive a positive benefit.

To address this knowledge gap, the investigators analyzed survival data from 28,563 participants in the Chinese Longitudinal Healthy Longevity Survey with a median age of 89 years at baseline.

Columbia University

“[This analysis] is from a highly respected ongoing longitudinal study of aging in China, which includes a large number of subjects and employs very strong research design and statistical analytical methods, so it has credibility,” John W. Rowe, MD, Julius B. Richmond Professor of Health Policy and Aging at Columbia University, New York, said in a written comment.

The investigators stratified frequency of socialization into five tiers: never, not monthly but sometimes, not weekly but at least once per month, not daily but at least once per week, and almost every day.

Survival proportions were calculated using the Kaplan-Meier method after accounting for a range of individual characteristics, including age, sex, household income, smoking status, diabetes, self-rated health, and others. Comparative findings were described in terms of time ratios using multivariable parametric accelerated failure time (AFT) models.

“The AFT model estimates the time ratio (TR), which is interpreted as the expected time to events in one category relative to the reference group,” the investigators wrote. “Unlike the interpretation of proportional hazard model results where hazard ratios larger than 1 are equal to higher risk, a TR of greater than 1 is considered to have a longer time to events, compared with the reference group.”

From baseline to 5 years, each socialization tier was significantly associated with prolonged survival, suggesting a general benefit. Compared with no socialization, socializing sometimes but not monthly was associated with 42% longer survival, at least monthly socialization was associated with 48% longer survival, at least weekly was associated with 110% longer survival, and socializing almost every day was associated with 87% longer survival.

The outsized benefit of daily socialization became clear in a long-term survival analysis, which spanned 5 years through the end of follow-up. Compared with no socialization, daily socialization tripled survival (TR, 3.04; P < .001), compared with prolongations ranging from 5% to 64% for less socialization, with just one of these lower tiers achieving statistical significance (P = .046).

Of note, the benefit of daily socialization was detected regardless of a person’s health status at baseline.

“No matter if elderly participants had chronic diseases or not, [and] no matter if older people had good self-rated health or not, the survival benefits of frequently participating in social activity were the same,” said principal author Sen He, MD, of Sichuan University, in a written comment.

“Socializing almost every day seems to be the most beneficial for a long life,” Dr. Sen added, noting that more research is needed to determine if there is an optimal type of social activity.

Dr. Rowe pointed out two key findings from the study. The first was that it confirmed “prior studies that have identified a beneficial effect of social activity on life expectancy.

“We have known that engagement is essential for successful aging and that isolation is toxic. While this finding is not novel, it is nice to see this confirmation of what we thought we knew,” he wrote.

Secondly, the study has identified “a threshold effect”, which is that “the long-term benefit on life expectancy was only seen in the presence of fairly intense social interactions, essentially daily,” he said.

University of Michigan

According to Preeti Malani, MD, professor of medicine and geriatrician at the University of Michigan, Ann Arbor, the findings are also helpful because they offer data from another part of the world, adding confidence in findings from Western countries.

“This [study] happens to focus on older adults in China, which is helpful since aging is not the same everywhere in the world,” Dr. Malani said. “While the numbers here may not be precise, it’s fair to say that socialization is good for your health – for everyone but especially for older adults.”

Considering the body of evidence now spanning a range of populations, Dr. Malani said physicians should be screening for, and recommending, socialization for all elderly patients, particularly because many aren’t getting enough of it.

“Work that my colleagues and I have done (with the National Poll on Healthy Aging) suggests that there is a portion of older adults that have very little to no social contact,” Dr. Malani said. “A physician may not know this unless they are asking routinely about socialization the way we might ask about diet and exercise. How much is enough? No one knows, but anything is better than nothing and likely more is better.”

She also suggested that personalization is key.

“Physical and emotional health may limit the ability to socialize, so not everyone can engage all the time,” Dr. Malani said. “Also, socialization can look different for different people. Technology allows for socialization even if an individual has trouble leaving their home. I especially worry about this issue for older adults that are also caregivers. Those individuals also need time for themselves” and on way to fulfill that need is by socializing with others.

The study was supported by Sichuan (China) Science and Technology Program, the National Key R&D Program of China, and the National Natural Science Foundation of China. The investigators, Dr. Rowe, and Dr. Malani disclosed no relevant conflicts of interest.

HONOLULU – With so many kids missing childhood vaccinations during the acute phase of the COVID-19 pandemic, think measles in patients who present with high fever, cough, and a maculopapular eruption.

“Measles is one of the most contagious of human viruses, and we are seeing a resurgence,” Adelaide A. Hebert, MD, professor of dermatology and pediatrics, and chief of pediatric dermatology at the Universtiy of Texas, Houston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “This is a re-emerging viral infection that dermatologists must recognize. Measles often starts behind the ears, and the eruption can look a lot like a drug eruption,” she noted. “Many of my pediatric colleagues have never seen a case of measles before because we have had a vaccine since 1963. Measles can almost entirely be prevented with vaccination. You get herd immunity if both doses have been administered to 95% of the population.”

In 2021, the World Health Organization estimated that 25 million children worldwide missed the measles vaccine. This caused 9 million cases of measles and 128,000 deaths in 22 countries, mainly from viral pneumonia, secondary bacterial pneumonia, and postviral encephalitis. According to the Centers for Disease Control and Prevention, 1,274 measles cases occurred in 31 states in 2019, mostly in individuals who were not vaccinated against it. Reported cases fell to 13 in 2020 but rose to 49 cases in 2021 and to 121 cases in 2022. As of Feb. 28, 2023, three cases have been reported in the United States.

“Measles spreads through direct contact with an infected person and through airborne transmission,” said Dr. Hebert, who recommended an article published in The Lancet for background on the topic. “Unlike COVID-19, measles has not mutated, so the original measles vaccine will work very well.”

Common clinical signs of measles include a generalized, maculopapular eruption lasting for 3 days or more, a temperature above 101° F plus cough, coryza, or conjunctivitis. Confirmation of measles can be made by PCR for viral RNA. Clinicians can also send a blood draw to the state public health lab for analysis. The serologic standard is a fourfold rise or fall in IgG titer with a paired sample sent 10-14 days after the initial collection.

“You can administer immune globulin up to 6 days after exposure to potentially prevent measles or decrease severity [in] immunocompromised hosts not previously vaccinated,” she said. The recommended intramuscular dose is 0.5 mL/kg, up to a dose of 15 mL/kg. Treatment is supportive and focused on relieving common symptoms and providing nutritional support. Administration of vitamin A is currently recommended for all children with acute measles.

Vitamin A supplements are available either as capsules (50,000 IU; 100,000 IU; 200,000 IU) or in liquid form. Parenteral formulations are also available. “Capsules need to be cut open and the contents squeezed into the mouths of children younger than 2 years,” Dr. Hebert said. “Capsules have the advantage that they can be given to mothers for administration at home.”

The recommended dosage of vitamin A in children is as follows, she said:

• Aged 12 months or older: 200,000 IU daily for 2 days.
• Aged 6 to 11 months: 100,000 IU daily for 2 days.
• Aged 6 months or younger: 50,000 IU daily for 2 days.

The American Academy of Pediatrics recommends a third dose given 2-4 weeks later to children with clinical signs and symptoms of vitamin A deficiency.

In an interview following the meeting, Moise L. Levy, MD, professor of internal medicine and pediatrics at the University of Texas, Austin, emphasized that when clinicians evaluate pediatric patients with viral symptoms such as fever, cough, and skin eruption, “measles should be in the differential diagnosis.” The 2022 uptick in measles cases “would be another reason to engage in regular vaccinations.”

Dr. Hebert disclosed that she is a consultant or advisor for AbbVie, Almirall, Amryt Pharma, Arcutis Biotherapeutics, Beiersdorf, Dermavant Sciences, Galderma Laboratories, L’Oreal, Novan, Ortho Dermatologics, Pfizer, and Verrica.

Dr. Levy disclosed that he is consultant or advisor for Abeona, Castle Creek, Dusa Pharma, Krystal Bio, Novan, Regeneron, and Sanofi-Genzyme.

MedscapeLIVE! and this news organization are owned by the same parent company.

HONOLULU – With so many kids missing childhood vaccinations during the acute phase of the COVID-19 pandemic, think measles in patients who present with high fever, cough, and a maculopapular eruption.

“Measles is one of the most contagious of human viruses, and we are seeing a resurgence,” Adelaide A. Hebert, MD, professor of dermatology and pediatrics, and chief of pediatric dermatology at the Universtiy of Texas, Houston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “This is a re-emerging viral infection that dermatologists must recognize. Measles often starts behind the ears, and the eruption can look a lot like a drug eruption,” she noted. “Many of my pediatric colleagues have never seen a case of measles before because we have had a vaccine since 1963. Measles can almost entirely be prevented with vaccination. You get herd immunity if both doses have been administered to 95% of the population.”

In 2021, the World Health Organization estimated that 25 million children worldwide missed the measles vaccine. This caused 9 million cases of measles and 128,000 deaths in 22 countries, mainly from viral pneumonia, secondary bacterial pneumonia, and postviral encephalitis. According to the Centers for Disease Control and Prevention, 1,274 measles cases occurred in 31 states in 2019, mostly in individuals who were not vaccinated against it. Reported cases fell to 13 in 2020 but rose to 49 cases in 2021 and to 121 cases in 2022. As of Feb. 28, 2023, three cases have been reported in the United States.

“Measles spreads through direct contact with an infected person and through airborne transmission,” said Dr. Hebert, who recommended an article published in The Lancet for background on the topic. “Unlike COVID-19, measles has not mutated, so the original measles vaccine will work very well.”

Common clinical signs of measles include a generalized, maculopapular eruption lasting for 3 days or more, a temperature above 101° F plus cough, coryza, or conjunctivitis. Confirmation of measles can be made by PCR for viral RNA. Clinicians can also send a blood draw to the state public health lab for analysis. The serologic standard is a fourfold rise or fall in IgG titer with a paired sample sent 10-14 days after the initial collection.

“You can administer immune globulin up to 6 days after exposure to potentially prevent measles or decrease severity [in] immunocompromised hosts not previously vaccinated,” she said. The recommended intramuscular dose is 0.5 mL/kg, up to a dose of 15 mL/kg. Treatment is supportive and focused on relieving common symptoms and providing nutritional support. Administration of vitamin A is currently recommended for all children with acute measles.

Vitamin A supplements are available either as capsules (50,000 IU; 100,000 IU; 200,000 IU) or in liquid form. Parenteral formulations are also available. “Capsules need to be cut open and the contents squeezed into the mouths of children younger than 2 years,” Dr. Hebert said. “Capsules have the advantage that they can be given to mothers for administration at home.”

The recommended dosage of vitamin A in children is as follows, she said:

• Aged 12 months or older: 200,000 IU daily for 2 days.
• Aged 6 to 11 months: 100,000 IU daily for 2 days.
• Aged 6 months or younger: 50,000 IU daily for 2 days.

The American Academy of Pediatrics recommends a third dose given 2-4 weeks later to children with clinical signs and symptoms of vitamin A deficiency.

In an interview following the meeting, Moise L. Levy, MD, professor of internal medicine and pediatrics at the University of Texas, Austin, emphasized that when clinicians evaluate pediatric patients with viral symptoms such as fever, cough, and skin eruption, “measles should be in the differential diagnosis.” The 2022 uptick in measles cases “would be another reason to engage in regular vaccinations.”

Dr. Hebert disclosed that she is a consultant or advisor for AbbVie, Almirall, Amryt Pharma, Arcutis Biotherapeutics, Beiersdorf, Dermavant Sciences, Galderma Laboratories, L’Oreal, Novan, Ortho Dermatologics, Pfizer, and Verrica.

Dr. Levy disclosed that he is consultant or advisor for Abeona, Castle Creek, Dusa Pharma, Krystal Bio, Novan, Regeneron, and Sanofi-Genzyme.

MedscapeLIVE! and this news organization are owned by the same parent company.

HONOLULU – With so many kids missing childhood vaccinations during the acute phase of the COVID-19 pandemic, think measles in patients who present with high fever, cough, and a maculopapular eruption.

“Measles is one of the most contagious of human viruses, and we are seeing a resurgence,” Adelaide A. Hebert, MD, professor of dermatology and pediatrics, and chief of pediatric dermatology at the Universtiy of Texas, Houston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “This is a re-emerging viral infection that dermatologists must recognize. Measles often starts behind the ears, and the eruption can look a lot like a drug eruption,” she noted. “Many of my pediatric colleagues have never seen a case of measles before because we have had a vaccine since 1963. Measles can almost entirely be prevented with vaccination. You get herd immunity if both doses have been administered to 95% of the population.”

In 2021, the World Health Organization estimated that 25 million children worldwide missed the measles vaccine. This caused 9 million cases of measles and 128,000 deaths in 22 countries, mainly from viral pneumonia, secondary bacterial pneumonia, and postviral encephalitis. According to the Centers for Disease Control and Prevention, 1,274 measles cases occurred in 31 states in 2019, mostly in individuals who were not vaccinated against it. Reported cases fell to 13 in 2020 but rose to 49 cases in 2021 and to 121 cases in 2022. As of Feb. 28, 2023, three cases have been reported in the United States.

“Measles spreads through direct contact with an infected person and through airborne transmission,” said Dr. Hebert, who recommended an article published in The Lancet for background on the topic. “Unlike COVID-19, measles has not mutated, so the original measles vaccine will work very well.”

Common clinical signs of measles include a generalized, maculopapular eruption lasting for 3 days or more, a temperature above 101° F plus cough, coryza, or conjunctivitis. Confirmation of measles can be made by PCR for viral RNA. Clinicians can also send a blood draw to the state public health lab for analysis. The serologic standard is a fourfold rise or fall in IgG titer with a paired sample sent 10-14 days after the initial collection.

“You can administer immune globulin up to 6 days after exposure to potentially prevent measles or decrease severity [in] immunocompromised hosts not previously vaccinated,” she said. The recommended intramuscular dose is 0.5 mL/kg, up to a dose of 15 mL/kg. Treatment is supportive and focused on relieving common symptoms and providing nutritional support. Administration of vitamin A is currently recommended for all children with acute measles.

Vitamin A supplements are available either as capsules (50,000 IU; 100,000 IU; 200,000 IU) or in liquid form. Parenteral formulations are also available. “Capsules need to be cut open and the contents squeezed into the mouths of children younger than 2 years,” Dr. Hebert said. “Capsules have the advantage that they can be given to mothers for administration at home.”

The recommended dosage of vitamin A in children is as follows, she said:

• Aged 12 months or older: 200,000 IU daily for 2 days.
• Aged 6 to 11 months: 100,000 IU daily for 2 days.
• Aged 6 months or younger: 50,000 IU daily for 2 days.

The American Academy of Pediatrics recommends a third dose given 2-4 weeks later to children with clinical signs and symptoms of vitamin A deficiency.

In an interview following the meeting, Moise L. Levy, MD, professor of internal medicine and pediatrics at the University of Texas, Austin, emphasized that when clinicians evaluate pediatric patients with viral symptoms such as fever, cough, and skin eruption, “measles should be in the differential diagnosis.” The 2022 uptick in measles cases “would be another reason to engage in regular vaccinations.”

Dr. Hebert disclosed that she is a consultant or advisor for AbbVie, Almirall, Amryt Pharma, Arcutis Biotherapeutics, Beiersdorf, Dermavant Sciences, Galderma Laboratories, L’Oreal, Novan, Ortho Dermatologics, Pfizer, and Verrica.

Dr. Levy disclosed that he is consultant or advisor for Abeona, Castle Creek, Dusa Pharma, Krystal Bio, Novan, Regeneron, and Sanofi-Genzyme.

MedscapeLIVE! and this news organization are owned by the same parent company.

An 81-year-old man was admitted to our skilled nursing facility (SNF) after hospitalization for an acute kidney injury secondary to bladder outflow obstruction. While at the hospital, he received hemodialysis for the acute kidney injury, underwent transurethral resection of the prostate for benign prostatic hyperplasia (BPH), and had lithotripsy for nephrolithiasis. He was admitted to our SNF with an indwelling urinary catheter that had been placed 3 days prior to discharge from the hospital for urinary retention and a serum creatinine level of 3.28 mg/dL (normal range, 0.7-1.3 mg/dL [male]). Four days after his admission, the nursing staff reported acute onset of purple urine in his catheter and collection bag (FIGURE).

Physical examination revealed an older man whose vital signs were normal and who had a regular heart rate and rhythm. He denied any pain, and his abdomen was soft and nontender with normal bowel sounds. There was no suprapubic or costovertebral angle tenderness, and his urinary catheter was correctly placed. His urine output was within normal limits, but the urine in the catheter and collection bag was purple.

The patient’s medical history was remarkable for mild cognitive impairment, BPH, and hypertension. A urine culture was significant for > 100,000 CFU/mL pan-sensitive Pseudomonas aeruginosa.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The diagnosis of purple urine bag syndrome (PUBS) was made based on the patient’s clinical presentation and medical history. PUBS is generally a benign condition that can occur in patients who have urinary catheters for prolonged periods of time and urinary tract infections (UTIs), often with ­constipation.¹

PUBS was first described in the literature in 1978.² Its prevalence has been estimated to be 9.8% in long-term wards and higher in patients with chronic catheters.^3-5 PUBS is reported more often in institutionalized older women, although it has been documented in men as well.¹ Risk factors include having a chronic indwelling urinary catheter; alkaline urine; the use of plastic, polyvinylchloride urine bags³; chronic constipation⁶; renal failure^4,5; and dementia.¹ In many cases, patients with PUBS have been found to have stable vitals and lack systemic symptoms, such as fever, that could indicate an infection.^1,5

Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.

The pathogenesis of PUBS has been associated with tryptophan.³ Gut bacteria metabolize tryptophan to indole, which is converted to indoxyl sulfate in the liver.^3,7 Then certain bacteria associated with UTIs, including Pseudomonas, Escherichia coli, Proteus mirabilis, Providencia spp, Enterococcus faecalis, and Klebsiella,^5-7 which contain indoxyl phosphatase and sulfatase enzymes, can convert indoxyl sulfate into indirubin (red) and indigo (blue) compounds; this results in a purple hue in the urine seen in a Foley catheter and bag.

Differential is generally limited to medication and food consumption

Clinical presentation and a detailed history and review of medication and/or food ingestion may distinguish PUBS from other conditions.

Medications and foods, such as rifampicin or beets, may discolor urine and need to be ruled out as a cause with a thorough history.³

Cyanide toxicity in those taking vitamin B₁₂can result in purple-tinged urine.⁸ Signs and symptoms can alsoinclude reddening of the skin, dyspnea, nausea, headache, erythema at the injection site, and a modest increase in blood pressure.⁸

Identify the infection and treat as needed

There have been some case reports regarding the progression of PUBS to Fournier gangrene,⁴ but such cases are rare and associated with immunocompromised patients.⁹ PUBS is generally a benign condition associated with UTIs. Management involves identifying the underlying infection, treating with antibiotics if indicated (ie, patient is symptomatic or immunocompromised),³ providing proper treatment of constipation if needed, and replacing the Foley catheter.⁴ Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.⁵

In light of his complicated urologic history, our patient was treated with a 10-day course of renally dosed intravenous cefepime (500 mg every 24 hours based on calculated creatine clearance of 21 mL/min) and Foley exchange. The patient’s urine color returned to normal after Foley exchange and 24 hours of antibiotics. His kidney function continued to improve and normalized by the time he was discharged from the facility approximately 2 weeks later.

An 81-year-old man was admitted to our skilled nursing facility (SNF) after hospitalization for an acute kidney injury secondary to bladder outflow obstruction. While at the hospital, he received hemodialysis for the acute kidney injury, underwent transurethral resection of the prostate for benign prostatic hyperplasia (BPH), and had lithotripsy for nephrolithiasis. He was admitted to our SNF with an indwelling urinary catheter that had been placed 3 days prior to discharge from the hospital for urinary retention and a serum creatinine level of 3.28 mg/dL (normal range, 0.7-1.3 mg/dL [male]). Four days after his admission, the nursing staff reported acute onset of purple urine in his catheter and collection bag (FIGURE).

Physical examination revealed an older man whose vital signs were normal and who had a regular heart rate and rhythm. He denied any pain, and his abdomen was soft and nontender with normal bowel sounds. There was no suprapubic or costovertebral angle tenderness, and his urinary catheter was correctly placed. His urine output was within normal limits, but the urine in the catheter and collection bag was purple.

The patient’s medical history was remarkable for mild cognitive impairment, BPH, and hypertension. A urine culture was significant for > 100,000 CFU/mL pan-sensitive Pseudomonas aeruginosa.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The diagnosis of purple urine bag syndrome (PUBS) was made based on the patient’s clinical presentation and medical history. PUBS is generally a benign condition that can occur in patients who have urinary catheters for prolonged periods of time and urinary tract infections (UTIs), often with ­constipation.¹

PUBS was first described in the literature in 1978.² Its prevalence has been estimated to be 9.8% in long-term wards and higher in patients with chronic catheters.^3-5 PUBS is reported more often in institutionalized older women, although it has been documented in men as well.¹ Risk factors include having a chronic indwelling urinary catheter; alkaline urine; the use of plastic, polyvinylchloride urine bags³; chronic constipation⁶; renal failure^4,5; and dementia.¹ In many cases, patients with PUBS have been found to have stable vitals and lack systemic symptoms, such as fever, that could indicate an infection.^1,5

Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.

The pathogenesis of PUBS has been associated with tryptophan.³ Gut bacteria metabolize tryptophan to indole, which is converted to indoxyl sulfate in the liver.^3,7 Then certain bacteria associated with UTIs, including Pseudomonas, Escherichia coli, Proteus mirabilis, Providencia spp, Enterococcus faecalis, and Klebsiella,^5-7 which contain indoxyl phosphatase and sulfatase enzymes, can convert indoxyl sulfate into indirubin (red) and indigo (blue) compounds; this results in a purple hue in the urine seen in a Foley catheter and bag.

Differential is generally limited to medication and food consumption

Clinical presentation and a detailed history and review of medication and/or food ingestion may distinguish PUBS from other conditions.

Medications and foods, such as rifampicin or beets, may discolor urine and need to be ruled out as a cause with a thorough history.³

Cyanide toxicity in those taking vitamin B₁₂can result in purple-tinged urine.⁸ Signs and symptoms can alsoinclude reddening of the skin, dyspnea, nausea, headache, erythema at the injection site, and a modest increase in blood pressure.⁸

Identify the infection and treat as needed

There have been some case reports regarding the progression of PUBS to Fournier gangrene,⁴ but such cases are rare and associated with immunocompromised patients.⁹ PUBS is generally a benign condition associated with UTIs. Management involves identifying the underlying infection, treating with antibiotics if indicated (ie, patient is symptomatic or immunocompromised),³ providing proper treatment of constipation if needed, and replacing the Foley catheter.⁴ Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.⁵

In light of his complicated urologic history, our patient was treated with a 10-day course of renally dosed intravenous cefepime (500 mg every 24 hours based on calculated creatine clearance of 21 mL/min) and Foley exchange. The patient’s urine color returned to normal after Foley exchange and 24 hours of antibiotics. His kidney function continued to improve and normalized by the time he was discharged from the facility approximately 2 weeks later.

An 81-year-old man was admitted to our skilled nursing facility (SNF) after hospitalization for an acute kidney injury secondary to bladder outflow obstruction. While at the hospital, he received hemodialysis for the acute kidney injury, underwent transurethral resection of the prostate for benign prostatic hyperplasia (BPH), and had lithotripsy for nephrolithiasis. He was admitted to our SNF with an indwelling urinary catheter that had been placed 3 days prior to discharge from the hospital for urinary retention and a serum creatinine level of 3.28 mg/dL (normal range, 0.7-1.3 mg/dL [male]). Four days after his admission, the nursing staff reported acute onset of purple urine in his catheter and collection bag (FIGURE).

Physical examination revealed an older man whose vital signs were normal and who had a regular heart rate and rhythm. He denied any pain, and his abdomen was soft and nontender with normal bowel sounds. There was no suprapubic or costovertebral angle tenderness, and his urinary catheter was correctly placed. His urine output was within normal limits, but the urine in the catheter and collection bag was purple.

The patient’s medical history was remarkable for mild cognitive impairment, BPH, and hypertension. A urine culture was significant for > 100,000 CFU/mL pan-sensitive Pseudomonas aeruginosa.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The diagnosis of purple urine bag syndrome (PUBS) was made based on the patient’s clinical presentation and medical history. PUBS is generally a benign condition that can occur in patients who have urinary catheters for prolonged periods of time and urinary tract infections (UTIs), often with ­constipation.¹

PUBS was first described in the literature in 1978.² Its prevalence has been estimated to be 9.8% in long-term wards and higher in patients with chronic catheters.^3-5 PUBS is reported more often in institutionalized older women, although it has been documented in men as well.¹ Risk factors include having a chronic indwelling urinary catheter; alkaline urine; the use of plastic, polyvinylchloride urine bags³; chronic constipation⁶; renal failure^4,5; and dementia.¹ In many cases, patients with PUBS have been found to have stable vitals and lack systemic symptoms, such as fever, that could indicate an infection.^1,5

Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.

The pathogenesis of PUBS has been associated with tryptophan.³ Gut bacteria metabolize tryptophan to indole, which is converted to indoxyl sulfate in the liver.^3,7 Then certain bacteria associated with UTIs, including Pseudomonas, Escherichia coli, Proteus mirabilis, Providencia spp, Enterococcus faecalis, and Klebsiella,^5-7 which contain indoxyl phosphatase and sulfatase enzymes, can convert indoxyl sulfate into indirubin (red) and indigo (blue) compounds; this results in a purple hue in the urine seen in a Foley catheter and bag.

Differential is generally limited to medication and food consumption

Clinical presentation and a detailed history and review of medication and/or food ingestion may distinguish PUBS from other conditions.

Medications and foods, such as rifampicin or beets, may discolor urine and need to be ruled out as a cause with a thorough history.³

Cyanide toxicity in those taking vitamin B₁₂can result in purple-tinged urine.⁸ Signs and symptoms can alsoinclude reddening of the skin, dyspnea, nausea, headache, erythema at the injection site, and a modest increase in blood pressure.⁸

Identify the infection and treat as needed

There have been some case reports regarding the progression of PUBS to Fournier gangrene,⁴ but such cases are rare and associated with immunocompromised patients.⁹ PUBS is generally a benign condition associated with UTIs. Management involves identifying the underlying infection, treating with antibiotics if indicated (ie, patient is symptomatic or immunocompromised),³ providing proper treatment of constipation if needed, and replacing the Foley catheter.⁴ Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.⁵

In light of his complicated urologic history, our patient was treated with a 10-day course of renally dosed intravenous cefepime (500 mg every 24 hours based on calculated creatine clearance of 21 mL/min) and Foley exchange. The patient’s urine color returned to normal after Foley exchange and 24 hours of antibiotics. His kidney function continued to improve and normalized by the time he was discharged from the facility approximately 2 weeks later.

THE CASE

A 44-year-old man with a history of morbid obesity reestablished care in our clinic. He had been treated in our health care system about 5 years previously, and prior lab testing showed a total cholesterol of 203 mg/dL; triglycerides, 191 mg/dL; high-density lipoprotein (HDL), 56 mg/dL; and low-density lipoprotein (LDL), 109 mg/dL. At that time, he weighed 299 lbs (BMI, 39.4). He then started a strict ketogenic diet and a regular exercise program (running ~ 16 miles per week and lifting weights), which he maintained for several years. He had experienced remarkable weight loss; upon reestablishing care, he weighed 199 lbs (BMI, 26.33).

However, lipid testing revealed a severely elevated total cholesterol of 334 mg/dL; LDL, 248 mg/dL; HDL, 67 mg/dL; and triglycerides, 95 mg/dL. He was advised to start statin therapy and to stop his ketogenic diet, but he was hesitant to take either step. He elected to have his lab work reevaluated in 6 months.

About 4 months later, he presented with new and increasing burning pain in his mid chest and upper abdomen. He rated the pain 6/10 in severity and said it occurred during exertion or at night when lying down. Resting would relieve the pain. Reduced intake of spicy foods and caffeine had also helped. He denied dyspnea, diaphoresis, palpitations, or nausea.

The patient was a nonsmoker but did have a strong family history of cardiovascular disease. His vital signs and physical examination were unremarkable, apart from mild epigastric and periumbilical tenderness on palpation.

THE DIAGNOSIS

The patient’s chest pain had features of both gastroesophageal reflux disease (GERD) and coronary artery disease (CAD) with exertional angina. His high-fat diet, nightly symptoms, and the partial relief he achieved by cutting back on spicy foods and caffeine suggested GERD, but the exertional nature of the chest pain and gradual relief with rest was highly suggestive of angina, so an outpatient electrocardiogram treadmill stress test was ordered.

The stress test was markedly abnormal, showing worsening ST depressions and T-wave inversions with exertion, and he experienced chest pain during testing. An urgent left heart catheterization was performed, showing severe multivessel CAD. He subsequently underwent 3-vessel coronary artery bypass grafting. A familial hypercholesterolemia panel failed to reveal any significant variants.

As a result of these findings, the patient received a diagnosis of severe ketogenic diet–associated hypercholesterolemia and early-onset CAD.

Continue to: DISCUSSION

Low-carbohydrate (low-carb) and ketogenic diets have grown in popularity throughout the United States over the past decade, particularly for weight loss, and the diet has entered the popular consciousness with several celebrities publicly supporting it.¹ Simultaneously, there also has been a growing interest in these diets for the treatment of chronic diseases, such as type 2 diabetes.² However, the long-term cardiovascular effects of low-carb diets are not well studied, and there is significant heterogeneity among these diets.

Low-carb vs low-fat. Multiple meta-analyses comparing low-carb diets to low-fat diets have found that those following low-carb diets have significantly higher total cholesterol and LDL levels.^3,4,5 The National Lipid Association’s review of evidence determined that LDL and total cholesterol responses vary in individuals following a low-carb diet, but that increasing LDL levels in particular were concerning enough to warrant lipid monitoring of patients on low-carb diets.⁶ Another meta-analysis evaluated the difference in estimated atherosclerotic cardiovascular disease (ASCVD) risk between low-carb and low-fat diets, finding those following a low-carb diet to have a lower estimated ASCVD risk but higher LDL levels.⁷

The severe worsening of this patient’s LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD.

Weighing the benefits and harms. Since our patient’s dramatic weight loss and greatly increased exercise level would be expected to lower his LDL levels, the severe worsening of his LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD. The benefits of low-carb diets for weight loss, contrasted with the consistent worsening of LDL levels, has prompted a debate about which parameters should be considered in estimating the long-term risk of these diets for patients. Diamond et al⁸ posit that these diets have beneficial effects on “the most reliable [cardiovascular disease] risk factors,” but long-term, patient-oriented outcome data are lacking, and these diets may not be appropriate for certain patients, as our case demonstrates.

A reasonable strategy for patients contemplating a low-carb diet specifically for weight loss would be to use such a diet for 3 to 6 months to achieve initial and rapid results, then continue with a heart-healthy diet and increased exercise levels to maintain weight loss and reduce long-term cardiovascular risk.

Our patient was started on a post­operative medication regimen of aspirin 81 mg/d, evolocumab 140 mg every 14 days, metoprolol tartrate 25 mg bid, and rosuva­statin 10 mg/d. A year later, he was able to resume a high level of physical activity (6-mile runs) without chest pain. His follow-up lipid panel showed a total cholesterol of 153 mg/dL; LDL, 53 mg/dL; HDL, 89 mg/dL; and triglycerides, 55 mg/dL. He had also switched to a regular diet and had been able to maintain his weight loss.

THE TAKEAWAY

Growing evidence suggests that low-carb diets may have a significant and detrimental effect on LDL levels. The long-term safety of these diets hasn’t been well studied, particularly regarding cardiovascular outcomes. At a minimum, patients who initiate low-carb diets should be counseled on general dietary recommendations regarding saturated fat and cholesterol intake, and they should have a follow-up lipid screening to evaluate for any significant worsening in total cholesterol and LDL levels.

CORRESPONDENCE
Samuel Dickmann, MD, 13611 NW 1st Lane, Suite 200, Newberry, FL 32669; sbcdickmann@ufl.edu

THE CASE

A 44-year-old man with a history of morbid obesity reestablished care in our clinic. He had been treated in our health care system about 5 years previously, and prior lab testing showed a total cholesterol of 203 mg/dL; triglycerides, 191 mg/dL; high-density lipoprotein (HDL), 56 mg/dL; and low-density lipoprotein (LDL), 109 mg/dL. At that time, he weighed 299 lbs (BMI, 39.4). He then started a strict ketogenic diet and a regular exercise program (running ~ 16 miles per week and lifting weights), which he maintained for several years. He had experienced remarkable weight loss; upon reestablishing care, he weighed 199 lbs (BMI, 26.33).

However, lipid testing revealed a severely elevated total cholesterol of 334 mg/dL; LDL, 248 mg/dL; HDL, 67 mg/dL; and triglycerides, 95 mg/dL. He was advised to start statin therapy and to stop his ketogenic diet, but he was hesitant to take either step. He elected to have his lab work reevaluated in 6 months.

About 4 months later, he presented with new and increasing burning pain in his mid chest and upper abdomen. He rated the pain 6/10 in severity and said it occurred during exertion or at night when lying down. Resting would relieve the pain. Reduced intake of spicy foods and caffeine had also helped. He denied dyspnea, diaphoresis, palpitations, or nausea.

The patient was a nonsmoker but did have a strong family history of cardiovascular disease. His vital signs and physical examination were unremarkable, apart from mild epigastric and periumbilical tenderness on palpation.

THE DIAGNOSIS

The patient’s chest pain had features of both gastroesophageal reflux disease (GERD) and coronary artery disease (CAD) with exertional angina. His high-fat diet, nightly symptoms, and the partial relief he achieved by cutting back on spicy foods and caffeine suggested GERD, but the exertional nature of the chest pain and gradual relief with rest was highly suggestive of angina, so an outpatient electrocardiogram treadmill stress test was ordered.

The stress test was markedly abnormal, showing worsening ST depressions and T-wave inversions with exertion, and he experienced chest pain during testing. An urgent left heart catheterization was performed, showing severe multivessel CAD. He subsequently underwent 3-vessel coronary artery bypass grafting. A familial hypercholesterolemia panel failed to reveal any significant variants.

As a result of these findings, the patient received a diagnosis of severe ketogenic diet–associated hypercholesterolemia and early-onset CAD.

Continue to: DISCUSSION

Low-carbohydrate (low-carb) and ketogenic diets have grown in popularity throughout the United States over the past decade, particularly for weight loss, and the diet has entered the popular consciousness with several celebrities publicly supporting it.¹ Simultaneously, there also has been a growing interest in these diets for the treatment of chronic diseases, such as type 2 diabetes.² However, the long-term cardiovascular effects of low-carb diets are not well studied, and there is significant heterogeneity among these diets.

Low-carb vs low-fat. Multiple meta-analyses comparing low-carb diets to low-fat diets have found that those following low-carb diets have significantly higher total cholesterol and LDL levels.^3,4,5 The National Lipid Association’s review of evidence determined that LDL and total cholesterol responses vary in individuals following a low-carb diet, but that increasing LDL levels in particular were concerning enough to warrant lipid monitoring of patients on low-carb diets.⁶ Another meta-analysis evaluated the difference in estimated atherosclerotic cardiovascular disease (ASCVD) risk between low-carb and low-fat diets, finding those following a low-carb diet to have a lower estimated ASCVD risk but higher LDL levels.⁷

The severe worsening of this patient’s LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD.

Weighing the benefits and harms. Since our patient’s dramatic weight loss and greatly increased exercise level would be expected to lower his LDL levels, the severe worsening of his LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD. The benefits of low-carb diets for weight loss, contrasted with the consistent worsening of LDL levels, has prompted a debate about which parameters should be considered in estimating the long-term risk of these diets for patients. Diamond et al⁸ posit that these diets have beneficial effects on “the most reliable [cardiovascular disease] risk factors,” but long-term, patient-oriented outcome data are lacking, and these diets may not be appropriate for certain patients, as our case demonstrates.

A reasonable strategy for patients contemplating a low-carb diet specifically for weight loss would be to use such a diet for 3 to 6 months to achieve initial and rapid results, then continue with a heart-healthy diet and increased exercise levels to maintain weight loss and reduce long-term cardiovascular risk.

Our patient was started on a post­operative medication regimen of aspirin 81 mg/d, evolocumab 140 mg every 14 days, metoprolol tartrate 25 mg bid, and rosuva­statin 10 mg/d. A year later, he was able to resume a high level of physical activity (6-mile runs) without chest pain. His follow-up lipid panel showed a total cholesterol of 153 mg/dL; LDL, 53 mg/dL; HDL, 89 mg/dL; and triglycerides, 55 mg/dL. He had also switched to a regular diet and had been able to maintain his weight loss.

THE TAKEAWAY

Growing evidence suggests that low-carb diets may have a significant and detrimental effect on LDL levels. The long-term safety of these diets hasn’t been well studied, particularly regarding cardiovascular outcomes. At a minimum, patients who initiate low-carb diets should be counseled on general dietary recommendations regarding saturated fat and cholesterol intake, and they should have a follow-up lipid screening to evaluate for any significant worsening in total cholesterol and LDL levels.

CORRESPONDENCE
Samuel Dickmann, MD, 13611 NW 1st Lane, Suite 200, Newberry, FL 32669; sbcdickmann@ufl.edu

THE CASE

A 44-year-old man with a history of morbid obesity reestablished care in our clinic. He had been treated in our health care system about 5 years previously, and prior lab testing showed a total cholesterol of 203 mg/dL; triglycerides, 191 mg/dL; high-density lipoprotein (HDL), 56 mg/dL; and low-density lipoprotein (LDL), 109 mg/dL. At that time, he weighed 299 lbs (BMI, 39.4). He then started a strict ketogenic diet and a regular exercise program (running ~ 16 miles per week and lifting weights), which he maintained for several years. He had experienced remarkable weight loss; upon reestablishing care, he weighed 199 lbs (BMI, 26.33).

However, lipid testing revealed a severely elevated total cholesterol of 334 mg/dL; LDL, 248 mg/dL; HDL, 67 mg/dL; and triglycerides, 95 mg/dL. He was advised to start statin therapy and to stop his ketogenic diet, but he was hesitant to take either step. He elected to have his lab work reevaluated in 6 months.

About 4 months later, he presented with new and increasing burning pain in his mid chest and upper abdomen. He rated the pain 6/10 in severity and said it occurred during exertion or at night when lying down. Resting would relieve the pain. Reduced intake of spicy foods and caffeine had also helped. He denied dyspnea, diaphoresis, palpitations, or nausea.

The patient was a nonsmoker but did have a strong family history of cardiovascular disease. His vital signs and physical examination were unremarkable, apart from mild epigastric and periumbilical tenderness on palpation.

THE DIAGNOSIS

The patient’s chest pain had features of both gastroesophageal reflux disease (GERD) and coronary artery disease (CAD) with exertional angina. His high-fat diet, nightly symptoms, and the partial relief he achieved by cutting back on spicy foods and caffeine suggested GERD, but the exertional nature of the chest pain and gradual relief with rest was highly suggestive of angina, so an outpatient electrocardiogram treadmill stress test was ordered.

The stress test was markedly abnormal, showing worsening ST depressions and T-wave inversions with exertion, and he experienced chest pain during testing. An urgent left heart catheterization was performed, showing severe multivessel CAD. He subsequently underwent 3-vessel coronary artery bypass grafting. A familial hypercholesterolemia panel failed to reveal any significant variants.

As a result of these findings, the patient received a diagnosis of severe ketogenic diet–associated hypercholesterolemia and early-onset CAD.

Continue to: DISCUSSION

Low-carbohydrate (low-carb) and ketogenic diets have grown in popularity throughout the United States over the past decade, particularly for weight loss, and the diet has entered the popular consciousness with several celebrities publicly supporting it.¹ Simultaneously, there also has been a growing interest in these diets for the treatment of chronic diseases, such as type 2 diabetes.² However, the long-term cardiovascular effects of low-carb diets are not well studied, and there is significant heterogeneity among these diets.

Low-carb vs low-fat. Multiple meta-analyses comparing low-carb diets to low-fat diets have found that those following low-carb diets have significantly higher total cholesterol and LDL levels.^3,4,5 The National Lipid Association’s review of evidence determined that LDL and total cholesterol responses vary in individuals following a low-carb diet, but that increasing LDL levels in particular were concerning enough to warrant lipid monitoring of patients on low-carb diets.⁶ Another meta-analysis evaluated the difference in estimated atherosclerotic cardiovascular disease (ASCVD) risk between low-carb and low-fat diets, finding those following a low-carb diet to have a lower estimated ASCVD risk but higher LDL levels.⁷

The severe worsening of this patient’s LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD.

Weighing the benefits and harms. Since our patient’s dramatic weight loss and greatly increased exercise level would be expected to lower his LDL levels, the severe worsening of his LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD. The benefits of low-carb diets for weight loss, contrasted with the consistent worsening of LDL levels, has prompted a debate about which parameters should be considered in estimating the long-term risk of these diets for patients. Diamond et al⁸ posit that these diets have beneficial effects on “the most reliable [cardiovascular disease] risk factors,” but long-term, patient-oriented outcome data are lacking, and these diets may not be appropriate for certain patients, as our case demonstrates.

A reasonable strategy for patients contemplating a low-carb diet specifically for weight loss would be to use such a diet for 3 to 6 months to achieve initial and rapid results, then continue with a heart-healthy diet and increased exercise levels to maintain weight loss and reduce long-term cardiovascular risk.

Our patient was started on a post­operative medication regimen of aspirin 81 mg/d, evolocumab 140 mg every 14 days, metoprolol tartrate 25 mg bid, and rosuva­statin 10 mg/d. A year later, he was able to resume a high level of physical activity (6-mile runs) without chest pain. His follow-up lipid panel showed a total cholesterol of 153 mg/dL; LDL, 53 mg/dL; HDL, 89 mg/dL; and triglycerides, 55 mg/dL. He had also switched to a regular diet and had been able to maintain his weight loss.

THE TAKEAWAY

Growing evidence suggests that low-carb diets may have a significant and detrimental effect on LDL levels. The long-term safety of these diets hasn’t been well studied, particularly regarding cardiovascular outcomes. At a minimum, patients who initiate low-carb diets should be counseled on general dietary recommendations regarding saturated fat and cholesterol intake, and they should have a follow-up lipid screening to evaluate for any significant worsening in total cholesterol and LDL levels.

CORRESPONDENCE
Samuel Dickmann, MD, 13611 NW 1st Lane, Suite 200, Newberry, FL 32669; sbcdickmann@ufl.edu

Last year, after a long delay due to COVID, my father’s ashes were finally laid to rest at Arlington National Cemetery. Among the loved ones who came was my favorite aunt, Tante Ilse, who was suffering from dementia. While she wasn’t “following” everything that was going on, she did perk up when she heard my father’s name and would comment on how she liked him and how wonderful he had been to her.

After the ceremony, our family of about 30 gathered at a restaurant where we shared stories and old pictures. Tante Ilse seemed to relish the photos and the time with family. She was doing so well that when we went back to my mom’s home after the reception, my cousins decided to bring Tante Ilse there, too. She had a great time, as evidenced by her famous total-body laugh. In the months before her death, we all commented about that day and how happy she seemed.

I would have hoped for something better than merely clearing amyloid for my aunt.

My aunt’s decline comes to mind as I reflect on media reports of 2 Alzheimer drugs— aducanumab and lecanemab—that have been billed by some as “gamechangers.” These new drugs are monoclonal antibodies directed at amyloid, one of several agents thought to cause Alzheimer disease. The details of aducanumab’s approval by the US Food and Drug Administration (FDA) generated a great deal of criticism—with good reason.

Two manufacturer-sponsored studies of aducanumab were halted due to futility of finding a benefit.¹ The FDA’s scientific advisory panel recommended against approval due to a lack of evidence that it did anything more than remove amyloid plaque from the brain. And yet aducanumab received accelerated approval from the FDA. (This author collaborated on an additional analysis using data presented to the FDA, after its approval, which also reported no clinically meaningful effects.²) The other agent, lecanemab, also reduces markers of amyloid and was shown to be only moderately better than placebo in decreasing the rate of decline on various measures of cognition.³ Quite notably, both aducanumab and lecanemab, which are administered parenterally, cost more than $25,000 per year^4,5 and cause amyloid-related imaging abnormalities (brain edema or hemorrhage).

Expensive agents without meaningful benefit. So far, neither of these agents has shown a reduction in things that are truly important to our patients and their families/caregivers: a reduction in caregiver burden and a reduction in the need for placement in long-term care facilities.

This is in contrast to cholinesterase inhibitors, which also slow the rate of cognitive decline.⁶ Among the differences that exist between these agents: Cholinesterase inhibitors are taken orally and are available as generics, which cost less than a thousand dollars per year.⁷ Limited data also suggest that they are associated with a lower risk for nursing home placement.^8,9 (A February 2023 search of clinicaltrials.gov did not reveal any completed or planned head-to-head comparisons of monoclonal antibodies and anticholinergic agents.)

Our patients, their families, and caregivers hold out hope for something that will improve the patient’s cognition and extend the meaningful time they have with their loved ones. So far, the best we have to offer falls far short of these goals. I certainly would have hoped for something better than merely clearing amyloid for my aunt.

It’s time that the FDA adopt more rigorous standards requiring new drugs to, among other things, demonstrate meaningful clinical benefits, provide real cost savings, and be safer than currently available therapies. Other nations seem to be able to do this.^10,11 It is bad enough to provide “hope in a bottle”; it is worse when what is offered is false hope.

Last year, after a long delay due to COVID, my father’s ashes were finally laid to rest at Arlington National Cemetery. Among the loved ones who came was my favorite aunt, Tante Ilse, who was suffering from dementia. While she wasn’t “following” everything that was going on, she did perk up when she heard my father’s name and would comment on how she liked him and how wonderful he had been to her.

After the ceremony, our family of about 30 gathered at a restaurant where we shared stories and old pictures. Tante Ilse seemed to relish the photos and the time with family. She was doing so well that when we went back to my mom’s home after the reception, my cousins decided to bring Tante Ilse there, too. She had a great time, as evidenced by her famous total-body laugh. In the months before her death, we all commented about that day and how happy she seemed.

I would have hoped for something better than merely clearing amyloid for my aunt.

My aunt’s decline comes to mind as I reflect on media reports of 2 Alzheimer drugs— aducanumab and lecanemab—that have been billed by some as “gamechangers.” These new drugs are monoclonal antibodies directed at amyloid, one of several agents thought to cause Alzheimer disease. The details of aducanumab’s approval by the US Food and Drug Administration (FDA) generated a great deal of criticism—with good reason.

Two manufacturer-sponsored studies of aducanumab were halted due to futility of finding a benefit.¹ The FDA’s scientific advisory panel recommended against approval due to a lack of evidence that it did anything more than remove amyloid plaque from the brain. And yet aducanumab received accelerated approval from the FDA. (This author collaborated on an additional analysis using data presented to the FDA, after its approval, which also reported no clinically meaningful effects.²) The other agent, lecanemab, also reduces markers of amyloid and was shown to be only moderately better than placebo in decreasing the rate of decline on various measures of cognition.³ Quite notably, both aducanumab and lecanemab, which are administered parenterally, cost more than $25,000 per year^4,5 and cause amyloid-related imaging abnormalities (brain edema or hemorrhage).

Expensive agents without meaningful benefit. So far, neither of these agents has shown a reduction in things that are truly important to our patients and their families/caregivers: a reduction in caregiver burden and a reduction in the need for placement in long-term care facilities.

This is in contrast to cholinesterase inhibitors, which also slow the rate of cognitive decline.⁶ Among the differences that exist between these agents: Cholinesterase inhibitors are taken orally and are available as generics, which cost less than a thousand dollars per year.⁷ Limited data also suggest that they are associated with a lower risk for nursing home placement.^8,9 (A February 2023 search of clinicaltrials.gov did not reveal any completed or planned head-to-head comparisons of monoclonal antibodies and anticholinergic agents.)

Our patients, their families, and caregivers hold out hope for something that will improve the patient’s cognition and extend the meaningful time they have with their loved ones. So far, the best we have to offer falls far short of these goals. I certainly would have hoped for something better than merely clearing amyloid for my aunt.

It’s time that the FDA adopt more rigorous standards requiring new drugs to, among other things, demonstrate meaningful clinical benefits, provide real cost savings, and be safer than currently available therapies. Other nations seem to be able to do this.^10,11 It is bad enough to provide “hope in a bottle”; it is worse when what is offered is false hope.

Last year, after a long delay due to COVID, my father’s ashes were finally laid to rest at Arlington National Cemetery. Among the loved ones who came was my favorite aunt, Tante Ilse, who was suffering from dementia. While she wasn’t “following” everything that was going on, she did perk up when she heard my father’s name and would comment on how she liked him and how wonderful he had been to her.

After the ceremony, our family of about 30 gathered at a restaurant where we shared stories and old pictures. Tante Ilse seemed to relish the photos and the time with family. She was doing so well that when we went back to my mom’s home after the reception, my cousins decided to bring Tante Ilse there, too. She had a great time, as evidenced by her famous total-body laugh. In the months before her death, we all commented about that day and how happy she seemed.

I would have hoped for something better than merely clearing amyloid for my aunt.

My aunt’s decline comes to mind as I reflect on media reports of 2 Alzheimer drugs— aducanumab and lecanemab—that have been billed by some as “gamechangers.” These new drugs are monoclonal antibodies directed at amyloid, one of several agents thought to cause Alzheimer disease. The details of aducanumab’s approval by the US Food and Drug Administration (FDA) generated a great deal of criticism—with good reason.

Two manufacturer-sponsored studies of aducanumab were halted due to futility of finding a benefit.¹ The FDA’s scientific advisory panel recommended against approval due to a lack of evidence that it did anything more than remove amyloid plaque from the brain. And yet aducanumab received accelerated approval from the FDA. (This author collaborated on an additional analysis using data presented to the FDA, after its approval, which also reported no clinically meaningful effects.²) The other agent, lecanemab, also reduces markers of amyloid and was shown to be only moderately better than placebo in decreasing the rate of decline on various measures of cognition.³ Quite notably, both aducanumab and lecanemab, which are administered parenterally, cost more than $25,000 per year^4,5 and cause amyloid-related imaging abnormalities (brain edema or hemorrhage).

Expensive agents without meaningful benefit. So far, neither of these agents has shown a reduction in things that are truly important to our patients and their families/caregivers: a reduction in caregiver burden and a reduction in the need for placement in long-term care facilities.

This is in contrast to cholinesterase inhibitors, which also slow the rate of cognitive decline.⁶ Among the differences that exist between these agents: Cholinesterase inhibitors are taken orally and are available as generics, which cost less than a thousand dollars per year.⁷ Limited data also suggest that they are associated with a lower risk for nursing home placement.^8,9 (A February 2023 search of clinicaltrials.gov did not reveal any completed or planned head-to-head comparisons of monoclonal antibodies and anticholinergic agents.)

Our patients, their families, and caregivers hold out hope for something that will improve the patient’s cognition and extend the meaningful time they have with their loved ones. So far, the best we have to offer falls far short of these goals. I certainly would have hoped for something better than merely clearing amyloid for my aunt.

It’s time that the FDA adopt more rigorous standards requiring new drugs to, among other things, demonstrate meaningful clinical benefits, provide real cost savings, and be safer than currently available therapies. Other nations seem to be able to do this.^10,11 It is bad enough to provide “hope in a bottle”; it is worse when what is offered is false hope.

Much of the work of the Advisory Committee on Immunization Practices (ACIP) in 2022 was devoted to vaccines to protect against coronavirus ­disease 2019 (COVID-19); details about the 4 available products can be found on the ­Centers for Disease Control and Prevention’s ­COVID vaccine website (www.cdc.gov/coronavirus/2019-ncov/vaccines/index.html).^1,2 However, ACIP also issued recommendations about 5 other (non-COVID) vaccines last year, and those are the focus of this Practice Alert.

A second MMR vaccine option

The United States has had only 1 measles, mumps, and rubella (MMR) vaccine approved for use since 1978: M-M-R II (Merck). In June 2022, the US Food and Drug Administration (FDA) approved a second MMR vaccine, ­PRIORIX (GlaxoSmithKline Biologicals), which ACIP now recommends as an option when MMR vaccine is indicated.³

ACIP considers the 2 MMR options fully interchangeable.³ Both vaccines produce similar levels of immunogenicity and the safety profiles are also equivalent—including the rate of febrile seizures 6 to 11 days after vaccination, estimated at 3.3 to 8.7 per 10,000 doses.⁴ Since PRIORIX has been used in other countries since 1997, the MMR workgroup was able to include 13 studies on immunogenicity and 4 on safety in its evidence assessment; these are summarized on the CDC website.⁴

It is desirable to have multiple manufacturers of recommended vaccines to prevent shortages if there a disruption in the supply chain of 1 manufacturer, as well as to provide competition for cost control. A second MMR vaccine is therefore a welcome addition to the US vaccine supply. However, there remains only 1 combination measles, mumps, rubella, and varicella vaccine approved for use in the United States: ProQuad (Merck).

Pneumococcal vaccine recommendations are revised and simplified

Adults. Last year, ACIP made recommendations regarding 2 new vaccine options for use against pneumococcal infections in adults: PCV15 (Vaxneuvance, Merck) and PCV20 (Prevnar20, Pfizer). These have been described in detail in a CDC publication and summarized in a recent Practice Alert.^5,6

ACIP revised and simplified its recommendations on vaccination to prevent pneumococcal disease in adults as follows⁵:

1. Maintained the cutoff of age 65 years for universal pneumococcal vaccination

2. Recommended pneumococcal vaccination (with either PCV15 or PCV20) for all adults ages 65 years and older and for those younger than 65 years with chronic medical conditions or immunocompromise

3. Recommended that if PCV15 is used, it should be followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23, Merck).

These revisions created a number of uncertain clinical situations, since patients could have already started and/or completed their pneumococcal vaccination with previously available products, including PCV7, PCV13, and PPSV23. At the October 2022 ACIP meeting, the pneumococcal workgroup addressed a number of “what if” clinical questions. These clinical considerations will soon be published in the Morbidity and Mortality Weekly Report (MMWR) but also can be reviewed by looking at the October ACIP meeting materials.⁷ The main considerations are summarized below⁷:

• For those who have previously received PCV7, either PCV15 or PCV20 should be given.
• If PPSV23 was inadvertently administered first, it should be followed by PCV15 or PCV20 at least 1 year later.
• Adults who have only received PPSV23 should receive a dose of either PCV20 or PCV15 at least 1 year after their last PPSV23 dose. When PCV15 is used in those with a history of PPSV23 receipt, it need not be followed by another dose of PPSV23.
• Adults who have received PCV13 only are recommended to complete their pneumococcal vaccine series by receiving either a dose of PCV20 at least 1 year after the PCV13 dose or PPSV23 as previously recommended.
• Shared clinical decision-making is recommended regarding administration of PCV20 for adults ages ≥ 65 years who have completed their recommended vaccine series with both PCV13 and PPSV23 but have not received PCV15 or PCV20. If a decision to administer PCV20 is made, a dose of PCV20 is recommended at least 5 years after the last pneumococcal vaccine dose.

Continue to: Children

Children. In 2022, PCV15 was licensed for use in children and adolescents ages 6 weeks to 17 years. PCV15 contains all the serotypes in the PCV13 vaccine, plus 22F and 33F. In June 2022, ACIP adopted recommendations regarding the use of PCV15 in children. The main recommendation is that PCV13 and PCV15 can be used interchangeably. The recommended schedule for PCV use in children and the catch-up schedule have not changed, nor has the use of PPSV23 in children with underlying medical conditions.^8,9

It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions.

Those who have been vaccinated with PCV13 do not need to be revaccinated with PCV15, and an incomplete series of PCV13 can be completed with PCV15. It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions. The recommended routine immunization and catch-up immunization schedules are published on the CDC website,⁹ and the pneumococcal-specific recommendations are described in a recent MMWR.⁸

Preferential choice for influenza vaccine in those ≥ 65 years

The ACIP now recommends 1 of 3 influenza vaccines be used preferentially in those ages 65 years and older: the high-dose quadrivalent vaccine (HD-IIV4), Fluzone; the adjuvanted quadrivalent influenza vaccine (aIIV4), Fluad; or the recombinant quadrivalent influenza vaccine (RIV4), Flublok. However, if none of these options are available, a standard-dose vaccine is acceptable.

Both HD-IIV4 and aIIV4 are approved only for those ≥ 65 years of age. The RIV4 is approved for ages ≥ 18 years and is produced by a process that does not involve eggs. These 3 products produce better antibody levels and improved clinical outcomes in older adults compared to other, standard-dose flu vaccines, but there is no convincing evidence that any 1 of these is more effective than the others. A more in-depth discussion of flu vaccines and the considerations that went into this preferential recommendation were described in a previous Practice Alert.¹⁰

Updates for 2 travel vaccines

Tick-borne encephalitis (TBE). A TBE vaccine (Ticovac; Pfizer) has been available in other countries for more than 20 years, with no serious safety concerns identified. The vaccine was approved for use in the United States by the FDA in August 2021, and in early 2022, the ACIP made 3 recommendations for its use (to be discussed shortly).

TBE is a neuroinvasive flavivirus spread by ticks in parts of Europe and Asia. There are 3 main subtypes of the virus, and they cause serious illness, with a fatality rate of 1% to 20% and a sequelae rate of 10% to 50%.¹¹ TBE ­infection is rare among US travelers, with only 11 cases documented between 2001 and 2020. There were 9 cases within the US military between 2006 and 2020.¹¹

The TBE vaccine contains inactivated TBE virus, which is produced in chick embryo cells. It is administered in 3 doses over a 12-month timeframe, and those with continued exposure should receive a booster after 3 years.¹² (See TABLE¹² for administration schedule.) More information about the vaccine, contraindications, and rates of adverse reactions is available in the FDA package insert.¹³

Continue to: The ACIP has made...

The ACIP has made the following recommendations for the TBE vaccine^11,12:

1. Vaccination is recommended for laboratory workers with a potential for exposure to TBE virus.

2. TBE vaccine also is recommended for individuals who are moving abroad or traveling to a TBE-endemic area and who will have extensive exposure to ticks based on their planned outdoor activities and itinerary.

3. TBE vaccine can be considered for people traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas where ticks are likely to be found. The decision to vaccinate should be based on an assessment of the patient’s planned activities and itinerary, risk factors for a poorer medical outcome, and personal perception and tolerance of risk.

Cholera. ACIP now recommends CVD 103-HgR (PaxVax, VAXCHORA), a single-dose, live attenuated oral cholera vaccine, for travelers as young as 2 years who plan to visit an area that has active cholera transmission.¹⁴ In February 2022, ACIP expanded its recommendation for adults ages 18 to 64 years to include children and adolescents ages 2 to 17 years. This followed a 2020 FDA approval for the vaccine in the younger age group. Details about the vaccine were described in an MMWR publication.¹⁴

Cholera is caused by toxigenic bacteria. Infection occurs by ingestion of contaminated water or food and can be prevented by consumption of safe water and food, along with good sanitation and handwashing. Cholera produces a profuse watery diarrhea that can rapidly lead to death in 50% of those infected who do not receive rehydration therapy.¹⁵ Cholera is endemic is many countries and can cause large outbreaks. The World Health Organization estimates that 1 to 4 million cases of cholera and 21,000 to 143,000 related deaths occur globally each year.¹⁶

Staying current is moreimportant than ever

Vaccines are one of the most successful public health interventions of the past century, and maintaining a robust vaccine approval and safety monitoring system is an important priority. However, to gain the most benefit from vaccines, physicians need to stay current on vaccine recommendations—something that is becoming increasingly difficult to accomplish as the options expand. Consulting the literature and visiting the CDC’s website (www.cdc.gov) with frequency can be helpful to that end.

Much of the work of the Advisory Committee on Immunization Practices (ACIP) in 2022 was devoted to vaccines to protect against coronavirus ­disease 2019 (COVID-19); details about the 4 available products can be found on the ­Centers for Disease Control and Prevention’s ­COVID vaccine website (www.cdc.gov/coronavirus/2019-ncov/vaccines/index.html).^1,2 However, ACIP also issued recommendations about 5 other (non-COVID) vaccines last year, and those are the focus of this Practice Alert.

A second MMR vaccine option

The United States has had only 1 measles, mumps, and rubella (MMR) vaccine approved for use since 1978: M-M-R II (Merck). In June 2022, the US Food and Drug Administration (FDA) approved a second MMR vaccine, ­PRIORIX (GlaxoSmithKline Biologicals), which ACIP now recommends as an option when MMR vaccine is indicated.³

ACIP considers the 2 MMR options fully interchangeable.³ Both vaccines produce similar levels of immunogenicity and the safety profiles are also equivalent—including the rate of febrile seizures 6 to 11 days after vaccination, estimated at 3.3 to 8.7 per 10,000 doses.⁴ Since PRIORIX has been used in other countries since 1997, the MMR workgroup was able to include 13 studies on immunogenicity and 4 on safety in its evidence assessment; these are summarized on the CDC website.⁴

It is desirable to have multiple manufacturers of recommended vaccines to prevent shortages if there a disruption in the supply chain of 1 manufacturer, as well as to provide competition for cost control. A second MMR vaccine is therefore a welcome addition to the US vaccine supply. However, there remains only 1 combination measles, mumps, rubella, and varicella vaccine approved for use in the United States: ProQuad (Merck).

Pneumococcal vaccine recommendations are revised and simplified

Adults. Last year, ACIP made recommendations regarding 2 new vaccine options for use against pneumococcal infections in adults: PCV15 (Vaxneuvance, Merck) and PCV20 (Prevnar20, Pfizer). These have been described in detail in a CDC publication and summarized in a recent Practice Alert.^5,6

ACIP revised and simplified its recommendations on vaccination to prevent pneumococcal disease in adults as follows⁵:

1. Maintained the cutoff of age 65 years for universal pneumococcal vaccination

2. Recommended pneumococcal vaccination (with either PCV15 or PCV20) for all adults ages 65 years and older and for those younger than 65 years with chronic medical conditions or immunocompromise

3. Recommended that if PCV15 is used, it should be followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23, Merck).

These revisions created a number of uncertain clinical situations, since patients could have already started and/or completed their pneumococcal vaccination with previously available products, including PCV7, PCV13, and PPSV23. At the October 2022 ACIP meeting, the pneumococcal workgroup addressed a number of “what if” clinical questions. These clinical considerations will soon be published in the Morbidity and Mortality Weekly Report (MMWR) but also can be reviewed by looking at the October ACIP meeting materials.⁷ The main considerations are summarized below⁷:

• For those who have previously received PCV7, either PCV15 or PCV20 should be given.
• If PPSV23 was inadvertently administered first, it should be followed by PCV15 or PCV20 at least 1 year later.
• Adults who have only received PPSV23 should receive a dose of either PCV20 or PCV15 at least 1 year after their last PPSV23 dose. When PCV15 is used in those with a history of PPSV23 receipt, it need not be followed by another dose of PPSV23.
• Adults who have received PCV13 only are recommended to complete their pneumococcal vaccine series by receiving either a dose of PCV20 at least 1 year after the PCV13 dose or PPSV23 as previously recommended.
• Shared clinical decision-making is recommended regarding administration of PCV20 for adults ages ≥ 65 years who have completed their recommended vaccine series with both PCV13 and PPSV23 but have not received PCV15 or PCV20. If a decision to administer PCV20 is made, a dose of PCV20 is recommended at least 5 years after the last pneumococcal vaccine dose.

Continue to: Children

Children. In 2022, PCV15 was licensed for use in children and adolescents ages 6 weeks to 17 years. PCV15 contains all the serotypes in the PCV13 vaccine, plus 22F and 33F. In June 2022, ACIP adopted recommendations regarding the use of PCV15 in children. The main recommendation is that PCV13 and PCV15 can be used interchangeably. The recommended schedule for PCV use in children and the catch-up schedule have not changed, nor has the use of PPSV23 in children with underlying medical conditions.^8,9

It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions.

Those who have been vaccinated with PCV13 do not need to be revaccinated with PCV15, and an incomplete series of PCV13 can be completed with PCV15. It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions. The recommended routine immunization and catch-up immunization schedules are published on the CDC website,⁹ and the pneumococcal-specific recommendations are described in a recent MMWR.⁸

Preferential choice for influenza vaccine in those ≥ 65 years

The ACIP now recommends 1 of 3 influenza vaccines be used preferentially in those ages 65 years and older: the high-dose quadrivalent vaccine (HD-IIV4), Fluzone; the adjuvanted quadrivalent influenza vaccine (aIIV4), Fluad; or the recombinant quadrivalent influenza vaccine (RIV4), Flublok. However, if none of these options are available, a standard-dose vaccine is acceptable.

Both HD-IIV4 and aIIV4 are approved only for those ≥ 65 years of age. The RIV4 is approved for ages ≥ 18 years and is produced by a process that does not involve eggs. These 3 products produce better antibody levels and improved clinical outcomes in older adults compared to other, standard-dose flu vaccines, but there is no convincing evidence that any 1 of these is more effective than the others. A more in-depth discussion of flu vaccines and the considerations that went into this preferential recommendation were described in a previous Practice Alert.¹⁰

Updates for 2 travel vaccines

Tick-borne encephalitis (TBE). A TBE vaccine (Ticovac; Pfizer) has been available in other countries for more than 20 years, with no serious safety concerns identified. The vaccine was approved for use in the United States by the FDA in August 2021, and in early 2022, the ACIP made 3 recommendations for its use (to be discussed shortly).

TBE is a neuroinvasive flavivirus spread by ticks in parts of Europe and Asia. There are 3 main subtypes of the virus, and they cause serious illness, with a fatality rate of 1% to 20% and a sequelae rate of 10% to 50%.¹¹ TBE ­infection is rare among US travelers, with only 11 cases documented between 2001 and 2020. There were 9 cases within the US military between 2006 and 2020.¹¹

The TBE vaccine contains inactivated TBE virus, which is produced in chick embryo cells. It is administered in 3 doses over a 12-month timeframe, and those with continued exposure should receive a booster after 3 years.¹² (See TABLE¹² for administration schedule.) More information about the vaccine, contraindications, and rates of adverse reactions is available in the FDA package insert.¹³

Continue to: The ACIP has made...

The ACIP has made the following recommendations for the TBE vaccine^11,12:

1. Vaccination is recommended for laboratory workers with a potential for exposure to TBE virus.

2. TBE vaccine also is recommended for individuals who are moving abroad or traveling to a TBE-endemic area and who will have extensive exposure to ticks based on their planned outdoor activities and itinerary.

3. TBE vaccine can be considered for people traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas where ticks are likely to be found. The decision to vaccinate should be based on an assessment of the patient’s planned activities and itinerary, risk factors for a poorer medical outcome, and personal perception and tolerance of risk.

Cholera. ACIP now recommends CVD 103-HgR (PaxVax, VAXCHORA), a single-dose, live attenuated oral cholera vaccine, for travelers as young as 2 years who plan to visit an area that has active cholera transmission.¹⁴ In February 2022, ACIP expanded its recommendation for adults ages 18 to 64 years to include children and adolescents ages 2 to 17 years. This followed a 2020 FDA approval for the vaccine in the younger age group. Details about the vaccine were described in an MMWR publication.¹⁴

Cholera is caused by toxigenic bacteria. Infection occurs by ingestion of contaminated water or food and can be prevented by consumption of safe water and food, along with good sanitation and handwashing. Cholera produces a profuse watery diarrhea that can rapidly lead to death in 50% of those infected who do not receive rehydration therapy.¹⁵ Cholera is endemic is many countries and can cause large outbreaks. The World Health Organization estimates that 1 to 4 million cases of cholera and 21,000 to 143,000 related deaths occur globally each year.¹⁶

Staying current is moreimportant than ever

Vaccines are one of the most successful public health interventions of the past century, and maintaining a robust vaccine approval and safety monitoring system is an important priority. However, to gain the most benefit from vaccines, physicians need to stay current on vaccine recommendations—something that is becoming increasingly difficult to accomplish as the options expand. Consulting the literature and visiting the CDC’s website (www.cdc.gov) with frequency can be helpful to that end.

Much of the work of the Advisory Committee on Immunization Practices (ACIP) in 2022 was devoted to vaccines to protect against coronavirus ­disease 2019 (COVID-19); details about the 4 available products can be found on the ­Centers for Disease Control and Prevention’s ­COVID vaccine website (www.cdc.gov/coronavirus/2019-ncov/vaccines/index.html).^1,2 However, ACIP also issued recommendations about 5 other (non-COVID) vaccines last year, and those are the focus of this Practice Alert.

A second MMR vaccine option

The United States has had only 1 measles, mumps, and rubella (MMR) vaccine approved for use since 1978: M-M-R II (Merck). In June 2022, the US Food and Drug Administration (FDA) approved a second MMR vaccine, ­PRIORIX (GlaxoSmithKline Biologicals), which ACIP now recommends as an option when MMR vaccine is indicated.³

ACIP considers the 2 MMR options fully interchangeable.³ Both vaccines produce similar levels of immunogenicity and the safety profiles are also equivalent—including the rate of febrile seizures 6 to 11 days after vaccination, estimated at 3.3 to 8.7 per 10,000 doses.⁴ Since PRIORIX has been used in other countries since 1997, the MMR workgroup was able to include 13 studies on immunogenicity and 4 on safety in its evidence assessment; these are summarized on the CDC website.⁴

It is desirable to have multiple manufacturers of recommended vaccines to prevent shortages if there a disruption in the supply chain of 1 manufacturer, as well as to provide competition for cost control. A second MMR vaccine is therefore a welcome addition to the US vaccine supply. However, there remains only 1 combination measles, mumps, rubella, and varicella vaccine approved for use in the United States: ProQuad (Merck).

Pneumococcal vaccine recommendations are revised and simplified

Adults. Last year, ACIP made recommendations regarding 2 new vaccine options for use against pneumococcal infections in adults: PCV15 (Vaxneuvance, Merck) and PCV20 (Prevnar20, Pfizer). These have been described in detail in a CDC publication and summarized in a recent Practice Alert.^5,6

ACIP revised and simplified its recommendations on vaccination to prevent pneumococcal disease in adults as follows⁵:

1. Maintained the cutoff of age 65 years for universal pneumococcal vaccination

2. Recommended pneumococcal vaccination (with either PCV15 or PCV20) for all adults ages 65 years and older and for those younger than 65 years with chronic medical conditions or immunocompromise

3. Recommended that if PCV15 is used, it should be followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23, Merck).

These revisions created a number of uncertain clinical situations, since patients could have already started and/or completed their pneumococcal vaccination with previously available products, including PCV7, PCV13, and PPSV23. At the October 2022 ACIP meeting, the pneumococcal workgroup addressed a number of “what if” clinical questions. These clinical considerations will soon be published in the Morbidity and Mortality Weekly Report (MMWR) but also can be reviewed by looking at the October ACIP meeting materials.⁷ The main considerations are summarized below⁷:

• For those who have previously received PCV7, either PCV15 or PCV20 should be given.
• If PPSV23 was inadvertently administered first, it should be followed by PCV15 or PCV20 at least 1 year later.
• Adults who have only received PPSV23 should receive a dose of either PCV20 or PCV15 at least 1 year after their last PPSV23 dose. When PCV15 is used in those with a history of PPSV23 receipt, it need not be followed by another dose of PPSV23.
• Adults who have received PCV13 only are recommended to complete their pneumococcal vaccine series by receiving either a dose of PCV20 at least 1 year after the PCV13 dose or PPSV23 as previously recommended.
• Shared clinical decision-making is recommended regarding administration of PCV20 for adults ages ≥ 65 years who have completed their recommended vaccine series with both PCV13 and PPSV23 but have not received PCV15 or PCV20. If a decision to administer PCV20 is made, a dose of PCV20 is recommended at least 5 years after the last pneumococcal vaccine dose.

Continue to: Children

Children. In 2022, PCV15 was licensed for use in children and adolescents ages 6 weeks to 17 years. PCV15 contains all the serotypes in the PCV13 vaccine, plus 22F and 33F. In June 2022, ACIP adopted recommendations regarding the use of PCV15 in children. The main recommendation is that PCV13 and PCV15 can be used interchangeably. The recommended schedule for PCV use in children and the catch-up schedule have not changed, nor has the use of PPSV23 in children with underlying medical conditions.^8,9

It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions.

Those who have been vaccinated with PCV13 do not need to be revaccinated with PCV15, and an incomplete series of PCV13 can be completed with PCV15. It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions. The recommended routine immunization and catch-up immunization schedules are published on the CDC website,⁹ and the pneumococcal-specific recommendations are described in a recent MMWR.⁸

Preferential choice for influenza vaccine in those ≥ 65 years

The ACIP now recommends 1 of 3 influenza vaccines be used preferentially in those ages 65 years and older: the high-dose quadrivalent vaccine (HD-IIV4), Fluzone; the adjuvanted quadrivalent influenza vaccine (aIIV4), Fluad; or the recombinant quadrivalent influenza vaccine (RIV4), Flublok. However, if none of these options are available, a standard-dose vaccine is acceptable.

Both HD-IIV4 and aIIV4 are approved only for those ≥ 65 years of age. The RIV4 is approved for ages ≥ 18 years and is produced by a process that does not involve eggs. These 3 products produce better antibody levels and improved clinical outcomes in older adults compared to other, standard-dose flu vaccines, but there is no convincing evidence that any 1 of these is more effective than the others. A more in-depth discussion of flu vaccines and the considerations that went into this preferential recommendation were described in a previous Practice Alert.¹⁰

Updates for 2 travel vaccines

Tick-borne encephalitis (TBE). A TBE vaccine (Ticovac; Pfizer) has been available in other countries for more than 20 years, with no serious safety concerns identified. The vaccine was approved for use in the United States by the FDA in August 2021, and in early 2022, the ACIP made 3 recommendations for its use (to be discussed shortly).

TBE is a neuroinvasive flavivirus spread by ticks in parts of Europe and Asia. There are 3 main subtypes of the virus, and they cause serious illness, with a fatality rate of 1% to 20% and a sequelae rate of 10% to 50%.¹¹ TBE ­infection is rare among US travelers, with only 11 cases documented between 2001 and 2020. There were 9 cases within the US military between 2006 and 2020.¹¹

The TBE vaccine contains inactivated TBE virus, which is produced in chick embryo cells. It is administered in 3 doses over a 12-month timeframe, and those with continued exposure should receive a booster after 3 years.¹² (See TABLE¹² for administration schedule.) More information about the vaccine, contraindications, and rates of adverse reactions is available in the FDA package insert.¹³

Continue to: The ACIP has made...

The ACIP has made the following recommendations for the TBE vaccine^11,12:

1. Vaccination is recommended for laboratory workers with a potential for exposure to TBE virus.

2. TBE vaccine also is recommended for individuals who are moving abroad or traveling to a TBE-endemic area and who will have extensive exposure to ticks based on their planned outdoor activities and itinerary.

3. TBE vaccine can be considered for people traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas where ticks are likely to be found. The decision to vaccinate should be based on an assessment of the patient’s planned activities and itinerary, risk factors for a poorer medical outcome, and personal perception and tolerance of risk.

Cholera. ACIP now recommends CVD 103-HgR (PaxVax, VAXCHORA), a single-dose, live attenuated oral cholera vaccine, for travelers as young as 2 years who plan to visit an area that has active cholera transmission.¹⁴ In February 2022, ACIP expanded its recommendation for adults ages 18 to 64 years to include children and adolescents ages 2 to 17 years. This followed a 2020 FDA approval for the vaccine in the younger age group. Details about the vaccine were described in an MMWR publication.¹⁴

Cholera is caused by toxigenic bacteria. Infection occurs by ingestion of contaminated water or food and can be prevented by consumption of safe water and food, along with good sanitation and handwashing. Cholera produces a profuse watery diarrhea that can rapidly lead to death in 50% of those infected who do not receive rehydration therapy.¹⁵ Cholera is endemic is many countries and can cause large outbreaks. The World Health Organization estimates that 1 to 4 million cases of cholera and 21,000 to 143,000 related deaths occur globally each year.¹⁶

Staying current is moreimportant than ever

Vaccines are one of the most successful public health interventions of the past century, and maintaining a robust vaccine approval and safety monitoring system is an important priority. However, to gain the most benefit from vaccines, physicians need to stay current on vaccine recommendations—something that is becoming increasingly difficult to accomplish as the options expand. Consulting the literature and visiting the CDC’s website (www.cdc.gov) with frequency can be helpful to that end.

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure (mPAP) have led to a reported increase in the number of patients given a diagnosis of PH. Although the evaluation and treatment of PH relies on the specialist, as we explain here, family physicians play a pivotal role in the diagnosis, reduction or elimination of risk factors for PH, and timely referral to a pulmonologist or cardiologist who has expertise in managing the disease. We also address the important finding that adult patients who have been evaluated, treated, and followed based on guidelines—updated just last year—have a longer life expectancy than patients who have not been treated properly or not treated at all.

Last, we summarize the etiology, evaluation, and management of PH in the pediatric population.

What is pulmonary hypertension? A revised definition

Prior to 2018, PH was defined as mPAP (measured by right heart catheterization [RHC]) ≥ 25 mm Hg at rest. Now, based on guidelines developed at the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, PH is defined as mPAP > 20 mm Hg.^1,2 That change was based on studies in which researchers noted higher mortality in adults who had mPAP below the traditional threshold.^3,4 There is no evidence, however, of increased mortality in the pediatric population in this lower mPAP range.⁵

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure have led to a reported increase in the number of patients given a diagnosis of PH.

PH is estimated to be present in approximately 1% of the population.⁶ PH due to other diseases—eg, cardiac disease, lung disease, or a chronic thromboembolic condition—­reflects the prevalence of the causative disease.⁷

How is pulmonary hypertension classified?

Based on the work of a Task Force of the 6th WSPH, PH is classified by underlying pathophysiology, hemodynamics, and functional status. Clinical classification comprises 5 categories, or “groups,” based on underlying pathophysiology (TABLE 1⁶).

Clinical classification

Group 1 PH includes patients with primary pulmonary hypertension, also referred to ­(including in this article) as pulmonary arterial hypertension (PAH). Hemodynamic criteria that define PAH include pulmonary vascular resistance (PVR) > 2 Woods units^a and pulmonary capillary wedge pressure > 15 mm Hg. Idiopathic PAH is the most common diagnosis in this group.

The incidence of PAH is approximately 6 cases for every 1 million adults; prevalence is 48 to 55 cases for every 1 million adults. PAH is more common in women.⁶

Continue to: Less common causes...

Less common causes in Group 1 include connective tissue disorders and exposure to toxins. Drugs and toxins that have a well-defined association with PAH include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Group 2 PH comprises patients whose disease results from left heart dysfunction, the most common cause of PH. This subgroup has an elevated pulmonary artery wedge pressure > 15 mm Hg.⁸ Patients have either isolated postcapillary PH or combined pre-capillary and postcapillary PH.

Group 3 PH comprises patients whose PH is secondary to chronic and hypoxic lung disease. Patients in this group have pre-­capillary PH; even a modest elevation in mPAP (20-29 mm Hg) is associated with a poor prognosis. Group 3 patients have elevated PVR, even with mild PH.² Exertional dyspnea disproportionate to the results of pulmonary function testing, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation with exercise all point to severe PH in these patients.⁹

Group 4 PH encompasses patients with pulmonary artery obstruction, the most common cause of which is related to chronic thromboembolism. Other causes include obstruction of the pulmonary artery from an extrinsic source. Patients with chronic thromboembolic pulmonary hypertension (CTEPH) also have pre-capillary PH, resulting from elevated pulmonary pressures secondary to thromboembolic burden, as well as pulmonary remodeling in unobstructed small arterioles.

Group 5 PH is a miscellaneous group secondary to unclear or multiple causes, including chronic hematologic anemia (eg, sickle cell disease), systemic disorders (eg, sarcoidosis), and metabolic disorders (eg, glycogen storage disease). Patients in Group 5 can have both pre-capillary and postcapillary hypertension.

Classification by functional status

The World Health Organization (WHO) Functional Classification of Patients with Pulmonary Hypertension is divided into 4 classes.¹⁰ This system is used to guide treatment and for prognostic purposes:

Class I. Patients have no limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope.

Continue to: Class II

Class II. Patients have slight limitation of physical activity. They are comfortable at rest but daily physical activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class III. These patients have marked limitation of physical activity. They are comfortable at rest, but less-than-ordinary activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class IV. Patients are unable to carry out any physical activity without symptoms. They manifest signs of right heart failure. Dyspnea or fatigue, or both, might be present even at rest.

How is the pathophysiology of PH described?

The term pulmonary hypertension refers to an elevation in PAP that can result from any number of causes. Pulmonary arterial hypertension is a subcategory of PH in which a rise in PAP is due to primary pathology in the arteries proper.

As noted, PH results from a variety of pathophysiologic mechanisms, reflected in the classification in TABLE 1.⁶

WSPH Group 1 patients are considered to have PAH; for most, disease is idiopathic. In small-caliber pulmonary arteries, hypertrophy of smooth muscle, endothelial cells, and adventitia leads to increased resistance. Production of nitric oxide and prostacyclins is also impaired in endothelial cells. Genetic mutation, environmental factors such as exposure to stimulant use, and collagen vascular disease have a role in different subtypes of PAH. Portopulmonary hypertension is a subtype of PAH in patients with portal hypertension.

WSPH Groups 2-5. Increased PVR can result from pulmonary vascular congestion due to left heart dysfunction; destruction of the alveolar capillary bed; chronic hypoxic vasoconstriction; and vascular occlusion from thromboembolism.

Continue to: Once approximately...

Once approximately 30% of the pulmonary vasculature is involved, pressure in the pulmonary circulation starts to rise. In all WSPH groups, this increase in PVR results in increased right ventricular afterload that, over time, leads to right ventricular ­dysfunction.^7,11,12

How does PH manifest?

Patients who have PH usually present with dyspnea, fatigue, chest pain, near-syncope, syncope, or lower-extremity edema, or any combination of these symptoms. The nonspecificity of presenting symptoms can lead to a delay in diagnosis.

In addition, suspicion of PH should be raised when a patient:

• presents with skin discoloration (light or dark) or a telangiectatic rash
• presents with difficulty swallowing
• has a history of connective tissue disease or hemolytic anemia
• has risk factors for HIV infection or liver disease
• takes an appetite suppressant
• has been exposed to other toxins known to increase the risk of PH.

A detailed medical history—looking for chronic lung or heart disease, thromboembolism, sleep-disordered breathing, a thyroid disorder, chronic renal failure, or a metabolic disorder—should be obtained.

Common findings on the physical exam in PH include:

• an increased P2 heart sound (pulmonic closure)
• high-pitched holosystolic murmur from tricuspid regurgitation
• pulmonic insufficiency murmur
• jugular venous distension
• hepatojugular reflux
• peripheral edema.

These findings are not specific to PH but, again, their presence warrants consideration of PH.

How best to approach evaluation and diagnosis?

The work-up for PH is broad; FIGURE 1^13,14 provides an outline of how to proceed when there is a concern for PH. For the work-up of symptoms and signs listed earlier, chest radiography and electrocardiography are recommended.

Continue to: Radiographic findings

Radiographic findings that suggest PH include enlargement of central pulmonary arteries and the right ventricle and dilation of the right atrium. Pulmonary vascular congestion might also be seen, secondary to left heart disease.⁷

Electrocardiographic findings of PH are demonstrated by signs of left ventricular hypertrophy, especially in Group 2 PH. Upright R waves in V₁-V₂ with deeper S waves in V₅-V₆ might represent right ventricular hypertrophy or right heart strain. Frequent premature atrial contractions and multifocal atrial tachycardia are also associated with PH.⁷

Brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. The level of BNP might be elevated in PH, but its role in the diagnostic process has not been established. BNP can, however, be used to monitor treatment effectiveness and prognosis.¹⁵ A normal electrocardiogram in tandem with a normal level of BNP or NT-proBNP is associated with a low likelihood of PH.⁶

Transthoracic echocardiography (TTE) is the initial evaluation tool whenever PH is suspected. Echocardiographic findings suggestive of PH include a combination of ­tricuspid regurgitation velocity > 2.8 m/s ­(FIGURE 2); estimated pulmonary artery systolic pressure > 35 mm Hg in younger adults and > 40 mm Hg in older adults; right ventricular hypertrophy or strain; or a combination of these. Other TTE findings suggestive of PH are related to the ventricles, pulmonary artery, inferior vena cava, and right atrium (TABLE 2⁶). The probability of PH based on TTE findings is categorized as low, intermediate, or high (see TABLE 2⁶ and TABLE 3¹⁶ for details).

Older guidelines, still used by some, rely on the estimated pulmonary artery systolic pressure (ePASP) reading on echocardiography.^13,17 However, studies have reported poor correlation between ePASP readings and values obtained from RHC.¹⁸

TTE also provides findings of left heart disease, such as left ventricular systolic and diastolic dysfunction and left-sided valvular pathology. Patients with suspected PH in whom evidence of left heart disease on TTE is insufficient for making the diagnosis should receive further evaluation for their possible status in Groups 3-5 PH.

Ventilation–perfusion (VQ) scan. If CTEPH is suspected, a VQ scan should be performed. The scan is highly sensitive for CTEPH; a normal VQ scan excludes CTEPH. Computed tomography (CT) of the chest is not helpful for identifying chronic thromboembolism.¹³

Continue to: Coagulation assays

Coagulation assays. When CTEPH is suspected, coagulopathy can be assessed by measuring anticardiolipin antibodies, lupus anticoagulant, and anti-b-2-glycoprotein ­antibodies.¹³

Chest CT will show radiographic findings in greater detail. An enlarged pulmonary artery (diameter ≥ 29 mm) or a ratio ≥ 1 of the diameter of the main pulmonary artery to the diameter of the ascending aorta is suggestive of PH.

Other tests. Overnight oximetry and testing for sleep-disordered breathing, performed in an appropriate setting, can be ­considered.^13,14,19

Pulmonary function testing with diffusion capacity for carbon monoxide, high-resolution chest CT, and a 6-minute walk test (6MWT) can be considered in patients who have risk factors for chronic lung disease. Pulmonary function testing, including measurement of the diffusing capacity of the lungs for carbon monoxide, arterial blood gas analysis, and CT, is used to aid in interpreting echocardiographic findings in patients with lung disease in whom PH is suspected.

Testing for comorbidities. A given patient’s predisposing conditions for PH might already be known; if not, laboratory evaluation for conditions such as sickle cell disease, liver disease, thyroid dysfunction, connective tissue disorders (antibody tests of antinuclear antibody, rheumatoid factor, anticentromere, anti-topoisomerase, anti-RNA polymerase III, anti-double stranded DNA, anti-Ro, anti-La, and anti-U1-RNP), and vasculitis (anti-­neutrophil cytoplasmic autoantibodies) should be undertaken.

Analysis of stool and urine for Schistosoma spp parasites can be considered in an appropriate clinical setting.¹³

Right heart catheterization. Once alternative diagnoses are excluded, RHC is recommended to make a definitive diagnosis and assess the contribution of left heart disease. Vasoreactivity—defined as a reduction in mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg with increased or unchanged cardiac output—is assessed during RHC by administering nitric oxide or another vasodilator. This definition of vasoreactivity helps guide medical management in patients with PAH.^7,20

Continue to: 6MWT

6MWT. Once the diagnosis of PH is made, a 6MWT helps establish baseline functional performance and will help you to monitor disease progression.

Who can benefit from screening for PH?

Annual evaluation of the risk of PAH is recommended for patients with systemic sclerosis or portal hypertension¹³ and can be considered in patients who have connective tissue disease with overlap features of systemic sclerosis.

Assessment for CTEPH or chronic thromboembolic pulmonary disease is recommended for patients with persistent or new-onset dyspnea or exercise limitation after pulmonary embolism.

Screening echocardiography for PH is recommended for patients who have been referred for liver transplantation.⁶

How risk is stratified

Risk stratification is used to manage PH and assess prognosis.

At diagnosis. Application of a 3-strata model of risk assessment (low, intermediate, high) is recommended.⁶ Pertinent data to determine risk include signs of right heart failure, progression of symptoms and clinical manifestations, report of syncope, WHO functional class, 6MWT, cardiopulmonary exercise testing, biomarkers (BNP or ­NT-proBNP), echocardiography, presence of pericardial effusion, and cardiac magnetic resonance imaging.

At follow-up. Use of a 4-strata model (low, intermediate–low, intermediate–high, and high risk) is recommended. Data used are WHO functional class, 6MWT, and results of either BNP or NT-proBNP testing.⁶

Continue to: When to refer

Specialty consultation^21-23 is recommended for:

• all patients with PAH
• PH patients in clinical Groups 2 and 3 whose disease is disproportionate to the extent of their left heart disease or hypoxic lung disease
• patients in whom there is concern about CTEPH and who therefore require early referral to a specialist for definitive treatment
• patients in whom the cause of PH is unclear or multifactorial (ie, clinical Group 5).

What are the options for managing PH?

Management of PH is based on the cause and classification of the individual patient’s ­disease.

Treatment for WSPH Group 1

Patients require referral to a specialty clinic for diagnosis, treatment, and monitoring of progression.¹⁰

First, regrettably, none of the medications approved by the US Food and Drug Administration for treating PAH prevent progression.⁷

Drugs and toxins associated with pulmonary arterial hypertension include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Patients with idiopathic, hereditary, or drug-induced PAH with positive vasoreactivity are treated with a calcium channel blocker (CCB). The dosage is titrated to optimize therapy for the individual patient.

The patient is then reassessed after 3 to 6 months of medical therapy. Current treatment is continued if the following goals have been met:

• WHO functional classification is I or II
• BNP < 50 ng/L or NT-proBNP < 300 ng/L
• hemodynamics are normal or near-normal (mPAP ≤ 30 mm Hg and PVR ≤ 4 WU).

If these goals have not been met, treatment is adjusted by following the algorithm described below.

Continue to: The treatment algorithm...

The treatment algorithm for idiopathic-, heritable-, drug-induced, and connective tissue disease–associated PAH highlights the importance of cardiopulmonary comorbidities and risk strata at the time treatment is initiated and then during follow-up.

Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, including obesity, hypertension, diabetes, and coronary artery disease. Pulmonary comorbidities can include signs of mild parenchymal lung disease and are often associated with a low carbon monoxide diffusing capacity (< 45% of predicted value). 

The management algorithm proceeds as follows:

• For patients without cardiopulmonary comorbidities and who are at low or intermediate risk, treatment of PAH with an endothelin receptor antagonist (ERA) plus a phosphodiesterase-5 (PDE5) inhibitor is recommended.
• For patients without cardiopulmonary comorbidities and who are at high risk, treatment with an ERA, a PDE5 inhibitor, and either an IV or subcutaneous prostacyclin analogue (PCA) can be considered.
• Patients in either of the preceding 2 categories should have regular follow-up assessment; at such follow-up, their risk should be stratified based on 4 strata (see “How risk is stratified”):
  • Low risk: Continue initial therapy.
  • Low-to-intermediate risk: Consider adding a prostacyclin receptor agonist to the initial regimen or switch to a PDE5 inhibitor or a soluble guanylate cyclase stimulator.
  • Intermediate-to-high or high risk: Consider adding a PCA (IV epoprostenol or IV or subcutaneous treprostinil). In addition, or alternatively, have the patient evaluated for lung transplantation.
• For patients with cardiopulmonary comorbidity—in any risk category—consider oral monotherapy with a PDE5 inhibitor or an ERA. Provide regular follow-up and individualize therapy.⁶

Treatment for WSPH Groups 2 and 3

Treatment is focused on the underlying cause of PH:

• Patients who have left heart disease with either severe pre-capillary component PH or markers of right ventricular dysfunction, or both, should be referred to a PH center.
• Patients with combined pre-capillary and postcapillary PH in whom pre-capillary PH is severe should be considered for an individualized approach.
• Consider prescribing the ERA bosentan in specific scenarios (eg, the Eisenmenger syndrome of left-right shunting resulting from a congenital cardiac defect) to improve exercise capacity. If PAH persists after corrected adult congenital heart disease, follow the PAH treatment algorithm for Group 1 patients (described earlier).
• For patients in Group 3, those who have severe PH should be referred to a PH center.
• Consider prescribing inhaled treprostinil in PH with interstitial lung disease.

Treatment for WSPH Group 4

Patients with CTEPH are the only ones for whom pulmonary endarterectomy (PEA), the treatment of choice, might be curative. Balloon angioplasty can be considered for inoperable cases⁶; these patients should be placed on lifelong anticoagulant therapy.

The nonspecificity of presenting symptoms of pulmonary hypertension— dyspnea, fatigue, chest pain, near syncope, syncope, lowerextremity edema—can lead to a delay in diagnosis.

Symptomatic patients who have inoperable CTEPH or persistent recurrent PH after PEA are medically managed; the agent of choice is riociguat. Patients who have undergone PEA or balloon angioplasty and those receiving pharmacotherapy should be followed long term.

Treatment for WSPH Group 5

Management of these patients focuses on associated conditions.

Continue to: Which medications for PAH?

CCBs. Four options in this class have shown utility, notably in patients who have had a positive vasoreactivity test (see “How best to approach evaluation and diagnosis?”):

• Nifedipine is started at 10 mg tid; target dosage is 20 to 60 mg, bid or tid.
• Diltiazem is started at 60 mg bid; target dosage is 120 to 360 mg bid.
• Amlodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.
• Felodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.

Felodipine and amlodipine have longer half-lives than other CCBs and are well ­tolerated.

ERA. Used as vasodilators are ambrinsentan (starting dosage, 5 mg/d; target dosage, 10 mg/d), macitentan (starting and target dosage, 10 mg/d), and bosentan (starting dosage, 62.5 mg bid; target dosage, 125 mg bid).

Nitric oxide–cyclic guanosine monophosphate enhancers. These are the PDE5 inhibitors sildenafil (starting and target dosages, 20 mg tid) and tadalafil (starting dosage, 20 or 40 mg/d; target dosage, 40 mg/d), and the guanylate cyclase stimulant riociguat (starting dosage, 1 mg tid; target dosage, 2.5 mg tid). All 3 agents enhance production of the potent vasodilator nitric oxide, production of which is impaired in PH.

Prostanoids. Several options are available:

• Beraprost sodium. For this oral prostacyclin analogue, starting dosage is 20 μg tid; target dosage is the maximum tolerated dosage (as high as 40 μg tid).
• Extended-release beraprost. Starting dosage is 60 μg bid; target dosage is the maximum tolerated dosage (as high as 180 μg bid).
• Oral treprostinil. Starting dosage is 0.25 mg bid or 0.125 mg tid; target dosage is the maximum tolerated dosage.
• Inhaled iloprost. Starting dosage of this prostacyclin analogue is 2.5 μg, 6 to 9 times per day; target dosage is 5 μg, 6 to 9 times per day.
• Inhaled treprostinil. Starting dosage is 18 μg qid; target dosage is 54 to 72 μg qid.
• Eproprostenol is administered by continuous IV infusion, at a starting dosage of 2 ng/kg/min; target dosage is determined by tolerability and effectiveness (typically, 30 ng/kg/min).
• IV treprostinil. Starting dosage 1.25 ng/kg/min; target dosage is determined by tolerability and effectiveness, with a typical dosage of 60 ng/kg/min.

Combination treatment with the agents listed above is often utilized.

Selexipag. This oral selective nonprostainoid prostacyclin receptor agonist is started at 200 μg bid; target dosage is the maximum tolerated, as high as 1600 μg bid.

Continue to: Supportive therapy

The need for oxygen should be addressed in patients with hypoxia in any setting—r­esting, exercise induced, and nocturnal.²⁴ Patients with an arterial blood oxygen pressure < 60 mm Hg (SaO₂ < 90 mm Hg) should be on long-term oxygen therapy.⁶

Common physical findings in pulmonary hypertension include an increased P2 heart sound, high-pitched holosystolic murmur from tricuspid regurgitation, and pulmonic insufficiency murmur.

Diuretics are beneficial in patients with chronic fluid retention from PH that is related to right ventricular failure.²⁴

Pulmonary rehabilitation and exercise. Contrary to common belief that exercise training is contraindicated in patients with PH, exercise training has emerged in the past decade as an effective tool to improve exercise capacity, ventilatory efficiency, and quality of life. While a patient is training, oxygen saturation, measured by pulse oximetry, should be maintained at > 90% throughout the exercise session to avoid hypoxic pulmonary artery vasoconstriction.²⁵

A patient who does not qualify for pulmonary or cardiac rehabilitation should be referred for physical therapy.²⁴

Ongoing follow-up in primary care

Instruct patients not to abruptly discontinue medications that have been prescribed for PH. Ongoing follow-up and monitoring involves assessing right heart function, exercise tolerance, and resting and ambulatory oximetry. Testing for the level of BNP provides prognostic information and allows assessment of treatment response.¹⁵ The frequency of 6MWT, echocardio­graphy, and RHC is decided on a case-by-case basis.

Other considerations

Pregnancy. PAH often affects patients of childbearing age. Because PAH-associated maternal mortality and the risk to the fetus during pregnancy are high, pregnancy is not recommended for patients with PAH. After a diagnosis of PAH in a patient of childbearing age, counseling should be offered at an expert center. Advice on effective contraception methods should be given early on.^10,26-29

Surgery. Every patient with clinically significant PH is at increased risk of perioperative morbidity and death.^30,31 Guidelines recommend that these patients avoid nonessential surgery; if surgery is necessary, care should be provided at a PH expert center.¹⁰

Continue to: Patients with severe PH...

Patients with severe PH should consider surgery for any indication carefully, discussing with the care team their risk and exploring nonsurgical options. Cardiothoracic surgical and liver transplantation services might have highly specific criteria for treating patients with PH, but other essential and nonessential surgeries require individualized risk stratification. Surgery for patients with severe PH and right ventricular dysfunction should be performed at a center equipped to handle high-risk patients.

Other preventive measures. Patients with PAH should^6,10:

• remain current with immunization against influenza virus, SARS-CoV-2, and pneumococcal pneumonia
• avoid high altitudes
• use supplemental oxygen during air travel to keep arterial oxygen saturation > 91%.

Lung transplantation. Patients eligible for transplantation who (1) are at intermediate-to-high risk or high risk or (2) have a REVEAL (Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management) risk score > 7, and who have had an inadequate response to oral combination therapy, should be referred for evaluation for lung transplantation. Placement on the list for lung transplantation is also recommended for patients at high risk of death and who have a REVEAL risk score ≥ 10 despite medical therapy, including a subcutaneous or IV prostacyclin analogue.⁶

PH in infants and children

The Pediatric Task Force of the 6th WSPH has applied the new definition proposed for adult PH (> 20 mm Hg mPAP) to children and infants > 3 months of age (see “Pulmonary hypertension in the pediatric population,” at left^32-36).

CORRESPONDENCE
Madhavi Singh, MD, 1850 East Park Ave., Suite 207, State College, PA 16803; msingh1@pennstatehealth.psu.edu

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure (mPAP) have led to a reported increase in the number of patients given a diagnosis of PH. Although the evaluation and treatment of PH relies on the specialist, as we explain here, family physicians play a pivotal role in the diagnosis, reduction or elimination of risk factors for PH, and timely referral to a pulmonologist or cardiologist who has expertise in managing the disease. We also address the important finding that adult patients who have been evaluated, treated, and followed based on guidelines—updated just last year—have a longer life expectancy than patients who have not been treated properly or not treated at all.

Last, we summarize the etiology, evaluation, and management of PH in the pediatric population.

What is pulmonary hypertension? A revised definition

Prior to 2018, PH was defined as mPAP (measured by right heart catheterization [RHC]) ≥ 25 mm Hg at rest. Now, based on guidelines developed at the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, PH is defined as mPAP > 20 mm Hg.^1,2 That change was based on studies in which researchers noted higher mortality in adults who had mPAP below the traditional threshold.^3,4 There is no evidence, however, of increased mortality in the pediatric population in this lower mPAP range.⁵

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure have led to a reported increase in the number of patients given a diagnosis of PH.

PH is estimated to be present in approximately 1% of the population.⁶ PH due to other diseases—eg, cardiac disease, lung disease, or a chronic thromboembolic condition—­reflects the prevalence of the causative disease.⁷

How is pulmonary hypertension classified?

Based on the work of a Task Force of the 6th WSPH, PH is classified by underlying pathophysiology, hemodynamics, and functional status. Clinical classification comprises 5 categories, or “groups,” based on underlying pathophysiology (TABLE 1⁶).

Clinical classification

Group 1 PH includes patients with primary pulmonary hypertension, also referred to ­(including in this article) as pulmonary arterial hypertension (PAH). Hemodynamic criteria that define PAH include pulmonary vascular resistance (PVR) > 2 Woods units^a and pulmonary capillary wedge pressure > 15 mm Hg. Idiopathic PAH is the most common diagnosis in this group.

The incidence of PAH is approximately 6 cases for every 1 million adults; prevalence is 48 to 55 cases for every 1 million adults. PAH is more common in women.⁶

Continue to: Less common causes...

Less common causes in Group 1 include connective tissue disorders and exposure to toxins. Drugs and toxins that have a well-defined association with PAH include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Group 2 PH comprises patients whose disease results from left heart dysfunction, the most common cause of PH. This subgroup has an elevated pulmonary artery wedge pressure > 15 mm Hg.⁸ Patients have either isolated postcapillary PH or combined pre-capillary and postcapillary PH.

Group 3 PH comprises patients whose PH is secondary to chronic and hypoxic lung disease. Patients in this group have pre-­capillary PH; even a modest elevation in mPAP (20-29 mm Hg) is associated with a poor prognosis. Group 3 patients have elevated PVR, even with mild PH.² Exertional dyspnea disproportionate to the results of pulmonary function testing, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation with exercise all point to severe PH in these patients.⁹

Group 4 PH encompasses patients with pulmonary artery obstruction, the most common cause of which is related to chronic thromboembolism. Other causes include obstruction of the pulmonary artery from an extrinsic source. Patients with chronic thromboembolic pulmonary hypertension (CTEPH) also have pre-capillary PH, resulting from elevated pulmonary pressures secondary to thromboembolic burden, as well as pulmonary remodeling in unobstructed small arterioles.

Group 5 PH is a miscellaneous group secondary to unclear or multiple causes, including chronic hematologic anemia (eg, sickle cell disease), systemic disorders (eg, sarcoidosis), and metabolic disorders (eg, glycogen storage disease). Patients in Group 5 can have both pre-capillary and postcapillary hypertension.

Classification by functional status

The World Health Organization (WHO) Functional Classification of Patients with Pulmonary Hypertension is divided into 4 classes.¹⁰ This system is used to guide treatment and for prognostic purposes:

Class I. Patients have no limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope.

Continue to: Class II

Class II. Patients have slight limitation of physical activity. They are comfortable at rest but daily physical activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class III. These patients have marked limitation of physical activity. They are comfortable at rest, but less-than-ordinary activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class IV. Patients are unable to carry out any physical activity without symptoms. They manifest signs of right heart failure. Dyspnea or fatigue, or both, might be present even at rest.

How is the pathophysiology of PH described?

The term pulmonary hypertension refers to an elevation in PAP that can result from any number of causes. Pulmonary arterial hypertension is a subcategory of PH in which a rise in PAP is due to primary pathology in the arteries proper.

As noted, PH results from a variety of pathophysiologic mechanisms, reflected in the classification in TABLE 1.⁶

WSPH Group 1 patients are considered to have PAH; for most, disease is idiopathic. In small-caliber pulmonary arteries, hypertrophy of smooth muscle, endothelial cells, and adventitia leads to increased resistance. Production of nitric oxide and prostacyclins is also impaired in endothelial cells. Genetic mutation, environmental factors such as exposure to stimulant use, and collagen vascular disease have a role in different subtypes of PAH. Portopulmonary hypertension is a subtype of PAH in patients with portal hypertension.

WSPH Groups 2-5. Increased PVR can result from pulmonary vascular congestion due to left heart dysfunction; destruction of the alveolar capillary bed; chronic hypoxic vasoconstriction; and vascular occlusion from thromboembolism.

Continue to: Once approximately...

Once approximately 30% of the pulmonary vasculature is involved, pressure in the pulmonary circulation starts to rise. In all WSPH groups, this increase in PVR results in increased right ventricular afterload that, over time, leads to right ventricular ­dysfunction.^7,11,12

How does PH manifest?

Patients who have PH usually present with dyspnea, fatigue, chest pain, near-syncope, syncope, or lower-extremity edema, or any combination of these symptoms. The nonspecificity of presenting symptoms can lead to a delay in diagnosis.

In addition, suspicion of PH should be raised when a patient:

• presents with skin discoloration (light or dark) or a telangiectatic rash
• presents with difficulty swallowing
• has a history of connective tissue disease or hemolytic anemia
• has risk factors for HIV infection or liver disease
• takes an appetite suppressant
• has been exposed to other toxins known to increase the risk of PH.

A detailed medical history—looking for chronic lung or heart disease, thromboembolism, sleep-disordered breathing, a thyroid disorder, chronic renal failure, or a metabolic disorder—should be obtained.

Common findings on the physical exam in PH include:

• an increased P2 heart sound (pulmonic closure)
• high-pitched holosystolic murmur from tricuspid regurgitation
• pulmonic insufficiency murmur
• jugular venous distension
• hepatojugular reflux
• peripheral edema.

These findings are not specific to PH but, again, their presence warrants consideration of PH.

How best to approach evaluation and diagnosis?

The work-up for PH is broad; FIGURE 1^13,14 provides an outline of how to proceed when there is a concern for PH. For the work-up of symptoms and signs listed earlier, chest radiography and electrocardiography are recommended.

Continue to: Radiographic findings

Radiographic findings that suggest PH include enlargement of central pulmonary arteries and the right ventricle and dilation of the right atrium. Pulmonary vascular congestion might also be seen, secondary to left heart disease.⁷

Electrocardiographic findings of PH are demonstrated by signs of left ventricular hypertrophy, especially in Group 2 PH. Upright R waves in V₁-V₂ with deeper S waves in V₅-V₆ might represent right ventricular hypertrophy or right heart strain. Frequent premature atrial contractions and multifocal atrial tachycardia are also associated with PH.⁷

Brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. The level of BNP might be elevated in PH, but its role in the diagnostic process has not been established. BNP can, however, be used to monitor treatment effectiveness and prognosis.¹⁵ A normal electrocardiogram in tandem with a normal level of BNP or NT-proBNP is associated with a low likelihood of PH.⁶

Transthoracic echocardiography (TTE) is the initial evaluation tool whenever PH is suspected. Echocardiographic findings suggestive of PH include a combination of ­tricuspid regurgitation velocity > 2.8 m/s ­(FIGURE 2); estimated pulmonary artery systolic pressure > 35 mm Hg in younger adults and > 40 mm Hg in older adults; right ventricular hypertrophy or strain; or a combination of these. Other TTE findings suggestive of PH are related to the ventricles, pulmonary artery, inferior vena cava, and right atrium (TABLE 2⁶). The probability of PH based on TTE findings is categorized as low, intermediate, or high (see TABLE 2⁶ and TABLE 3¹⁶ for details).

Older guidelines, still used by some, rely on the estimated pulmonary artery systolic pressure (ePASP) reading on echocardiography.^13,17 However, studies have reported poor correlation between ePASP readings and values obtained from RHC.¹⁸

TTE also provides findings of left heart disease, such as left ventricular systolic and diastolic dysfunction and left-sided valvular pathology. Patients with suspected PH in whom evidence of left heart disease on TTE is insufficient for making the diagnosis should receive further evaluation for their possible status in Groups 3-5 PH.

Ventilation–perfusion (VQ) scan. If CTEPH is suspected, a VQ scan should be performed. The scan is highly sensitive for CTEPH; a normal VQ scan excludes CTEPH. Computed tomography (CT) of the chest is not helpful for identifying chronic thromboembolism.¹³

Continue to: Coagulation assays

Coagulation assays. When CTEPH is suspected, coagulopathy can be assessed by measuring anticardiolipin antibodies, lupus anticoagulant, and anti-b-2-glycoprotein ­antibodies.¹³

Chest CT will show radiographic findings in greater detail. An enlarged pulmonary artery (diameter ≥ 29 mm) or a ratio ≥ 1 of the diameter of the main pulmonary artery to the diameter of the ascending aorta is suggestive of PH.

Other tests. Overnight oximetry and testing for sleep-disordered breathing, performed in an appropriate setting, can be ­considered.^13,14,19

Pulmonary function testing with diffusion capacity for carbon monoxide, high-resolution chest CT, and a 6-minute walk test (6MWT) can be considered in patients who have risk factors for chronic lung disease. Pulmonary function testing, including measurement of the diffusing capacity of the lungs for carbon monoxide, arterial blood gas analysis, and CT, is used to aid in interpreting echocardiographic findings in patients with lung disease in whom PH is suspected.

Testing for comorbidities. A given patient’s predisposing conditions for PH might already be known; if not, laboratory evaluation for conditions such as sickle cell disease, liver disease, thyroid dysfunction, connective tissue disorders (antibody tests of antinuclear antibody, rheumatoid factor, anticentromere, anti-topoisomerase, anti-RNA polymerase III, anti-double stranded DNA, anti-Ro, anti-La, and anti-U1-RNP), and vasculitis (anti-­neutrophil cytoplasmic autoantibodies) should be undertaken.

Analysis of stool and urine for Schistosoma spp parasites can be considered in an appropriate clinical setting.¹³

Right heart catheterization. Once alternative diagnoses are excluded, RHC is recommended to make a definitive diagnosis and assess the contribution of left heart disease. Vasoreactivity—defined as a reduction in mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg with increased or unchanged cardiac output—is assessed during RHC by administering nitric oxide or another vasodilator. This definition of vasoreactivity helps guide medical management in patients with PAH.^7,20

Continue to: 6MWT

6MWT. Once the diagnosis of PH is made, a 6MWT helps establish baseline functional performance and will help you to monitor disease progression.

Who can benefit from screening for PH?

Annual evaluation of the risk of PAH is recommended for patients with systemic sclerosis or portal hypertension¹³ and can be considered in patients who have connective tissue disease with overlap features of systemic sclerosis.

Assessment for CTEPH or chronic thromboembolic pulmonary disease is recommended for patients with persistent or new-onset dyspnea or exercise limitation after pulmonary embolism.

Screening echocardiography for PH is recommended for patients who have been referred for liver transplantation.⁶

How risk is stratified

Risk stratification is used to manage PH and assess prognosis.

At diagnosis. Application of a 3-strata model of risk assessment (low, intermediate, high) is recommended.⁶ Pertinent data to determine risk include signs of right heart failure, progression of symptoms and clinical manifestations, report of syncope, WHO functional class, 6MWT, cardiopulmonary exercise testing, biomarkers (BNP or ­NT-proBNP), echocardiography, presence of pericardial effusion, and cardiac magnetic resonance imaging.

At follow-up. Use of a 4-strata model (low, intermediate–low, intermediate–high, and high risk) is recommended. Data used are WHO functional class, 6MWT, and results of either BNP or NT-proBNP testing.⁶

Continue to: When to refer

Specialty consultation^21-23 is recommended for:

• all patients with PAH
• PH patients in clinical Groups 2 and 3 whose disease is disproportionate to the extent of their left heart disease or hypoxic lung disease
• patients in whom there is concern about CTEPH and who therefore require early referral to a specialist for definitive treatment
• patients in whom the cause of PH is unclear or multifactorial (ie, clinical Group 5).

What are the options for managing PH?

Management of PH is based on the cause and classification of the individual patient’s ­disease.

Treatment for WSPH Group 1

Patients require referral to a specialty clinic for diagnosis, treatment, and monitoring of progression.¹⁰

First, regrettably, none of the medications approved by the US Food and Drug Administration for treating PAH prevent progression.⁷

Drugs and toxins associated with pulmonary arterial hypertension include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Patients with idiopathic, hereditary, or drug-induced PAH with positive vasoreactivity are treated with a calcium channel blocker (CCB). The dosage is titrated to optimize therapy for the individual patient.

The patient is then reassessed after 3 to 6 months of medical therapy. Current treatment is continued if the following goals have been met:

• WHO functional classification is I or II
• BNP < 50 ng/L or NT-proBNP < 300 ng/L
• hemodynamics are normal or near-normal (mPAP ≤ 30 mm Hg and PVR ≤ 4 WU).

If these goals have not been met, treatment is adjusted by following the algorithm described below.

Continue to: The treatment algorithm...

The treatment algorithm for idiopathic-, heritable-, drug-induced, and connective tissue disease–associated PAH highlights the importance of cardiopulmonary comorbidities and risk strata at the time treatment is initiated and then during follow-up.

Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, including obesity, hypertension, diabetes, and coronary artery disease. Pulmonary comorbidities can include signs of mild parenchymal lung disease and are often associated with a low carbon monoxide diffusing capacity (< 45% of predicted value). 

The management algorithm proceeds as follows:

• For patients without cardiopulmonary comorbidities and who are at low or intermediate risk, treatment of PAH with an endothelin receptor antagonist (ERA) plus a phosphodiesterase-5 (PDE5) inhibitor is recommended.
• For patients without cardiopulmonary comorbidities and who are at high risk, treatment with an ERA, a PDE5 inhibitor, and either an IV or subcutaneous prostacyclin analogue (PCA) can be considered.
• Patients in either of the preceding 2 categories should have regular follow-up assessment; at such follow-up, their risk should be stratified based on 4 strata (see “How risk is stratified”):
  • Low risk: Continue initial therapy.
  • Low-to-intermediate risk: Consider adding a prostacyclin receptor agonist to the initial regimen or switch to a PDE5 inhibitor or a soluble guanylate cyclase stimulator.
  • Intermediate-to-high or high risk: Consider adding a PCA (IV epoprostenol or IV or subcutaneous treprostinil). In addition, or alternatively, have the patient evaluated for lung transplantation.
• For patients with cardiopulmonary comorbidity—in any risk category—consider oral monotherapy with a PDE5 inhibitor or an ERA. Provide regular follow-up and individualize therapy.⁶

Treatment for WSPH Groups 2 and 3

Treatment is focused on the underlying cause of PH:

• Patients who have left heart disease with either severe pre-capillary component PH or markers of right ventricular dysfunction, or both, should be referred to a PH center.
• Patients with combined pre-capillary and postcapillary PH in whom pre-capillary PH is severe should be considered for an individualized approach.
• Consider prescribing the ERA bosentan in specific scenarios (eg, the Eisenmenger syndrome of left-right shunting resulting from a congenital cardiac defect) to improve exercise capacity. If PAH persists after corrected adult congenital heart disease, follow the PAH treatment algorithm for Group 1 patients (described earlier).
• For patients in Group 3, those who have severe PH should be referred to a PH center.
• Consider prescribing inhaled treprostinil in PH with interstitial lung disease.

Treatment for WSPH Group 4

Patients with CTEPH are the only ones for whom pulmonary endarterectomy (PEA), the treatment of choice, might be curative. Balloon angioplasty can be considered for inoperable cases⁶; these patients should be placed on lifelong anticoagulant therapy.

The nonspecificity of presenting symptoms of pulmonary hypertension— dyspnea, fatigue, chest pain, near syncope, syncope, lowerextremity edema—can lead to a delay in diagnosis.

Symptomatic patients who have inoperable CTEPH or persistent recurrent PH after PEA are medically managed; the agent of choice is riociguat. Patients who have undergone PEA or balloon angioplasty and those receiving pharmacotherapy should be followed long term.

Treatment for WSPH Group 5

Management of these patients focuses on associated conditions.

Continue to: Which medications for PAH?

CCBs. Four options in this class have shown utility, notably in patients who have had a positive vasoreactivity test (see “How best to approach evaluation and diagnosis?”):

• Nifedipine is started at 10 mg tid; target dosage is 20 to 60 mg, bid or tid.
• Diltiazem is started at 60 mg bid; target dosage is 120 to 360 mg bid.
• Amlodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.
• Felodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.

Felodipine and amlodipine have longer half-lives than other CCBs and are well ­tolerated.

ERA. Used as vasodilators are ambrinsentan (starting dosage, 5 mg/d; target dosage, 10 mg/d), macitentan (starting and target dosage, 10 mg/d), and bosentan (starting dosage, 62.5 mg bid; target dosage, 125 mg bid).

Nitric oxide–cyclic guanosine monophosphate enhancers. These are the PDE5 inhibitors sildenafil (starting and target dosages, 20 mg tid) and tadalafil (starting dosage, 20 or 40 mg/d; target dosage, 40 mg/d), and the guanylate cyclase stimulant riociguat (starting dosage, 1 mg tid; target dosage, 2.5 mg tid). All 3 agents enhance production of the potent vasodilator nitric oxide, production of which is impaired in PH.

Prostanoids. Several options are available:

• Beraprost sodium. For this oral prostacyclin analogue, starting dosage is 20 μg tid; target dosage is the maximum tolerated dosage (as high as 40 μg tid).
• Extended-release beraprost. Starting dosage is 60 μg bid; target dosage is the maximum tolerated dosage (as high as 180 μg bid).
• Oral treprostinil. Starting dosage is 0.25 mg bid or 0.125 mg tid; target dosage is the maximum tolerated dosage.
• Inhaled iloprost. Starting dosage of this prostacyclin analogue is 2.5 μg, 6 to 9 times per day; target dosage is 5 μg, 6 to 9 times per day.
• Inhaled treprostinil. Starting dosage is 18 μg qid; target dosage is 54 to 72 μg qid.
• Eproprostenol is administered by continuous IV infusion, at a starting dosage of 2 ng/kg/min; target dosage is determined by tolerability and effectiveness (typically, 30 ng/kg/min).
• IV treprostinil. Starting dosage 1.25 ng/kg/min; target dosage is determined by tolerability and effectiveness, with a typical dosage of 60 ng/kg/min.

Combination treatment with the agents listed above is often utilized.

Selexipag. This oral selective nonprostainoid prostacyclin receptor agonist is started at 200 μg bid; target dosage is the maximum tolerated, as high as 1600 μg bid.

Continue to: Supportive therapy

The need for oxygen should be addressed in patients with hypoxia in any setting—r­esting, exercise induced, and nocturnal.²⁴ Patients with an arterial blood oxygen pressure < 60 mm Hg (SaO₂ < 90 mm Hg) should be on long-term oxygen therapy.⁶

Common physical findings in pulmonary hypertension include an increased P2 heart sound, high-pitched holosystolic murmur from tricuspid regurgitation, and pulmonic insufficiency murmur.

Diuretics are beneficial in patients with chronic fluid retention from PH that is related to right ventricular failure.²⁴

Pulmonary rehabilitation and exercise. Contrary to common belief that exercise training is contraindicated in patients with PH, exercise training has emerged in the past decade as an effective tool to improve exercise capacity, ventilatory efficiency, and quality of life. While a patient is training, oxygen saturation, measured by pulse oximetry, should be maintained at > 90% throughout the exercise session to avoid hypoxic pulmonary artery vasoconstriction.²⁵

A patient who does not qualify for pulmonary or cardiac rehabilitation should be referred for physical therapy.²⁴

Ongoing follow-up in primary care

Instruct patients not to abruptly discontinue medications that have been prescribed for PH. Ongoing follow-up and monitoring involves assessing right heart function, exercise tolerance, and resting and ambulatory oximetry. Testing for the level of BNP provides prognostic information and allows assessment of treatment response.¹⁵ The frequency of 6MWT, echocardio­graphy, and RHC is decided on a case-by-case basis.

Other considerations

Pregnancy. PAH often affects patients of childbearing age. Because PAH-associated maternal mortality and the risk to the fetus during pregnancy are high, pregnancy is not recommended for patients with PAH. After a diagnosis of PAH in a patient of childbearing age, counseling should be offered at an expert center. Advice on effective contraception methods should be given early on.^10,26-29

Surgery. Every patient with clinically significant PH is at increased risk of perioperative morbidity and death.^30,31 Guidelines recommend that these patients avoid nonessential surgery; if surgery is necessary, care should be provided at a PH expert center.¹⁰

Continue to: Patients with severe PH...

Patients with severe PH should consider surgery for any indication carefully, discussing with the care team their risk and exploring nonsurgical options. Cardiothoracic surgical and liver transplantation services might have highly specific criteria for treating patients with PH, but other essential and nonessential surgeries require individualized risk stratification. Surgery for patients with severe PH and right ventricular dysfunction should be performed at a center equipped to handle high-risk patients.

Other preventive measures. Patients with PAH should^6,10:

• remain current with immunization against influenza virus, SARS-CoV-2, and pneumococcal pneumonia
• avoid high altitudes
• use supplemental oxygen during air travel to keep arterial oxygen saturation > 91%.

Lung transplantation. Patients eligible for transplantation who (1) are at intermediate-to-high risk or high risk or (2) have a REVEAL (Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management) risk score > 7, and who have had an inadequate response to oral combination therapy, should be referred for evaluation for lung transplantation. Placement on the list for lung transplantation is also recommended for patients at high risk of death and who have a REVEAL risk score ≥ 10 despite medical therapy, including a subcutaneous or IV prostacyclin analogue.⁶

PH in infants and children

The Pediatric Task Force of the 6th WSPH has applied the new definition proposed for adult PH (> 20 mm Hg mPAP) to children and infants > 3 months of age (see “Pulmonary hypertension in the pediatric population,” at left^32-36).

CORRESPONDENCE
Madhavi Singh, MD, 1850 East Park Ave., Suite 207, State College, PA 16803; msingh1@pennstatehealth.psu.edu

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure (mPAP) have led to a reported increase in the number of patients given a diagnosis of PH. Although the evaluation and treatment of PH relies on the specialist, as we explain here, family physicians play a pivotal role in the diagnosis, reduction or elimination of risk factors for PH, and timely referral to a pulmonologist or cardiologist who has expertise in managing the disease. We also address the important finding that adult patients who have been evaluated, treated, and followed based on guidelines—updated just last year—have a longer life expectancy than patients who have not been treated properly or not treated at all.

Last, we summarize the etiology, evaluation, and management of PH in the pediatric population.

What is pulmonary hypertension? A revised definition

Prior to 2018, PH was defined as mPAP (measured by right heart catheterization [RHC]) ≥ 25 mm Hg at rest. Now, based on guidelines developed at the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, PH is defined as mPAP > 20 mm Hg.^1,2 That change was based on studies in which researchers noted higher mortality in adults who had mPAP below the traditional threshold.^3,4 There is no evidence, however, of increased mortality in the pediatric population in this lower mPAP range.⁵

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure have led to a reported increase in the number of patients given a diagnosis of PH.

PH is estimated to be present in approximately 1% of the population.⁶ PH due to other diseases—eg, cardiac disease, lung disease, or a chronic thromboembolic condition—­reflects the prevalence of the causative disease.⁷

How is pulmonary hypertension classified?

Based on the work of a Task Force of the 6th WSPH, PH is classified by underlying pathophysiology, hemodynamics, and functional status. Clinical classification comprises 5 categories, or “groups,” based on underlying pathophysiology (TABLE 1⁶).

Clinical classification

Group 1 PH includes patients with primary pulmonary hypertension, also referred to ­(including in this article) as pulmonary arterial hypertension (PAH). Hemodynamic criteria that define PAH include pulmonary vascular resistance (PVR) > 2 Woods units^a and pulmonary capillary wedge pressure > 15 mm Hg. Idiopathic PAH is the most common diagnosis in this group.

The incidence of PAH is approximately 6 cases for every 1 million adults; prevalence is 48 to 55 cases for every 1 million adults. PAH is more common in women.⁶

Continue to: Less common causes...

Less common causes in Group 1 include connective tissue disorders and exposure to toxins. Drugs and toxins that have a well-defined association with PAH include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Group 2 PH comprises patients whose disease results from left heart dysfunction, the most common cause of PH. This subgroup has an elevated pulmonary artery wedge pressure > 15 mm Hg.⁸ Patients have either isolated postcapillary PH or combined pre-capillary and postcapillary PH.

Group 3 PH comprises patients whose PH is secondary to chronic and hypoxic lung disease. Patients in this group have pre-­capillary PH; even a modest elevation in mPAP (20-29 mm Hg) is associated with a poor prognosis. Group 3 patients have elevated PVR, even with mild PH.² Exertional dyspnea disproportionate to the results of pulmonary function testing, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation with exercise all point to severe PH in these patients.⁹

Group 4 PH encompasses patients with pulmonary artery obstruction, the most common cause of which is related to chronic thromboembolism. Other causes include obstruction of the pulmonary artery from an extrinsic source. Patients with chronic thromboembolic pulmonary hypertension (CTEPH) also have pre-capillary PH, resulting from elevated pulmonary pressures secondary to thromboembolic burden, as well as pulmonary remodeling in unobstructed small arterioles.

Group 5 PH is a miscellaneous group secondary to unclear or multiple causes, including chronic hematologic anemia (eg, sickle cell disease), systemic disorders (eg, sarcoidosis), and metabolic disorders (eg, glycogen storage disease). Patients in Group 5 can have both pre-capillary and postcapillary hypertension.

Classification by functional status

The World Health Organization (WHO) Functional Classification of Patients with Pulmonary Hypertension is divided into 4 classes.¹⁰ This system is used to guide treatment and for prognostic purposes:

Class I. Patients have no limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope.

Continue to: Class II

Class II. Patients have slight limitation of physical activity. They are comfortable at rest but daily physical activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class III. These patients have marked limitation of physical activity. They are comfortable at rest, but less-than-ordinary activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class IV. Patients are unable to carry out any physical activity without symptoms. They manifest signs of right heart failure. Dyspnea or fatigue, or both, might be present even at rest.

How is the pathophysiology of PH described?

The term pulmonary hypertension refers to an elevation in PAP that can result from any number of causes. Pulmonary arterial hypertension is a subcategory of PH in which a rise in PAP is due to primary pathology in the arteries proper.

As noted, PH results from a variety of pathophysiologic mechanisms, reflected in the classification in TABLE 1.⁶

WSPH Group 1 patients are considered to have PAH; for most, disease is idiopathic. In small-caliber pulmonary arteries, hypertrophy of smooth muscle, endothelial cells, and adventitia leads to increased resistance. Production of nitric oxide and prostacyclins is also impaired in endothelial cells. Genetic mutation, environmental factors such as exposure to stimulant use, and collagen vascular disease have a role in different subtypes of PAH. Portopulmonary hypertension is a subtype of PAH in patients with portal hypertension.

WSPH Groups 2-5. Increased PVR can result from pulmonary vascular congestion due to left heart dysfunction; destruction of the alveolar capillary bed; chronic hypoxic vasoconstriction; and vascular occlusion from thromboembolism.

Continue to: Once approximately...

Once approximately 30% of the pulmonary vasculature is involved, pressure in the pulmonary circulation starts to rise. In all WSPH groups, this increase in PVR results in increased right ventricular afterload that, over time, leads to right ventricular ­dysfunction.^7,11,12

How does PH manifest?

Patients who have PH usually present with dyspnea, fatigue, chest pain, near-syncope, syncope, or lower-extremity edema, or any combination of these symptoms. The nonspecificity of presenting symptoms can lead to a delay in diagnosis.

In addition, suspicion of PH should be raised when a patient:

• presents with skin discoloration (light or dark) or a telangiectatic rash
• presents with difficulty swallowing
• has a history of connective tissue disease or hemolytic anemia
• has risk factors for HIV infection or liver disease
• takes an appetite suppressant
• has been exposed to other toxins known to increase the risk of PH.

A detailed medical history—looking for chronic lung or heart disease, thromboembolism, sleep-disordered breathing, a thyroid disorder, chronic renal failure, or a metabolic disorder—should be obtained.

Common findings on the physical exam in PH include:

• an increased P2 heart sound (pulmonic closure)
• high-pitched holosystolic murmur from tricuspid regurgitation
• pulmonic insufficiency murmur
• jugular venous distension
• hepatojugular reflux
• peripheral edema.

These findings are not specific to PH but, again, their presence warrants consideration of PH.

How best to approach evaluation and diagnosis?

The work-up for PH is broad; FIGURE 1^13,14 provides an outline of how to proceed when there is a concern for PH. For the work-up of symptoms and signs listed earlier, chest radiography and electrocardiography are recommended.

Continue to: Radiographic findings

Radiographic findings that suggest PH include enlargement of central pulmonary arteries and the right ventricle and dilation of the right atrium. Pulmonary vascular congestion might also be seen, secondary to left heart disease.⁷

Electrocardiographic findings of PH are demonstrated by signs of left ventricular hypertrophy, especially in Group 2 PH. Upright R waves in V₁-V₂ with deeper S waves in V₅-V₆ might represent right ventricular hypertrophy or right heart strain. Frequent premature atrial contractions and multifocal atrial tachycardia are also associated with PH.⁷

Brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. The level of BNP might be elevated in PH, but its role in the diagnostic process has not been established. BNP can, however, be used to monitor treatment effectiveness and prognosis.¹⁵ A normal electrocardiogram in tandem with a normal level of BNP or NT-proBNP is associated with a low likelihood of PH.⁶

Transthoracic echocardiography (TTE) is the initial evaluation tool whenever PH is suspected. Echocardiographic findings suggestive of PH include a combination of ­tricuspid regurgitation velocity > 2.8 m/s ­(FIGURE 2); estimated pulmonary artery systolic pressure > 35 mm Hg in younger adults and > 40 mm Hg in older adults; right ventricular hypertrophy or strain; or a combination of these. Other TTE findings suggestive of PH are related to the ventricles, pulmonary artery, inferior vena cava, and right atrium (TABLE 2⁶). The probability of PH based on TTE findings is categorized as low, intermediate, or high (see TABLE 2⁶ and TABLE 3¹⁶ for details).

Older guidelines, still used by some, rely on the estimated pulmonary artery systolic pressure (ePASP) reading on echocardiography.^13,17 However, studies have reported poor correlation between ePASP readings and values obtained from RHC.¹⁸

TTE also provides findings of left heart disease, such as left ventricular systolic and diastolic dysfunction and left-sided valvular pathology. Patients with suspected PH in whom evidence of left heart disease on TTE is insufficient for making the diagnosis should receive further evaluation for their possible status in Groups 3-5 PH.

Ventilation–perfusion (VQ) scan. If CTEPH is suspected, a VQ scan should be performed. The scan is highly sensitive for CTEPH; a normal VQ scan excludes CTEPH. Computed tomography (CT) of the chest is not helpful for identifying chronic thromboembolism.¹³

Continue to: Coagulation assays

Coagulation assays. When CTEPH is suspected, coagulopathy can be assessed by measuring anticardiolipin antibodies, lupus anticoagulant, and anti-b-2-glycoprotein ­antibodies.¹³

Chest CT will show radiographic findings in greater detail. An enlarged pulmonary artery (diameter ≥ 29 mm) or a ratio ≥ 1 of the diameter of the main pulmonary artery to the diameter of the ascending aorta is suggestive of PH.

Other tests. Overnight oximetry and testing for sleep-disordered breathing, performed in an appropriate setting, can be ­considered.^13,14,19

Pulmonary function testing with diffusion capacity for carbon monoxide, high-resolution chest CT, and a 6-minute walk test (6MWT) can be considered in patients who have risk factors for chronic lung disease. Pulmonary function testing, including measurement of the diffusing capacity of the lungs for carbon monoxide, arterial blood gas analysis, and CT, is used to aid in interpreting echocardiographic findings in patients with lung disease in whom PH is suspected.

Testing for comorbidities. A given patient’s predisposing conditions for PH might already be known; if not, laboratory evaluation for conditions such as sickle cell disease, liver disease, thyroid dysfunction, connective tissue disorders (antibody tests of antinuclear antibody, rheumatoid factor, anticentromere, anti-topoisomerase, anti-RNA polymerase III, anti-double stranded DNA, anti-Ro, anti-La, and anti-U1-RNP), and vasculitis (anti-­neutrophil cytoplasmic autoantibodies) should be undertaken.

Analysis of stool and urine for Schistosoma spp parasites can be considered in an appropriate clinical setting.¹³

Right heart catheterization. Once alternative diagnoses are excluded, RHC is recommended to make a definitive diagnosis and assess the contribution of left heart disease. Vasoreactivity—defined as a reduction in mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg with increased or unchanged cardiac output—is assessed during RHC by administering nitric oxide or another vasodilator. This definition of vasoreactivity helps guide medical management in patients with PAH.^7,20

Continue to: 6MWT

6MWT. Once the diagnosis of PH is made, a 6MWT helps establish baseline functional performance and will help you to monitor disease progression.

Who can benefit from screening for PH?

Annual evaluation of the risk of PAH is recommended for patients with systemic sclerosis or portal hypertension¹³ and can be considered in patients who have connective tissue disease with overlap features of systemic sclerosis.

Assessment for CTEPH or chronic thromboembolic pulmonary disease is recommended for patients with persistent or new-onset dyspnea or exercise limitation after pulmonary embolism.

Screening echocardiography for PH is recommended for patients who have been referred for liver transplantation.⁶

How risk is stratified

Risk stratification is used to manage PH and assess prognosis.

At diagnosis. Application of a 3-strata model of risk assessment (low, intermediate, high) is recommended.⁶ Pertinent data to determine risk include signs of right heart failure, progression of symptoms and clinical manifestations, report of syncope, WHO functional class, 6MWT, cardiopulmonary exercise testing, biomarkers (BNP or ­NT-proBNP), echocardiography, presence of pericardial effusion, and cardiac magnetic resonance imaging.

At follow-up. Use of a 4-strata model (low, intermediate–low, intermediate–high, and high risk) is recommended. Data used are WHO functional class, 6MWT, and results of either BNP or NT-proBNP testing.⁶

Continue to: When to refer

Specialty consultation^21-23 is recommended for:

• all patients with PAH
• PH patients in clinical Groups 2 and 3 whose disease is disproportionate to the extent of their left heart disease or hypoxic lung disease
• patients in whom there is concern about CTEPH and who therefore require early referral to a specialist for definitive treatment
• patients in whom the cause of PH is unclear or multifactorial (ie, clinical Group 5).

What are the options for managing PH?

Management of PH is based on the cause and classification of the individual patient’s ­disease.

Treatment for WSPH Group 1

Patients require referral to a specialty clinic for diagnosis, treatment, and monitoring of progression.¹⁰

First, regrettably, none of the medications approved by the US Food and Drug Administration for treating PAH prevent progression.⁷

Drugs and toxins associated with pulmonary arterial hypertension include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Patients with idiopathic, hereditary, or drug-induced PAH with positive vasoreactivity are treated with a calcium channel blocker (CCB). The dosage is titrated to optimize therapy for the individual patient.

The patient is then reassessed after 3 to 6 months of medical therapy. Current treatment is continued if the following goals have been met:

• WHO functional classification is I or II
• BNP < 50 ng/L or NT-proBNP < 300 ng/L
• hemodynamics are normal or near-normal (mPAP ≤ 30 mm Hg and PVR ≤ 4 WU).

If these goals have not been met, treatment is adjusted by following the algorithm described below.

Continue to: The treatment algorithm...

The treatment algorithm for idiopathic-, heritable-, drug-induced, and connective tissue disease–associated PAH highlights the importance of cardiopulmonary comorbidities and risk strata at the time treatment is initiated and then during follow-up.

Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, including obesity, hypertension, diabetes, and coronary artery disease. Pulmonary comorbidities can include signs of mild parenchymal lung disease and are often associated with a low carbon monoxide diffusing capacity (< 45% of predicted value). 

The management algorithm proceeds as follows:

• For patients without cardiopulmonary comorbidities and who are at low or intermediate risk, treatment of PAH with an endothelin receptor antagonist (ERA) plus a phosphodiesterase-5 (PDE5) inhibitor is recommended.
• For patients without cardiopulmonary comorbidities and who are at high risk, treatment with an ERA, a PDE5 inhibitor, and either an IV or subcutaneous prostacyclin analogue (PCA) can be considered.
• Patients in either of the preceding 2 categories should have regular follow-up assessment; at such follow-up, their risk should be stratified based on 4 strata (see “How risk is stratified”):
  • Low risk: Continue initial therapy.
  • Low-to-intermediate risk: Consider adding a prostacyclin receptor agonist to the initial regimen or switch to a PDE5 inhibitor or a soluble guanylate cyclase stimulator.
  • Intermediate-to-high or high risk: Consider adding a PCA (IV epoprostenol or IV or subcutaneous treprostinil). In addition, or alternatively, have the patient evaluated for lung transplantation.
• For patients with cardiopulmonary comorbidity—in any risk category—consider oral monotherapy with a PDE5 inhibitor or an ERA. Provide regular follow-up and individualize therapy.⁶

Treatment for WSPH Groups 2 and 3

Treatment is focused on the underlying cause of PH:

• Patients who have left heart disease with either severe pre-capillary component PH or markers of right ventricular dysfunction, or both, should be referred to a PH center.
• Patients with combined pre-capillary and postcapillary PH in whom pre-capillary PH is severe should be considered for an individualized approach.
• Consider prescribing the ERA bosentan in specific scenarios (eg, the Eisenmenger syndrome of left-right shunting resulting from a congenital cardiac defect) to improve exercise capacity. If PAH persists after corrected adult congenital heart disease, follow the PAH treatment algorithm for Group 1 patients (described earlier).
• For patients in Group 3, those who have severe PH should be referred to a PH center.
• Consider prescribing inhaled treprostinil in PH with interstitial lung disease.

Treatment for WSPH Group 4

Patients with CTEPH are the only ones for whom pulmonary endarterectomy (PEA), the treatment of choice, might be curative. Balloon angioplasty can be considered for inoperable cases⁶; these patients should be placed on lifelong anticoagulant therapy.

The nonspecificity of presenting symptoms of pulmonary hypertension— dyspnea, fatigue, chest pain, near syncope, syncope, lowerextremity edema—can lead to a delay in diagnosis.

Symptomatic patients who have inoperable CTEPH or persistent recurrent PH after PEA are medically managed; the agent of choice is riociguat. Patients who have undergone PEA or balloon angioplasty and those receiving pharmacotherapy should be followed long term.

Treatment for WSPH Group 5

Management of these patients focuses on associated conditions.

Continue to: Which medications for PAH?

CCBs. Four options in this class have shown utility, notably in patients who have had a positive vasoreactivity test (see “How best to approach evaluation and diagnosis?”):

• Nifedipine is started at 10 mg tid; target dosage is 20 to 60 mg, bid or tid.
• Diltiazem is started at 60 mg bid; target dosage is 120 to 360 mg bid.
• Amlodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.
• Felodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.

Felodipine and amlodipine have longer half-lives than other CCBs and are well ­tolerated.

ERA. Used as vasodilators are ambrinsentan (starting dosage, 5 mg/d; target dosage, 10 mg/d), macitentan (starting and target dosage, 10 mg/d), and bosentan (starting dosage, 62.5 mg bid; target dosage, 125 mg bid).

Nitric oxide–cyclic guanosine monophosphate enhancers. These are the PDE5 inhibitors sildenafil (starting and target dosages, 20 mg tid) and tadalafil (starting dosage, 20 or 40 mg/d; target dosage, 40 mg/d), and the guanylate cyclase stimulant riociguat (starting dosage, 1 mg tid; target dosage, 2.5 mg tid). All 3 agents enhance production of the potent vasodilator nitric oxide, production of which is impaired in PH.

Prostanoids. Several options are available:

• Beraprost sodium. For this oral prostacyclin analogue, starting dosage is 20 μg tid; target dosage is the maximum tolerated dosage (as high as 40 μg tid).
• Extended-release beraprost. Starting dosage is 60 μg bid; target dosage is the maximum tolerated dosage (as high as 180 μg bid).
• Oral treprostinil. Starting dosage is 0.25 mg bid or 0.125 mg tid; target dosage is the maximum tolerated dosage.
• Inhaled iloprost. Starting dosage of this prostacyclin analogue is 2.5 μg, 6 to 9 times per day; target dosage is 5 μg, 6 to 9 times per day.
• Inhaled treprostinil. Starting dosage is 18 μg qid; target dosage is 54 to 72 μg qid.
• Eproprostenol is administered by continuous IV infusion, at a starting dosage of 2 ng/kg/min; target dosage is determined by tolerability and effectiveness (typically, 30 ng/kg/min).
• IV treprostinil. Starting dosage 1.25 ng/kg/min; target dosage is determined by tolerability and effectiveness, with a typical dosage of 60 ng/kg/min.

Combination treatment with the agents listed above is often utilized.

Selexipag. This oral selective nonprostainoid prostacyclin receptor agonist is started at 200 μg bid; target dosage is the maximum tolerated, as high as 1600 μg bid.

Continue to: Supportive therapy

The need for oxygen should be addressed in patients with hypoxia in any setting—r­esting, exercise induced, and nocturnal.²⁴ Patients with an arterial blood oxygen pressure < 60 mm Hg (SaO₂ < 90 mm Hg) should be on long-term oxygen therapy.⁶

Common physical findings in pulmonary hypertension include an increased P2 heart sound, high-pitched holosystolic murmur from tricuspid regurgitation, and pulmonic insufficiency murmur.

Diuretics are beneficial in patients with chronic fluid retention from PH that is related to right ventricular failure.²⁴

Pulmonary rehabilitation and exercise. Contrary to common belief that exercise training is contraindicated in patients with PH, exercise training has emerged in the past decade as an effective tool to improve exercise capacity, ventilatory efficiency, and quality of life. While a patient is training, oxygen saturation, measured by pulse oximetry, should be maintained at > 90% throughout the exercise session to avoid hypoxic pulmonary artery vasoconstriction.²⁵

A patient who does not qualify for pulmonary or cardiac rehabilitation should be referred for physical therapy.²⁴

Ongoing follow-up in primary care

Instruct patients not to abruptly discontinue medications that have been prescribed for PH. Ongoing follow-up and monitoring involves assessing right heart function, exercise tolerance, and resting and ambulatory oximetry. Testing for the level of BNP provides prognostic information and allows assessment of treatment response.¹⁵ The frequency of 6MWT, echocardio­graphy, and RHC is decided on a case-by-case basis.

Other considerations

Pregnancy. PAH often affects patients of childbearing age. Because PAH-associated maternal mortality and the risk to the fetus during pregnancy are high, pregnancy is not recommended for patients with PAH. After a diagnosis of PAH in a patient of childbearing age, counseling should be offered at an expert center. Advice on effective contraception methods should be given early on.^10,26-29

Surgery. Every patient with clinically significant PH is at increased risk of perioperative morbidity and death.^30,31 Guidelines recommend that these patients avoid nonessential surgery; if surgery is necessary, care should be provided at a PH expert center.¹⁰

Continue to: Patients with severe PH...

Patients with severe PH should consider surgery for any indication carefully, discussing with the care team their risk and exploring nonsurgical options. Cardiothoracic surgical and liver transplantation services might have highly specific criteria for treating patients with PH, but other essential and nonessential surgeries require individualized risk stratification. Surgery for patients with severe PH and right ventricular dysfunction should be performed at a center equipped to handle high-risk patients.

Other preventive measures. Patients with PAH should^6,10:

• remain current with immunization against influenza virus, SARS-CoV-2, and pneumococcal pneumonia
• avoid high altitudes
• use supplemental oxygen during air travel to keep arterial oxygen saturation > 91%.

Lung transplantation. Patients eligible for transplantation who (1) are at intermediate-to-high risk or high risk or (2) have a REVEAL (Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management) risk score > 7, and who have had an inadequate response to oral combination therapy, should be referred for evaluation for lung transplantation. Placement on the list for lung transplantation is also recommended for patients at high risk of death and who have a REVEAL risk score ≥ 10 despite medical therapy, including a subcutaneous or IV prostacyclin analogue.⁶

PH in infants and children

The Pediatric Task Force of the 6th WSPH has applied the new definition proposed for adult PH (> 20 mm Hg mPAP) to children and infants > 3 months of age (see “Pulmonary hypertension in the pediatric population,” at left^32-36).

CORRESPONDENCE
Madhavi Singh, MD, 1850 East Park Ave., Suite 207, State College, PA 16803; msingh1@pennstatehealth.psu.edu

WASHINGTON – On the heels the recently published final report from the SYMPLICITY HTN-3 renal denervation trial, a new analysis showed that Black patients, like non-Blacks, had sustained blood pressure control.

Contrary to a signal from earlier results, “there is nothing race specific about renal denervation,” said presenter Deepak L. Bhatt, MD, at the Cardiovascular Research Technologies conference, sponsored by MedStar Heart & Vascular Institute.

This did not prove to be the case during the 6-month controlled phase of the trial. When patients randomized to renal denervation or the sham procedure were stratified by race, the primary endpoint of reduction in office systolic blood pressure (SBP) reached significance in the experimental arm among non-Black patients (–6.63 mm Hg; P = .01), but not among Black patients (–2.25 mm Hg; P = .09).
 

Blacks comprised 26% of SYMPLICITY HTN-3 trial

In the initial controlled analysis, published in the New England Journal of Medicine, the lack of benefit in the substantial Black enrollment – representing 26% of the study total – weighed against the ability of the trial to demonstrate a benefit, but Dr. Bhatt pointed out that BP reductions were unexpectedly high in the sham group regardless of race. Patients randomized to the sham group were encouraged to adhere to antihypertensive therapy, and based on response, this was particularly effective in the Black sham subgroup.

In SYMPLICITY HTN-3, patients with treatment-resistant hypertension were randomized to renal denervation or a sham procedure in a 2:1 ratio. While the controlled phase lasted just 6 months, the follow-up after the study was unblinded has continued out to 3 years. Safety and efficacy were assessed at 12, 24, and 36 months.

Unlike the disappointing results at 6 months, renal denervation has been consistently associated with significantly lower BP over long-term follow-up, even though those randomized to the sham procedure were permitted to cross over. About two-thirds of the sham group did so.

In the recently published final report of SYMPLICITY, the overall median change in office SBP at 3 years regardless of race was –26.4 mm Hg in the group initially randomized to renal denervation versus –5.7 mm Hg (P < .0001) among those randomized to the sham procedure.

In the subgroup analysis presented by Dr. Bhatt, the relative control of office SBP, as well as other measures of blood pressure, were similarly and significantly reduced in both Black and non-Black patients. In general, the relative control offered by being randomized initially to renal denervation increased over time in both groups.

For example, the relative reduction in office SBP favoring renal denervation climbed from –12.0 mm Hg at 12 months (P = .0066) to –21.0 at 18 months (P = .0002) and then to –24.9 mm Hg (P < .0001) at 36 months in the Black subgroup. In non-Blacks, the same type of relative reductions were seen at each time point, climbing from –13.5 (P < .0001) to –20.5 (P < .0001) and then to –21.0 (P < .0001).

The comparisons for other measures of BP control, including office diastolic BP, 24-hour SBP, and BP control during morning, day, and night periods were also statistically and similarly improved for those initially randomized to renal denervation rather than a sham procedure among both Blacks and non-Blacks.

Renal denervation safe in Black and non-Black patients

Renal denervation was well tolerated in both Black and non-Black participants with no signal of long-term risks over 36 months in either group. Among Blacks, rates of death at 36 months (3% vs. 11%) and stroke (7% vs. 11%) were lower among those randomized to renal denervation relative to sham patients who never crossed over, but Dr. Bhatt said the numbers are too small to draw any conclusions about outcomes.

While this subgroup analysis, along with the final SYMPLICITY report, supports the efficacy of renal denervation over the long term, these data are also consistent with the recently published analysis of SPYRAL ON-MED . Together, these data have led many experts, including Dr. Bhatt, to conclude that renal denervation is effective and deserves regulatory approval.

“In out-of-control blood pressure, when patients have maxed out on medications and lifestyle, I think renal denervation is efficacious, and it is equally efficacious in Blacks and non-Blacks,” Dr. Bhatt said.

This subgroup analysis is important because of the need for options in treatment-resistant hypertension among Black as well as non-Black patients, pointed out Sripal Bangalore, MBBS, director of complex coronary intervention at New York University.

“I am glad that we did not conclude too soon that it does not work in Blacks,” Dr. Bangalore said. If renal denervation is approved, he expects this procedure to be a valuable tool in this racial group.

Dr. Bhatt reported financial relationship with more than 20 pharmaceutical and device companies, including Medtronic, which provided funding for the SYMPLICITY HTN-3 trial. Dr. Bangalore has financial relationships with Abbott Vascular, Amgen, Biotronik, Inari, Pfizer, Reata, and Truvic.

WASHINGTON – On the heels the recently published final report from the SYMPLICITY HTN-3 renal denervation trial, a new analysis showed that Black patients, like non-Blacks, had sustained blood pressure control.

Contrary to a signal from earlier results, “there is nothing race specific about renal denervation,” said presenter Deepak L. Bhatt, MD, at the Cardiovascular Research Technologies conference, sponsored by MedStar Heart & Vascular Institute.

This did not prove to be the case during the 6-month controlled phase of the trial. When patients randomized to renal denervation or the sham procedure were stratified by race, the primary endpoint of reduction in office systolic blood pressure (SBP) reached significance in the experimental arm among non-Black patients (–6.63 mm Hg; P = .01), but not among Black patients (–2.25 mm Hg; P = .09).
 

Blacks comprised 26% of SYMPLICITY HTN-3 trial

In the initial controlled analysis, published in the New England Journal of Medicine, the lack of benefit in the substantial Black enrollment – representing 26% of the study total – weighed against the ability of the trial to demonstrate a benefit, but Dr. Bhatt pointed out that BP reductions were unexpectedly high in the sham group regardless of race. Patients randomized to the sham group were encouraged to adhere to antihypertensive therapy, and based on response, this was particularly effective in the Black sham subgroup.

In SYMPLICITY HTN-3, patients with treatment-resistant hypertension were randomized to renal denervation or a sham procedure in a 2:1 ratio. While the controlled phase lasted just 6 months, the follow-up after the study was unblinded has continued out to 3 years. Safety and efficacy were assessed at 12, 24, and 36 months.

Unlike the disappointing results at 6 months, renal denervation has been consistently associated with significantly lower BP over long-term follow-up, even though those randomized to the sham procedure were permitted to cross over. About two-thirds of the sham group did so.

In the recently published final report of SYMPLICITY, the overall median change in office SBP at 3 years regardless of race was –26.4 mm Hg in the group initially randomized to renal denervation versus –5.7 mm Hg (P < .0001) among those randomized to the sham procedure.

In the subgroup analysis presented by Dr. Bhatt, the relative control of office SBP, as well as other measures of blood pressure, were similarly and significantly reduced in both Black and non-Black patients. In general, the relative control offered by being randomized initially to renal denervation increased over time in both groups.

For example, the relative reduction in office SBP favoring renal denervation climbed from –12.0 mm Hg at 12 months (P = .0066) to –21.0 at 18 months (P = .0002) and then to –24.9 mm Hg (P < .0001) at 36 months in the Black subgroup. In non-Blacks, the same type of relative reductions were seen at each time point, climbing from –13.5 (P < .0001) to –20.5 (P < .0001) and then to –21.0 (P < .0001).

The comparisons for other measures of BP control, including office diastolic BP, 24-hour SBP, and BP control during morning, day, and night periods were also statistically and similarly improved for those initially randomized to renal denervation rather than a sham procedure among both Blacks and non-Blacks.

Renal denervation safe in Black and non-Black patients

Renal denervation was well tolerated in both Black and non-Black participants with no signal of long-term risks over 36 months in either group. Among Blacks, rates of death at 36 months (3% vs. 11%) and stroke (7% vs. 11%) were lower among those randomized to renal denervation relative to sham patients who never crossed over, but Dr. Bhatt said the numbers are too small to draw any conclusions about outcomes.

While this subgroup analysis, along with the final SYMPLICITY report, supports the efficacy of renal denervation over the long term, these data are also consistent with the recently published analysis of SPYRAL ON-MED . Together, these data have led many experts, including Dr. Bhatt, to conclude that renal denervation is effective and deserves regulatory approval.

“In out-of-control blood pressure, when patients have maxed out on medications and lifestyle, I think renal denervation is efficacious, and it is equally efficacious in Blacks and non-Blacks,” Dr. Bhatt said.

This subgroup analysis is important because of the need for options in treatment-resistant hypertension among Black as well as non-Black patients, pointed out Sripal Bangalore, MBBS, director of complex coronary intervention at New York University.

“I am glad that we did not conclude too soon that it does not work in Blacks,” Dr. Bangalore said. If renal denervation is approved, he expects this procedure to be a valuable tool in this racial group.

Dr. Bhatt reported financial relationship with more than 20 pharmaceutical and device companies, including Medtronic, which provided funding for the SYMPLICITY HTN-3 trial. Dr. Bangalore has financial relationships with Abbott Vascular, Amgen, Biotronik, Inari, Pfizer, Reata, and Truvic.

WASHINGTON – On the heels the recently published final report from the SYMPLICITY HTN-3 renal denervation trial, a new analysis showed that Black patients, like non-Blacks, had sustained blood pressure control.

Contrary to a signal from earlier results, “there is nothing race specific about renal denervation,” said presenter Deepak L. Bhatt, MD, at the Cardiovascular Research Technologies conference, sponsored by MedStar Heart & Vascular Institute.

This did not prove to be the case during the 6-month controlled phase of the trial. When patients randomized to renal denervation or the sham procedure were stratified by race, the primary endpoint of reduction in office systolic blood pressure (SBP) reached significance in the experimental arm among non-Black patients (–6.63 mm Hg; P = .01), but not among Black patients (–2.25 mm Hg; P = .09).
 

Blacks comprised 26% of SYMPLICITY HTN-3 trial

In the initial controlled analysis, published in the New England Journal of Medicine, the lack of benefit in the substantial Black enrollment – representing 26% of the study total – weighed against the ability of the trial to demonstrate a benefit, but Dr. Bhatt pointed out that BP reductions were unexpectedly high in the sham group regardless of race. Patients randomized to the sham group were encouraged to adhere to antihypertensive therapy, and based on response, this was particularly effective in the Black sham subgroup.

In SYMPLICITY HTN-3, patients with treatment-resistant hypertension were randomized to renal denervation or a sham procedure in a 2:1 ratio. While the controlled phase lasted just 6 months, the follow-up after the study was unblinded has continued out to 3 years. Safety and efficacy were assessed at 12, 24, and 36 months.

Unlike the disappointing results at 6 months, renal denervation has been consistently associated with significantly lower BP over long-term follow-up, even though those randomized to the sham procedure were permitted to cross over. About two-thirds of the sham group did so.

In the recently published final report of SYMPLICITY, the overall median change in office SBP at 3 years regardless of race was –26.4 mm Hg in the group initially randomized to renal denervation versus –5.7 mm Hg (P < .0001) among those randomized to the sham procedure.

In the subgroup analysis presented by Dr. Bhatt, the relative control of office SBP, as well as other measures of blood pressure, were similarly and significantly reduced in both Black and non-Black patients. In general, the relative control offered by being randomized initially to renal denervation increased over time in both groups.

For example, the relative reduction in office SBP favoring renal denervation climbed from –12.0 mm Hg at 12 months (P = .0066) to –21.0 at 18 months (P = .0002) and then to –24.9 mm Hg (P < .0001) at 36 months in the Black subgroup. In non-Blacks, the same type of relative reductions were seen at each time point, climbing from –13.5 (P < .0001) to –20.5 (P < .0001) and then to –21.0 (P < .0001).

The comparisons for other measures of BP control, including office diastolic BP, 24-hour SBP, and BP control during morning, day, and night periods were also statistically and similarly improved for those initially randomized to renal denervation rather than a sham procedure among both Blacks and non-Blacks.

Renal denervation safe in Black and non-Black patients

Renal denervation was well tolerated in both Black and non-Black participants with no signal of long-term risks over 36 months in either group. Among Blacks, rates of death at 36 months (3% vs. 11%) and stroke (7% vs. 11%) were lower among those randomized to renal denervation relative to sham patients who never crossed over, but Dr. Bhatt said the numbers are too small to draw any conclusions about outcomes.

While this subgroup analysis, along with the final SYMPLICITY report, supports the efficacy of renal denervation over the long term, these data are also consistent with the recently published analysis of SPYRAL ON-MED . Together, these data have led many experts, including Dr. Bhatt, to conclude that renal denervation is effective and deserves regulatory approval.

“In out-of-control blood pressure, when patients have maxed out on medications and lifestyle, I think renal denervation is efficacious, and it is equally efficacious in Blacks and non-Blacks,” Dr. Bhatt said.

This subgroup analysis is important because of the need for options in treatment-resistant hypertension among Black as well as non-Black patients, pointed out Sripal Bangalore, MBBS, director of complex coronary intervention at New York University.

“I am glad that we did not conclude too soon that it does not work in Blacks,” Dr. Bangalore said. If renal denervation is approved, he expects this procedure to be a valuable tool in this racial group.

Dr. Bhatt reported financial relationship with more than 20 pharmaceutical and device companies, including Medtronic, which provided funding for the SYMPLICITY HTN-3 trial. Dr. Bangalore has financial relationships with Abbott Vascular, Amgen, Biotronik, Inari, Pfizer, Reata, and Truvic.

For adults with eosinophilic esophagitis (EoE), eliminating animal milk alone appears to be as effective for treating the disease as forgoing milk and five other foods, according to a new report.

A one-food elimination diet (1FED) led to histologic remission in 34% of patients, as determined on the basis of eosinophil count at 6 weeks, and in 40% of patients who followed a six-food elimination diet (6FED) – a nonstatistical difference, the research team wrote.

“The takeaway message is that one-food (milk) elimination is an effective treatment and a reasonable first-line treatment for EoE,” senior study author Marc Rothenberg, MD, PhD, a professor of pediatrics and director of the allergy and immunology division at the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, said in an interview.

“The study was designed by the Consortium of Eosinophilic Disease Researchers (CEGIR), which includes the nation’s top institutions working with patient advocacy groups, together with the National Institutes of Health,” he said. “The group, under advice from patients, determined that it was an important question to research if one-food elimination would be effective – and how effective – compared with six-food elimination.”

The study was published in The Lancet Gastroenterology and Hepatology.
 

Studying EOE and food elimination

Previous studies have found that eliminating six common foods that trigger esophageal injury – milk, eggs, wheat, soy, fish, and nuts – can substantially reduce EoE symptoms. The 6FED has become a common approach to managing the disease.

In recent years, however, researchers have conducted small, nonrandomized studies of the less restrictive 1FED and have found some success.

In a multisite, randomized trial, Dr. Rothenberg and colleagues compared the 6FED with the 1FED among 129 adults aged 18-60 years with a confirmed EoE diagnosis, active EoE symptoms, and a high number of eosinophils in esophageal tissue. The participants enrolled at 1 of 10 U.S. medical centers that participate in CEGIR, which is part of the NIH-funded Rare Diseases Clinical Research Network.

Between 2016 and 2019, 67 participants were assigned to the 1FED group, which eliminated only animal milk from the diet, and 62 participants were assigned to the 6FED group, which eliminated milk, eggs, wheat, soy, fish/shellfish, and peanuts/tree nuts. After following the diet for 6 weeks, participants underwent an upper endoscopy exam and esophageal tissue biopsy. The primary endpoint was the proportion of patients with histologic remission, or a peak count of less than 15 eosinophils per high-power field (eos/hpf).

If the number of eosinophils indicated that EoE was in remission, the participant exited the study. If EoE wasn’t in remission, those who were on 1FED could proceed to 6FED, and those who were on 6FED could take fluticasone propionate 880 mcg two times per day with an unrestricted diet. Both groups followed the protocols for 6 weeks and underwent another exam with tissue biopsy.

At 6 weeks, 25 patients (40%) on 6FED and 23 patients (34%) on 1FED achieved histologic remission. The difference was not statistically significant.

There were also no significant differences between the groups at stricter thresholds for partial remission, defined as peak counts of 10 eos/hpf or less and 6 eos/hpf or less. The rate of complete remission (at a peak count of ≤ 1 eos/hpf) favored 6FED, at 19% versus 6% among 1FED.

The two diets had a similar impact across several other measures, including reduction in peak eosinophil counts, reduction in EoE symptoms, and improvement in quality of life. For 6FED versus 1FED, the mean changes from baseline in the Eosinophilic Esophagitis Histology Scoring System were –0.23 versus –0.15. In addition, the mean changes in the Eosinophilic Esophagitis Endoscopic Reference Score were 1 versus –0.6, and in the Eosinophilic Esophagitis Activity Index, they were –8.2 versus –3. None of the differences were significant.

Among the patients who didn’t respond to 1FED, 21 opted to follow 6FED in the study’s second phase. Of those patients, nine (43%) attained remission after following the more restrictive diet. Among the 11 patients who didn’t initially respond to 6FED and who opted to receive fluticasone propionate, nine patients (82%) achieved remission.

“We examined a series of validated endpoints that have not previously been examined in diet trials,” Dr. Rothenberg said. “We are surprised to see that one food was equally effective as six foods.”
 

Incorporating food elimination therapy

Dr. Rothenberg and colleagues are continuing their research into EoE and food-elimination diets, with a strong focus on furthering diet therapy. In particular, the research team wants to understand how to potentially add milk – and other foods – back to the diet.

Wael Sayej, MD, associate professor of pediatrics at the University of Massachusetts Baystate Regional Campus, Springfield, has found success with the one-food elimination diet among children with EoE, he said in an interview.

In a retrospective study, Dr. Sayej and colleagues found that a one-food elimination diet was an effective first-line treatment option for pediatric patients.

“Once we get past the one-food or two-food elimination, it becomes much more difficult and cumbersome for patients to follow,” said Dr. Sayej, who is also a pediatric gastroenterologist with Baystate Health in Springfield and who wasn’t involved with the CEGIR study. “Obviously, I prefer my patients to follow a strict dairy-free diet as long-term therapy, rather than have them on a medication for the rest of their life.”

Dr. Sayej advises patients to follow the one-food elimination diet in his practice. If patients aren’t responsive, he offers options for additional dietary elimination or initiation of steroid therapy.

“The most important thing about initiating dietary elimination therapy is to take the time to educate the patient and family about the disease, the risks or complications associated with untreated disease, and the pros and cons of the treatment options,” he said.

The study was cofunded by the National Institute of Allergy and Infectious Diseases, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have research, consultant, and leadership relationships with several pharmaceutical companies and organizations not related to this study. Dr. Sayej disclosed no relevant financial relationships.
 

For adults with eosinophilic esophagitis (EoE), eliminating animal milk alone appears to be as effective for treating the disease as forgoing milk and five other foods, according to a new report.

A one-food elimination diet (1FED) led to histologic remission in 34% of patients, as determined on the basis of eosinophil count at 6 weeks, and in 40% of patients who followed a six-food elimination diet (6FED) – a nonstatistical difference, the research team wrote.

“The takeaway message is that one-food (milk) elimination is an effective treatment and a reasonable first-line treatment for EoE,” senior study author Marc Rothenberg, MD, PhD, a professor of pediatrics and director of the allergy and immunology division at the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, said in an interview.

“The study was designed by the Consortium of Eosinophilic Disease Researchers (CEGIR), which includes the nation’s top institutions working with patient advocacy groups, together with the National Institutes of Health,” he said. “The group, under advice from patients, determined that it was an important question to research if one-food elimination would be effective – and how effective – compared with six-food elimination.”

The study was published in The Lancet Gastroenterology and Hepatology.
 

Studying EOE and food elimination

Previous studies have found that eliminating six common foods that trigger esophageal injury – milk, eggs, wheat, soy, fish, and nuts – can substantially reduce EoE symptoms. The 6FED has become a common approach to managing the disease.

In recent years, however, researchers have conducted small, nonrandomized studies of the less restrictive 1FED and have found some success.

In a multisite, randomized trial, Dr. Rothenberg and colleagues compared the 6FED with the 1FED among 129 adults aged 18-60 years with a confirmed EoE diagnosis, active EoE symptoms, and a high number of eosinophils in esophageal tissue. The participants enrolled at 1 of 10 U.S. medical centers that participate in CEGIR, which is part of the NIH-funded Rare Diseases Clinical Research Network.

Between 2016 and 2019, 67 participants were assigned to the 1FED group, which eliminated only animal milk from the diet, and 62 participants were assigned to the 6FED group, which eliminated milk, eggs, wheat, soy, fish/shellfish, and peanuts/tree nuts. After following the diet for 6 weeks, participants underwent an upper endoscopy exam and esophageal tissue biopsy. The primary endpoint was the proportion of patients with histologic remission, or a peak count of less than 15 eosinophils per high-power field (eos/hpf).

If the number of eosinophils indicated that EoE was in remission, the participant exited the study. If EoE wasn’t in remission, those who were on 1FED could proceed to 6FED, and those who were on 6FED could take fluticasone propionate 880 mcg two times per day with an unrestricted diet. Both groups followed the protocols for 6 weeks and underwent another exam with tissue biopsy.

At 6 weeks, 25 patients (40%) on 6FED and 23 patients (34%) on 1FED achieved histologic remission. The difference was not statistically significant.

There were also no significant differences between the groups at stricter thresholds for partial remission, defined as peak counts of 10 eos/hpf or less and 6 eos/hpf or less. The rate of complete remission (at a peak count of ≤ 1 eos/hpf) favored 6FED, at 19% versus 6% among 1FED.

The two diets had a similar impact across several other measures, including reduction in peak eosinophil counts, reduction in EoE symptoms, and improvement in quality of life. For 6FED versus 1FED, the mean changes from baseline in the Eosinophilic Esophagitis Histology Scoring System were –0.23 versus –0.15. In addition, the mean changes in the Eosinophilic Esophagitis Endoscopic Reference Score were 1 versus –0.6, and in the Eosinophilic Esophagitis Activity Index, they were –8.2 versus –3. None of the differences were significant.

Among the patients who didn’t respond to 1FED, 21 opted to follow 6FED in the study’s second phase. Of those patients, nine (43%) attained remission after following the more restrictive diet. Among the 11 patients who didn’t initially respond to 6FED and who opted to receive fluticasone propionate, nine patients (82%) achieved remission.

“We examined a series of validated endpoints that have not previously been examined in diet trials,” Dr. Rothenberg said. “We are surprised to see that one food was equally effective as six foods.”
 

Incorporating food elimination therapy

Dr. Rothenberg and colleagues are continuing their research into EoE and food-elimination diets, with a strong focus on furthering diet therapy. In particular, the research team wants to understand how to potentially add milk – and other foods – back to the diet.

Wael Sayej, MD, associate professor of pediatrics at the University of Massachusetts Baystate Regional Campus, Springfield, has found success with the one-food elimination diet among children with EoE, he said in an interview.

In a retrospective study, Dr. Sayej and colleagues found that a one-food elimination diet was an effective first-line treatment option for pediatric patients.

“Once we get past the one-food or two-food elimination, it becomes much more difficult and cumbersome for patients to follow,” said Dr. Sayej, who is also a pediatric gastroenterologist with Baystate Health in Springfield and who wasn’t involved with the CEGIR study. “Obviously, I prefer my patients to follow a strict dairy-free diet as long-term therapy, rather than have them on a medication for the rest of their life.”

Dr. Sayej advises patients to follow the one-food elimination diet in his practice. If patients aren’t responsive, he offers options for additional dietary elimination or initiation of steroid therapy.

“The most important thing about initiating dietary elimination therapy is to take the time to educate the patient and family about the disease, the risks or complications associated with untreated disease, and the pros and cons of the treatment options,” he said.

The study was cofunded by the National Institute of Allergy and Infectious Diseases, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have research, consultant, and leadership relationships with several pharmaceutical companies and organizations not related to this study. Dr. Sayej disclosed no relevant financial relationships.
 

For adults with eosinophilic esophagitis (EoE), eliminating animal milk alone appears to be as effective for treating the disease as forgoing milk and five other foods, according to a new report.

A one-food elimination diet (1FED) led to histologic remission in 34% of patients, as determined on the basis of eosinophil count at 6 weeks, and in 40% of patients who followed a six-food elimination diet (6FED) – a nonstatistical difference, the research team wrote.

“The takeaway message is that one-food (milk) elimination is an effective treatment and a reasonable first-line treatment for EoE,” senior study author Marc Rothenberg, MD, PhD, a professor of pediatrics and director of the allergy and immunology division at the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, said in an interview.

“The study was designed by the Consortium of Eosinophilic Disease Researchers (CEGIR), which includes the nation’s top institutions working with patient advocacy groups, together with the National Institutes of Health,” he said. “The group, under advice from patients, determined that it was an important question to research if one-food elimination would be effective – and how effective – compared with six-food elimination.”

The study was published in The Lancet Gastroenterology and Hepatology.
 

Studying EOE and food elimination

Previous studies have found that eliminating six common foods that trigger esophageal injury – milk, eggs, wheat, soy, fish, and nuts – can substantially reduce EoE symptoms. The 6FED has become a common approach to managing the disease.

In recent years, however, researchers have conducted small, nonrandomized studies of the less restrictive 1FED and have found some success.

In a multisite, randomized trial, Dr. Rothenberg and colleagues compared the 6FED with the 1FED among 129 adults aged 18-60 years with a confirmed EoE diagnosis, active EoE symptoms, and a high number of eosinophils in esophageal tissue. The participants enrolled at 1 of 10 U.S. medical centers that participate in CEGIR, which is part of the NIH-funded Rare Diseases Clinical Research Network.

Between 2016 and 2019, 67 participants were assigned to the 1FED group, which eliminated only animal milk from the diet, and 62 participants were assigned to the 6FED group, which eliminated milk, eggs, wheat, soy, fish/shellfish, and peanuts/tree nuts. After following the diet for 6 weeks, participants underwent an upper endoscopy exam and esophageal tissue biopsy. The primary endpoint was the proportion of patients with histologic remission, or a peak count of less than 15 eosinophils per high-power field (eos/hpf).

If the number of eosinophils indicated that EoE was in remission, the participant exited the study. If EoE wasn’t in remission, those who were on 1FED could proceed to 6FED, and those who were on 6FED could take fluticasone propionate 880 mcg two times per day with an unrestricted diet. Both groups followed the protocols for 6 weeks and underwent another exam with tissue biopsy.

At 6 weeks, 25 patients (40%) on 6FED and 23 patients (34%) on 1FED achieved histologic remission. The difference was not statistically significant.

There were also no significant differences between the groups at stricter thresholds for partial remission, defined as peak counts of 10 eos/hpf or less and 6 eos/hpf or less. The rate of complete remission (at a peak count of ≤ 1 eos/hpf) favored 6FED, at 19% versus 6% among 1FED.

The two diets had a similar impact across several other measures, including reduction in peak eosinophil counts, reduction in EoE symptoms, and improvement in quality of life. For 6FED versus 1FED, the mean changes from baseline in the Eosinophilic Esophagitis Histology Scoring System were –0.23 versus –0.15. In addition, the mean changes in the Eosinophilic Esophagitis Endoscopic Reference Score were 1 versus –0.6, and in the Eosinophilic Esophagitis Activity Index, they were –8.2 versus –3. None of the differences were significant.

Among the patients who didn’t respond to 1FED, 21 opted to follow 6FED in the study’s second phase. Of those patients, nine (43%) attained remission after following the more restrictive diet. Among the 11 patients who didn’t initially respond to 6FED and who opted to receive fluticasone propionate, nine patients (82%) achieved remission.

“We examined a series of validated endpoints that have not previously been examined in diet trials,” Dr. Rothenberg said. “We are surprised to see that one food was equally effective as six foods.”
 

Incorporating food elimination therapy

Dr. Rothenberg and colleagues are continuing their research into EoE and food-elimination diets, with a strong focus on furthering diet therapy. In particular, the research team wants to understand how to potentially add milk – and other foods – back to the diet.

Wael Sayej, MD, associate professor of pediatrics at the University of Massachusetts Baystate Regional Campus, Springfield, has found success with the one-food elimination diet among children with EoE, he said in an interview.

In a retrospective study, Dr. Sayej and colleagues found that a one-food elimination diet was an effective first-line treatment option for pediatric patients.

“Once we get past the one-food or two-food elimination, it becomes much more difficult and cumbersome for patients to follow,” said Dr. Sayej, who is also a pediatric gastroenterologist with Baystate Health in Springfield and who wasn’t involved with the CEGIR study. “Obviously, I prefer my patients to follow a strict dairy-free diet as long-term therapy, rather than have them on a medication for the rest of their life.”

Dr. Sayej advises patients to follow the one-food elimination diet in his practice. If patients aren’t responsive, he offers options for additional dietary elimination or initiation of steroid therapy.

“The most important thing about initiating dietary elimination therapy is to take the time to educate the patient and family about the disease, the risks or complications associated with untreated disease, and the pros and cons of the treatment options,” he said.

The study was cofunded by the National Institute of Allergy and Infectious Diseases, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have research, consultant, and leadership relationships with several pharmaceutical companies and organizations not related to this study. Dr. Sayej disclosed no relevant financial relationships.
 

This patient had erythroderma, which involves widespread erythema and scaling of the majority of the skin. Erythroderma can be caused by severe variants of several skin disorders, including atopic dermatitis, contact dermatitis, and psoriasis. In this case, a punch biopsy from the forearm was most consistent with erythrodermic psoriasis.

Erythrodermic psoriasis is a rare subtype of psoriasis and most often develops as an exacerbation of preexisting plaque psoriasis and is defined by erythema, scale, and desquamation covering 75% to 90% of the body surface.¹ The alteration in the skin negatively affects heat exchange and hemodynamics and can be life threatening. Many cases develop as a rebound reaction in patients with preexisting psoriasis treated with systemic steroids that are discontinued. Patients with dehydration, poor urinary output, hypotension, or significant weakness may benefit from supportive inpatient care while treatment is initiated.¹

Initial treatment options for patients with erythrodermic psoriasis include biologics and steroid-sparing immunosuppressants, such as cyclosporine and acitretin. While a patient awaits the initiation of a definitive therapy, topical triamcinolone 0.1% may be applied over the entire skin surface twice daily and covered with 2 layers of scrubs or pajamas. The pair closest to the skin should be slightly damp and the outer pair should be dry to help retain heat. These are referred to as wet wraps or wet pajama wraps.

The patient described here was hemodynamically stable and was allowed to initiate wet pajama wrap therapy at home while awaiting initiation of adalimumab as an outpatient. He has improved dramatically with adalimumab given subcutaneously every 2 weeks.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

This patient had erythroderma, which involves widespread erythema and scaling of the majority of the skin. Erythroderma can be caused by severe variants of several skin disorders, including atopic dermatitis, contact dermatitis, and psoriasis. In this case, a punch biopsy from the forearm was most consistent with erythrodermic psoriasis.

Erythrodermic psoriasis is a rare subtype of psoriasis and most often develops as an exacerbation of preexisting plaque psoriasis and is defined by erythema, scale, and desquamation covering 75% to 90% of the body surface.¹ The alteration in the skin negatively affects heat exchange and hemodynamics and can be life threatening. Many cases develop as a rebound reaction in patients with preexisting psoriasis treated with systemic steroids that are discontinued. Patients with dehydration, poor urinary output, hypotension, or significant weakness may benefit from supportive inpatient care while treatment is initiated.¹

Initial treatment options for patients with erythrodermic psoriasis include biologics and steroid-sparing immunosuppressants, such as cyclosporine and acitretin. While a patient awaits the initiation of a definitive therapy, topical triamcinolone 0.1% may be applied over the entire skin surface twice daily and covered with 2 layers of scrubs or pajamas. The pair closest to the skin should be slightly damp and the outer pair should be dry to help retain heat. These are referred to as wet wraps or wet pajama wraps.

The patient described here was hemodynamically stable and was allowed to initiate wet pajama wrap therapy at home while awaiting initiation of adalimumab as an outpatient. He has improved dramatically with adalimumab given subcutaneously every 2 weeks.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

This patient had erythroderma, which involves widespread erythema and scaling of the majority of the skin. Erythroderma can be caused by severe variants of several skin disorders, including atopic dermatitis, contact dermatitis, and psoriasis. In this case, a punch biopsy from the forearm was most consistent with erythrodermic psoriasis.

Erythrodermic psoriasis is a rare subtype of psoriasis and most often develops as an exacerbation of preexisting plaque psoriasis and is defined by erythema, scale, and desquamation covering 75% to 90% of the body surface.¹ The alteration in the skin negatively affects heat exchange and hemodynamics and can be life threatening. Many cases develop as a rebound reaction in patients with preexisting psoriasis treated with systemic steroids that are discontinued. Patients with dehydration, poor urinary output, hypotension, or significant weakness may benefit from supportive inpatient care while treatment is initiated.¹

Initial treatment options for patients with erythrodermic psoriasis include biologics and steroid-sparing immunosuppressants, such as cyclosporine and acitretin. While a patient awaits the initiation of a definitive therapy, topical triamcinolone 0.1% may be applied over the entire skin surface twice daily and covered with 2 layers of scrubs or pajamas. The pair closest to the skin should be slightly damp and the outer pair should be dry to help retain heat. These are referred to as wet wraps or wet pajama wraps.

The patient described here was hemodynamically stable and was allowed to initiate wet pajama wrap therapy at home while awaiting initiation of adalimumab as an outpatient. He has improved dramatically with adalimumab given subcutaneously every 2 weeks.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.