Ann Thomas, MD, MPH

A few years ago, Kim Lori Sandler, MD, realized many patients newly diagnosed with lung cancer had never been screened for the disease — they received CT scans only because they were symptomatic.

But Dr. Sandler, a radiologist at Vanderbilt University Medical Center in Nashville, Tennessee, could see in medical charts that most of these patients had been eligible for a screening before becoming symptomatic. And for women, most had received decades worth of mammograms. She saw an opportunity and launched a study to find out if an intervention would work.

Low-dose CT and mammography services often are available in the same imaging facility, so women who qualified for a lung cancer screening were offered the scan during their mammography visit. Over a 3-year period, monthly rates of lung scans in women rose by 50% at one facility and 36% at the other.

“What we found is that women are really receptive, if you talk to them about it,” Dr. Sandler said. “I don’t think that lung cancer is thought of as a disease in women.”

Although lung cancer is the leading cause of cancer deaths in the United States, a recent study in JAMA Internal Medicine found only 18% of eligible patients were screened in 2022, a far cry from the rates of 72% for colon cancer — which itself falls short of goals from US medical groups like the American Cancer Society (ACS). Among those eligible, rates of lung screenings were lowest among younger people without comorbid conditions, who did not have health insurance or a usual source of care, and those living in southern states and states that did not expand Medicaid as part of the Affordable Care Act.

But researchers and clinicians, from those working in an urban health center for the homeless to clinics in the poorest counties in the tobacco belt, have used strategies to raise their rates of screening for lung cancer.

Getting patients screened is lifesaving: 27% of people with lung cancer survive 5 years after diagnosis. But the survival rate rises to 63% when cases are diagnosed at an early stage.
 

Increasing Uptake

The formal recommendation to use low-dose chest CT to screen for lung cancer is only a decade old. The approach was first endorsed by the United States Preventive Services Task Force (USPSTF) on the basis of an influential trial that found such testing was linked to a 20% reduction in mortality from the disease. Updated 2021 USPSTF guidelines call for annual screening of people aged 50-80 years who have a 20 pack-year history of smoking and currently smoke or have quit within the past 15 years.

But implementing the recommendation is not always simple. Unlike a colorectal or breast cancer screening, which is recommended primarily on patient age, eligibility for a lung cancer screening requires calculating pack-years of smoking, and, for past smokers, knowledge of when they quit.

The structured fields in most electronic medical records (EMRs) inquire about current or past use of cigarettes and the number of daily packs smoked. But few EMRs can calculate when a patient starts smoking two cigarettes a day but then increases to a pack a day and cuts down again. EMRs also do not track when a patient has stopped smoking permanently. Individual clinicians or health systems must identify patients who are eligible for screening, but the lack of automated calculations makes that job more difficult.

Dr. Sandler and colleagues turned to the informatics team at Vanderbilt to develop a natural language processing approach that extracts smoking data directly from clinician notes instead of using standard variables in their EMR.

The number of patients identified as needing a screening using the algorithm nearly doubled from baseline, from 5887 to 10,231 over a 3-year period, according to results from another study that Dr. Sandler published.

Although the algorithm may occasionally flag someone who does not need screening as eligible, “you can always have a conversation with the patient to determine if they actually meet eligibility criteria,” Dr. Sandler said.
 

Patient Navigators to the Rescue?

About a decade ago, Travis Baggett, MD, MPH, an associate professor of internal medicine at Harvard Medical School, Boston, Massachusetts, received pilot funding from the ACS to study cancer epidemiology among patients at Boston Health Care for the Homeless Program (BHCHP), which serves nearly 10,000 patients at a variety of Boston-area clinics each year.

“We found that both the incidence and mortality rates for lung cancer were more than twofold higher than in the general population,” Dr. Baggett, who is also the director of research at BHCHP, said.

He also discovered that BHCHP patients were diagnosed at significantly later stages than people in the general population for malignancies like breast and colorectal cancer.

Screening for lung cancer was a new recommendation at the time. With additional funding from the ACS, he launched a clinical trial in 2020 that randomized patients who were eligible for lung cancer screening to either work with a patient navigator or receive usual care.

The navigators eased the burden on primary care clinicians: They facilitated shared decision-making visits, helped participants make and attend appointments for low-dose CT, assisted with transportation, and arranged follow-up as needed.

The 3-year study found 43% of patients who received navigation services underwent screening for lung cancer, compared with 9% in the usual-care arm. Participants said the navigators played a critical role in educating them about the importance of screening, coordinating care, and providing emotional support.

“At the root of it all, it was quite clear that one thing that made the navigator successful was their interpersonal qualities and having someone that the patient could trust to help guide them through the process,” Dr. Baggett said.

The navigator program, however, stopped when the funding for the study ended.

But another health system has implemented navigators in a sustainable way through a quality improvement project. Michael Gieske, MD, director of lung cancer screening at St. Elizabeth Healthcare in Edgewood, Kentucky, starts his Friday morning meeting with a multidisciplinary group, including a thoracic surgeon, radiologist, pulmonologist, and several screening nurse navigators. They review the week’s chest CTs, with approximately one-third from patients who underwent lung cancer screening.

Nurse navigators at St. Elizabeth Healthcare follow up with any patient whose scan is suspicious for lung cancer and guide them through the process of seeing specialists and obtaining additional testing.

“They essentially hold the patient’s hand through this scary time in their life and make sure that everything flows smoothly and efficiently,” said Dr. Gieske, a family medicine physician.

St. Elizabeth’s program also draws on several evidence-based strategies used for other cancer screening programs, such as patient and provider education and quarterly feedback to their 194 primary care clinicians on rates of lung cancer screening among their eligible patients.

Several requirements for reimbursement for a lung cancer screening from the US Centers for Medicare & Medicaid Services can also serve as barriers to getting patients screened: Clinicians must identify who is eligible, provide tobacco cessation counseling, and document the shared decision-making process.

To streamline the steps, St. Elizabeth’s clinicians use an EMR smart set that reminds clinicians to verify smoking history and helps them document the required counseling.

Last year, 47% of eligible patients received their recommended screening, and Dr. Gieske said he expects even more improvement.

“We’re on track this year to complete 60% uptake if things continue,” he said, adding that 76% of the new cases of lung cancer are now diagnosed in stage I, with only 5% diagnosed in stage IV.

Dr. Gieske has shared his experience with many clinics in Appalachia, home to some of the highest rates of mortality from lung cancer in the country. A major part of his role with the Appalachian Community Cancer Alliance is helping educate primary care clinicians in the region about the importance of early detection of lung cancer.

“I think one of the most important things is just to convey a message of hope,” he said. “We’re trying to get the good word out there that if you screen individuals, you’re going to catch it early, when you have an extremely high chance of curing the lung cancer.”

Dr. Baggett reported support from grants from the ACS and the Massachusetts General Hospital Research Scholars Program. Dr. Sandler and Dr. Gieske reported no financial conflicts.

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

A few years ago, Kim Lori Sandler, MD, realized many patients newly diagnosed with lung cancer had never been screened for the disease — they received CT scans only because they were symptomatic.

But Dr. Sandler, a radiologist at Vanderbilt University Medical Center in Nashville, Tennessee, could see in medical charts that most of these patients had been eligible for a screening before becoming symptomatic. And for women, most had received decades worth of mammograms. She saw an opportunity and launched a study to find out if an intervention would work.

Low-dose CT and mammography services often are available in the same imaging facility, so women who qualified for a lung cancer screening were offered the scan during their mammography visit. Over a 3-year period, monthly rates of lung scans in women rose by 50% at one facility and 36% at the other.

“What we found is that women are really receptive, if you talk to them about it,” Dr. Sandler said. “I don’t think that lung cancer is thought of as a disease in women.”

Although lung cancer is the leading cause of cancer deaths in the United States, a recent study in JAMA Internal Medicine found only 18% of eligible patients were screened in 2022, a far cry from the rates of 72% for colon cancer — which itself falls short of goals from US medical groups like the American Cancer Society (ACS). Among those eligible, rates of lung screenings were lowest among younger people without comorbid conditions, who did not have health insurance or a usual source of care, and those living in southern states and states that did not expand Medicaid as part of the Affordable Care Act.

But researchers and clinicians, from those working in an urban health center for the homeless to clinics in the poorest counties in the tobacco belt, have used strategies to raise their rates of screening for lung cancer.

Getting patients screened is lifesaving: 27% of people with lung cancer survive 5 years after diagnosis. But the survival rate rises to 63% when cases are diagnosed at an early stage.
 

Increasing Uptake

The formal recommendation to use low-dose chest CT to screen for lung cancer is only a decade old. The approach was first endorsed by the United States Preventive Services Task Force (USPSTF) on the basis of an influential trial that found such testing was linked to a 20% reduction in mortality from the disease. Updated 2021 USPSTF guidelines call for annual screening of people aged 50-80 years who have a 20 pack-year history of smoking and currently smoke or have quit within the past 15 years.

But implementing the recommendation is not always simple. Unlike a colorectal or breast cancer screening, which is recommended primarily on patient age, eligibility for a lung cancer screening requires calculating pack-years of smoking, and, for past smokers, knowledge of when they quit.

The structured fields in most electronic medical records (EMRs) inquire about current or past use of cigarettes and the number of daily packs smoked. But few EMRs can calculate when a patient starts smoking two cigarettes a day but then increases to a pack a day and cuts down again. EMRs also do not track when a patient has stopped smoking permanently. Individual clinicians or health systems must identify patients who are eligible for screening, but the lack of automated calculations makes that job more difficult.

Dr. Sandler and colleagues turned to the informatics team at Vanderbilt to develop a natural language processing approach that extracts smoking data directly from clinician notes instead of using standard variables in their EMR.

The number of patients identified as needing a screening using the algorithm nearly doubled from baseline, from 5887 to 10,231 over a 3-year period, according to results from another study that Dr. Sandler published.

Although the algorithm may occasionally flag someone who does not need screening as eligible, “you can always have a conversation with the patient to determine if they actually meet eligibility criteria,” Dr. Sandler said.
 

Patient Navigators to the Rescue?

About a decade ago, Travis Baggett, MD, MPH, an associate professor of internal medicine at Harvard Medical School, Boston, Massachusetts, received pilot funding from the ACS to study cancer epidemiology among patients at Boston Health Care for the Homeless Program (BHCHP), which serves nearly 10,000 patients at a variety of Boston-area clinics each year.

“We found that both the incidence and mortality rates for lung cancer were more than twofold higher than in the general population,” Dr. Baggett, who is also the director of research at BHCHP, said.

He also discovered that BHCHP patients were diagnosed at significantly later stages than people in the general population for malignancies like breast and colorectal cancer.

Screening for lung cancer was a new recommendation at the time. With additional funding from the ACS, he launched a clinical trial in 2020 that randomized patients who were eligible for lung cancer screening to either work with a patient navigator or receive usual care.

The navigators eased the burden on primary care clinicians: They facilitated shared decision-making visits, helped participants make and attend appointments for low-dose CT, assisted with transportation, and arranged follow-up as needed.

The 3-year study found 43% of patients who received navigation services underwent screening for lung cancer, compared with 9% in the usual-care arm. Participants said the navigators played a critical role in educating them about the importance of screening, coordinating care, and providing emotional support.

“At the root of it all, it was quite clear that one thing that made the navigator successful was their interpersonal qualities and having someone that the patient could trust to help guide them through the process,” Dr. Baggett said.

The navigator program, however, stopped when the funding for the study ended.

But another health system has implemented navigators in a sustainable way through a quality improvement project. Michael Gieske, MD, director of lung cancer screening at St. Elizabeth Healthcare in Edgewood, Kentucky, starts his Friday morning meeting with a multidisciplinary group, including a thoracic surgeon, radiologist, pulmonologist, and several screening nurse navigators. They review the week’s chest CTs, with approximately one-third from patients who underwent lung cancer screening.

Nurse navigators at St. Elizabeth Healthcare follow up with any patient whose scan is suspicious for lung cancer and guide them through the process of seeing specialists and obtaining additional testing.

“They essentially hold the patient’s hand through this scary time in their life and make sure that everything flows smoothly and efficiently,” said Dr. Gieske, a family medicine physician.

St. Elizabeth’s program also draws on several evidence-based strategies used for other cancer screening programs, such as patient and provider education and quarterly feedback to their 194 primary care clinicians on rates of lung cancer screening among their eligible patients.

Several requirements for reimbursement for a lung cancer screening from the US Centers for Medicare & Medicaid Services can also serve as barriers to getting patients screened: Clinicians must identify who is eligible, provide tobacco cessation counseling, and document the shared decision-making process.

To streamline the steps, St. Elizabeth’s clinicians use an EMR smart set that reminds clinicians to verify smoking history and helps them document the required counseling.

Last year, 47% of eligible patients received their recommended screening, and Dr. Gieske said he expects even more improvement.

“We’re on track this year to complete 60% uptake if things continue,” he said, adding that 76% of the new cases of lung cancer are now diagnosed in stage I, with only 5% diagnosed in stage IV.

Dr. Gieske has shared his experience with many clinics in Appalachia, home to some of the highest rates of mortality from lung cancer in the country. A major part of his role with the Appalachian Community Cancer Alliance is helping educate primary care clinicians in the region about the importance of early detection of lung cancer.

“I think one of the most important things is just to convey a message of hope,” he said. “We’re trying to get the good word out there that if you screen individuals, you’re going to catch it early, when you have an extremely high chance of curing the lung cancer.”

Dr. Baggett reported support from grants from the ACS and the Massachusetts General Hospital Research Scholars Program. Dr. Sandler and Dr. Gieske reported no financial conflicts.

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

A few years ago, Kim Lori Sandler, MD, realized many patients newly diagnosed with lung cancer had never been screened for the disease — they received CT scans only because they were symptomatic.

But Dr. Sandler, a radiologist at Vanderbilt University Medical Center in Nashville, Tennessee, could see in medical charts that most of these patients had been eligible for a screening before becoming symptomatic. And for women, most had received decades worth of mammograms. She saw an opportunity and launched a study to find out if an intervention would work.

Low-dose CT and mammography services often are available in the same imaging facility, so women who qualified for a lung cancer screening were offered the scan during their mammography visit. Over a 3-year period, monthly rates of lung scans in women rose by 50% at one facility and 36% at the other.

“What we found is that women are really receptive, if you talk to them about it,” Dr. Sandler said. “I don’t think that lung cancer is thought of as a disease in women.”

Although lung cancer is the leading cause of cancer deaths in the United States, a recent study in JAMA Internal Medicine found only 18% of eligible patients were screened in 2022, a far cry from the rates of 72% for colon cancer — which itself falls short of goals from US medical groups like the American Cancer Society (ACS). Among those eligible, rates of lung screenings were lowest among younger people without comorbid conditions, who did not have health insurance or a usual source of care, and those living in southern states and states that did not expand Medicaid as part of the Affordable Care Act.

But researchers and clinicians, from those working in an urban health center for the homeless to clinics in the poorest counties in the tobacco belt, have used strategies to raise their rates of screening for lung cancer.

Getting patients screened is lifesaving: 27% of people with lung cancer survive 5 years after diagnosis. But the survival rate rises to 63% when cases are diagnosed at an early stage.
 

Increasing Uptake

The formal recommendation to use low-dose chest CT to screen for lung cancer is only a decade old. The approach was first endorsed by the United States Preventive Services Task Force (USPSTF) on the basis of an influential trial that found such testing was linked to a 20% reduction in mortality from the disease. Updated 2021 USPSTF guidelines call for annual screening of people aged 50-80 years who have a 20 pack-year history of smoking and currently smoke or have quit within the past 15 years.

But implementing the recommendation is not always simple. Unlike a colorectal or breast cancer screening, which is recommended primarily on patient age, eligibility for a lung cancer screening requires calculating pack-years of smoking, and, for past smokers, knowledge of when they quit.

The structured fields in most electronic medical records (EMRs) inquire about current or past use of cigarettes and the number of daily packs smoked. But few EMRs can calculate when a patient starts smoking two cigarettes a day but then increases to a pack a day and cuts down again. EMRs also do not track when a patient has stopped smoking permanently. Individual clinicians or health systems must identify patients who are eligible for screening, but the lack of automated calculations makes that job more difficult.

Dr. Sandler and colleagues turned to the informatics team at Vanderbilt to develop a natural language processing approach that extracts smoking data directly from clinician notes instead of using standard variables in their EMR.

The number of patients identified as needing a screening using the algorithm nearly doubled from baseline, from 5887 to 10,231 over a 3-year period, according to results from another study that Dr. Sandler published.

Although the algorithm may occasionally flag someone who does not need screening as eligible, “you can always have a conversation with the patient to determine if they actually meet eligibility criteria,” Dr. Sandler said.
 

Patient Navigators to the Rescue?

About a decade ago, Travis Baggett, MD, MPH, an associate professor of internal medicine at Harvard Medical School, Boston, Massachusetts, received pilot funding from the ACS to study cancer epidemiology among patients at Boston Health Care for the Homeless Program (BHCHP), which serves nearly 10,000 patients at a variety of Boston-area clinics each year.

“We found that both the incidence and mortality rates for lung cancer were more than twofold higher than in the general population,” Dr. Baggett, who is also the director of research at BHCHP, said.

He also discovered that BHCHP patients were diagnosed at significantly later stages than people in the general population for malignancies like breast and colorectal cancer.

Screening for lung cancer was a new recommendation at the time. With additional funding from the ACS, he launched a clinical trial in 2020 that randomized patients who were eligible for lung cancer screening to either work with a patient navigator or receive usual care.

The navigators eased the burden on primary care clinicians: They facilitated shared decision-making visits, helped participants make and attend appointments for low-dose CT, assisted with transportation, and arranged follow-up as needed.

The 3-year study found 43% of patients who received navigation services underwent screening for lung cancer, compared with 9% in the usual-care arm. Participants said the navigators played a critical role in educating them about the importance of screening, coordinating care, and providing emotional support.

“At the root of it all, it was quite clear that one thing that made the navigator successful was their interpersonal qualities and having someone that the patient could trust to help guide them through the process,” Dr. Baggett said.

The navigator program, however, stopped when the funding for the study ended.

But another health system has implemented navigators in a sustainable way through a quality improvement project. Michael Gieske, MD, director of lung cancer screening at St. Elizabeth Healthcare in Edgewood, Kentucky, starts his Friday morning meeting with a multidisciplinary group, including a thoracic surgeon, radiologist, pulmonologist, and several screening nurse navigators. They review the week’s chest CTs, with approximately one-third from patients who underwent lung cancer screening.

Nurse navigators at St. Elizabeth Healthcare follow up with any patient whose scan is suspicious for lung cancer and guide them through the process of seeing specialists and obtaining additional testing.

“They essentially hold the patient’s hand through this scary time in their life and make sure that everything flows smoothly and efficiently,” said Dr. Gieske, a family medicine physician.

St. Elizabeth’s program also draws on several evidence-based strategies used for other cancer screening programs, such as patient and provider education and quarterly feedback to their 194 primary care clinicians on rates of lung cancer screening among their eligible patients.

Several requirements for reimbursement for a lung cancer screening from the US Centers for Medicare & Medicaid Services can also serve as barriers to getting patients screened: Clinicians must identify who is eligible, provide tobacco cessation counseling, and document the shared decision-making process.

To streamline the steps, St. Elizabeth’s clinicians use an EMR smart set that reminds clinicians to verify smoking history and helps them document the required counseling.

Last year, 47% of eligible patients received their recommended screening, and Dr. Gieske said he expects even more improvement.

“We’re on track this year to complete 60% uptake if things continue,” he said, adding that 76% of the new cases of lung cancer are now diagnosed in stage I, with only 5% diagnosed in stage IV.

Dr. Gieske has shared his experience with many clinics in Appalachia, home to some of the highest rates of mortality from lung cancer in the country. A major part of his role with the Appalachian Community Cancer Alliance is helping educate primary care clinicians in the region about the importance of early detection of lung cancer.

“I think one of the most important things is just to convey a message of hope,” he said. “We’re trying to get the good word out there that if you screen individuals, you’re going to catch it early, when you have an extremely high chance of curing the lung cancer.”

Dr. Baggett reported support from grants from the ACS and the Massachusetts General Hospital Research Scholars Program. Dr. Sandler and Dr. Gieske reported no financial conflicts.

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

As the pendulum has swung against recommending aspirin for the primary prevention of heart attacks and strokes, clinicians should focus on other ways to help patients avoid cardiovascular events.

A landmark study published in 1988 in The New England Journal of Medicine reported an astonishing 44% drop in the number of heart attacks among US male physicians aged 40-84 years who took aspirin.

Aspirin subsequently became a daily habit for millions of Americans. In 2017, nearly a quarter of Americans over age 40 who did not have cardiovascular disease (CVD) took the drug, and over 20% of those were doing so without a physician’s recommendation.

But in 2018, three studies (ASCEND, ARRIVE, and ASPREE) showed a stunning reversal in the purported benefit, according to John Wong, MD, vice-chair of the US Preventive Services Task Force (USPSTF).

The calculus for taking aspirin appeared to have changed dramatically: The drug decreased the risk for myocardial infarction by only 11% among study subjects, while its potential harms were much more pronounced.

According to Dr. Wong, who is also a professor of medicine and a primary care physician at Tufts University School of Medicine in Boston, Massachusetts, patients taking low-dose aspirin had a 58% increase in their risk for gastrointestinal bleeding compared with those not on aspirin, as well as a 31% increased risk for intracranial bleeding.

Did aspirin suddenly lose its magic powers in preventing heart attacks? Dr. Wong attributed the decline in effectiveness of aspirin in preventing heart attacks to other “primary care interventions that help reduce the cardiovascular disease risk in patients who haven’t had a heart attack or stroke.”

Fewer Americans smoke cigarettes, more realize the benefits of a healthy diet and physical activity, and the medical community better recognizes and treats hypertension. New classes of medications such as statins for high cholesterol are also moving the needle.

But a newer class of drugs may provide a safer replacement for aspirin, according to Muhammad Maqsood, MD, a cardiology fellow at DeBakey Heart and Vascular Center at Methodist Hospital in Houston, Texas. P2Y purinoceptor 12 (P2Y12) inhibitors are effective in lowering the risk for heart attack and stroke in patients with acute coronary syndrome or those undergoing elective percutaneous coronary interventions.

“They have shown a better bleeding profile, especially clopidogrel compared to aspirin,” Dr. Maqsood said.

However, the findings come from trials of patients who already had CVD, so results cannot yet be extrapolated to primary prevention. Dr. Maqsood said the gap highlights the need for clinical trials that evaluate P2Y12 inhibitors for primary prevention, but no such study is registered on clinicaltrials.gov.
 

Benefits Persist for Some Patients

The new evidence led the USPSTF to publish new guidelines in 2022, downgrading the recommendation for low-dose aspirin use for primary prevention. Previously, the organization stated that clinicians “should” initiate daily low-dose aspirin in adults aged 50-59 years and “consider” its use in adults aged 60-69 years whose 10-year risk for CVD was higher than 10%.

The updated guidelines stated that the decision to initiate low-dose aspirin in adults aged 40-59 years with a greater than 10% risk for CVD “should be an individual one,” based on professional judgment and individual patient preferences. The USPSTF also recommended against the use of aspirin in anyone over the age of 60.

Meanwhile, the American College of Cardiology and American Heart Association also dialed down previously strong recommendations on low-dose aspirin to a more nuanced recommendation stating, “low-dose aspirin might be considered for primary prevention of ASCVD among select adults 40-70 years of age.”

With a varying age limit for recommending aspirin, clinicians may take into consideration several variables.

“Is there a magic age? I don’t think there is,” said Douglas Lloyd-Jones, the former president of the American Heart Association and current chair of the Department of Preventive Medicine and a practicing cardiologist at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

For a patient over age 60 who is at a high risk for adverse cardiovascular outcomes, is unable to quit smoking, and is not likely to experience problematic bleeding, a clinician might recommend aspirin, Dr. Lloyd-Jones said. He said he sometimes also assesses coronary artery calcium to guide his clinical decisions: If elevated (an Agatston score above 100), he might recommend low-dose aspirin.

Dr. Lloyd-Jones also reiterated that patients should continue taking low-dose aspirin if they have already experienced a heart attack, stroke, episode of atrial fibrillation, or required a vascular stent.

Unless a patient with established CVD has intractable bleeding, “the aspirin is really for life,” Dr. Lloyd-Jones said. Patients who have a stent or who are at high risk for recurrence of stroke are more likely to experience thrombosis, and aspirin can decrease the risk.

“In our cardiology community, we don’t just strictly use the age of 70; the decision is always individualized,” Dr. Maqsood said.

Dr. Wong said primary care providers should focus on the USPSTF’s other recommendations that address CVD (Table), such as smoking cessation and screening for hypertension.

“I think our challenge is that we have so many of those A and B recommendations,” Dr. Wong said. “And I think part of the challenge for us is working with the patient to find out what’s most important to them.”

Discussing heart attacks and strokes often will strike a chord with patients because someone they know has been affected.

Dr. Maqsood emphasized the importance of behavioral interventions, such as helping patients decrease their body mass index and control their hyperlipidemia.

“The behavioral interventions are those which are the most cost-effective without any side effects,” he said.

His other piece of advice is to inquire with younger patients about a family history of heart attacks. Familial hypercholesteremia is unlikely to be controlled by diet and exercise and will need medical therapy.

Dr. Lloyd-Jones described the discussions he has with patients about preventing heart attacks as “the most important conversations we can have: Remember that cardiovascular disease is still the leading cause of death and disability in the world and in the United States.”

Dr. Wong, Dr. Lloyd-Jones, and Dr. Maqsood reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

As the pendulum has swung against recommending aspirin for the primary prevention of heart attacks and strokes, clinicians should focus on other ways to help patients avoid cardiovascular events.

A landmark study published in 1988 in The New England Journal of Medicine reported an astonishing 44% drop in the number of heart attacks among US male physicians aged 40-84 years who took aspirin.

Aspirin subsequently became a daily habit for millions of Americans. In 2017, nearly a quarter of Americans over age 40 who did not have cardiovascular disease (CVD) took the drug, and over 20% of those were doing so without a physician’s recommendation.

But in 2018, three studies (ASCEND, ARRIVE, and ASPREE) showed a stunning reversal in the purported benefit, according to John Wong, MD, vice-chair of the US Preventive Services Task Force (USPSTF).

The calculus for taking aspirin appeared to have changed dramatically: The drug decreased the risk for myocardial infarction by only 11% among study subjects, while its potential harms were much more pronounced.

According to Dr. Wong, who is also a professor of medicine and a primary care physician at Tufts University School of Medicine in Boston, Massachusetts, patients taking low-dose aspirin had a 58% increase in their risk for gastrointestinal bleeding compared with those not on aspirin, as well as a 31% increased risk for intracranial bleeding.

Did aspirin suddenly lose its magic powers in preventing heart attacks? Dr. Wong attributed the decline in effectiveness of aspirin in preventing heart attacks to other “primary care interventions that help reduce the cardiovascular disease risk in patients who haven’t had a heart attack or stroke.”

Fewer Americans smoke cigarettes, more realize the benefits of a healthy diet and physical activity, and the medical community better recognizes and treats hypertension. New classes of medications such as statins for high cholesterol are also moving the needle.

But a newer class of drugs may provide a safer replacement for aspirin, according to Muhammad Maqsood, MD, a cardiology fellow at DeBakey Heart and Vascular Center at Methodist Hospital in Houston, Texas. P2Y purinoceptor 12 (P2Y12) inhibitors are effective in lowering the risk for heart attack and stroke in patients with acute coronary syndrome or those undergoing elective percutaneous coronary interventions.

“They have shown a better bleeding profile, especially clopidogrel compared to aspirin,” Dr. Maqsood said.

However, the findings come from trials of patients who already had CVD, so results cannot yet be extrapolated to primary prevention. Dr. Maqsood said the gap highlights the need for clinical trials that evaluate P2Y12 inhibitors for primary prevention, but no such study is registered on clinicaltrials.gov.
 

Benefits Persist for Some Patients

The new evidence led the USPSTF to publish new guidelines in 2022, downgrading the recommendation for low-dose aspirin use for primary prevention. Previously, the organization stated that clinicians “should” initiate daily low-dose aspirin in adults aged 50-59 years and “consider” its use in adults aged 60-69 years whose 10-year risk for CVD was higher than 10%.

The updated guidelines stated that the decision to initiate low-dose aspirin in adults aged 40-59 years with a greater than 10% risk for CVD “should be an individual one,” based on professional judgment and individual patient preferences. The USPSTF also recommended against the use of aspirin in anyone over the age of 60.

Meanwhile, the American College of Cardiology and American Heart Association also dialed down previously strong recommendations on low-dose aspirin to a more nuanced recommendation stating, “low-dose aspirin might be considered for primary prevention of ASCVD among select adults 40-70 years of age.”

With a varying age limit for recommending aspirin, clinicians may take into consideration several variables.

“Is there a magic age? I don’t think there is,” said Douglas Lloyd-Jones, the former president of the American Heart Association and current chair of the Department of Preventive Medicine and a practicing cardiologist at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

For a patient over age 60 who is at a high risk for adverse cardiovascular outcomes, is unable to quit smoking, and is not likely to experience problematic bleeding, a clinician might recommend aspirin, Dr. Lloyd-Jones said. He said he sometimes also assesses coronary artery calcium to guide his clinical decisions: If elevated (an Agatston score above 100), he might recommend low-dose aspirin.

Dr. Lloyd-Jones also reiterated that patients should continue taking low-dose aspirin if they have already experienced a heart attack, stroke, episode of atrial fibrillation, or required a vascular stent.

Unless a patient with established CVD has intractable bleeding, “the aspirin is really for life,” Dr. Lloyd-Jones said. Patients who have a stent or who are at high risk for recurrence of stroke are more likely to experience thrombosis, and aspirin can decrease the risk.

“In our cardiology community, we don’t just strictly use the age of 70; the decision is always individualized,” Dr. Maqsood said.

Dr. Wong said primary care providers should focus on the USPSTF’s other recommendations that address CVD (Table), such as smoking cessation and screening for hypertension.

“I think our challenge is that we have so many of those A and B recommendations,” Dr. Wong said. “And I think part of the challenge for us is working with the patient to find out what’s most important to them.”

Discussing heart attacks and strokes often will strike a chord with patients because someone they know has been affected.

Dr. Maqsood emphasized the importance of behavioral interventions, such as helping patients decrease their body mass index and control their hyperlipidemia.

“The behavioral interventions are those which are the most cost-effective without any side effects,” he said.

His other piece of advice is to inquire with younger patients about a family history of heart attacks. Familial hypercholesteremia is unlikely to be controlled by diet and exercise and will need medical therapy.

Dr. Lloyd-Jones described the discussions he has with patients about preventing heart attacks as “the most important conversations we can have: Remember that cardiovascular disease is still the leading cause of death and disability in the world and in the United States.”

Dr. Wong, Dr. Lloyd-Jones, and Dr. Maqsood reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

As the pendulum has swung against recommending aspirin for the primary prevention of heart attacks and strokes, clinicians should focus on other ways to help patients avoid cardiovascular events.

A landmark study published in 1988 in The New England Journal of Medicine reported an astonishing 44% drop in the number of heart attacks among US male physicians aged 40-84 years who took aspirin.

Aspirin subsequently became a daily habit for millions of Americans. In 2017, nearly a quarter of Americans over age 40 who did not have cardiovascular disease (CVD) took the drug, and over 20% of those were doing so without a physician’s recommendation.

But in 2018, three studies (ASCEND, ARRIVE, and ASPREE) showed a stunning reversal in the purported benefit, according to John Wong, MD, vice-chair of the US Preventive Services Task Force (USPSTF).

The calculus for taking aspirin appeared to have changed dramatically: The drug decreased the risk for myocardial infarction by only 11% among study subjects, while its potential harms were much more pronounced.

According to Dr. Wong, who is also a professor of medicine and a primary care physician at Tufts University School of Medicine in Boston, Massachusetts, patients taking low-dose aspirin had a 58% increase in their risk for gastrointestinal bleeding compared with those not on aspirin, as well as a 31% increased risk for intracranial bleeding.

Did aspirin suddenly lose its magic powers in preventing heart attacks? Dr. Wong attributed the decline in effectiveness of aspirin in preventing heart attacks to other “primary care interventions that help reduce the cardiovascular disease risk in patients who haven’t had a heart attack or stroke.”

Fewer Americans smoke cigarettes, more realize the benefits of a healthy diet and physical activity, and the medical community better recognizes and treats hypertension. New classes of medications such as statins for high cholesterol are also moving the needle.

But a newer class of drugs may provide a safer replacement for aspirin, according to Muhammad Maqsood, MD, a cardiology fellow at DeBakey Heart and Vascular Center at Methodist Hospital in Houston, Texas. P2Y purinoceptor 12 (P2Y12) inhibitors are effective in lowering the risk for heart attack and stroke in patients with acute coronary syndrome or those undergoing elective percutaneous coronary interventions.

“They have shown a better bleeding profile, especially clopidogrel compared to aspirin,” Dr. Maqsood said.

However, the findings come from trials of patients who already had CVD, so results cannot yet be extrapolated to primary prevention. Dr. Maqsood said the gap highlights the need for clinical trials that evaluate P2Y12 inhibitors for primary prevention, but no such study is registered on clinicaltrials.gov.
 

Benefits Persist for Some Patients

The new evidence led the USPSTF to publish new guidelines in 2022, downgrading the recommendation for low-dose aspirin use for primary prevention. Previously, the organization stated that clinicians “should” initiate daily low-dose aspirin in adults aged 50-59 years and “consider” its use in adults aged 60-69 years whose 10-year risk for CVD was higher than 10%.

The updated guidelines stated that the decision to initiate low-dose aspirin in adults aged 40-59 years with a greater than 10% risk for CVD “should be an individual one,” based on professional judgment and individual patient preferences. The USPSTF also recommended against the use of aspirin in anyone over the age of 60.

Meanwhile, the American College of Cardiology and American Heart Association also dialed down previously strong recommendations on low-dose aspirin to a more nuanced recommendation stating, “low-dose aspirin might be considered for primary prevention of ASCVD among select adults 40-70 years of age.”

With a varying age limit for recommending aspirin, clinicians may take into consideration several variables.

“Is there a magic age? I don’t think there is,” said Douglas Lloyd-Jones, the former president of the American Heart Association and current chair of the Department of Preventive Medicine and a practicing cardiologist at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

For a patient over age 60 who is at a high risk for adverse cardiovascular outcomes, is unable to quit smoking, and is not likely to experience problematic bleeding, a clinician might recommend aspirin, Dr. Lloyd-Jones said. He said he sometimes also assesses coronary artery calcium to guide his clinical decisions: If elevated (an Agatston score above 100), he might recommend low-dose aspirin.

Dr. Lloyd-Jones also reiterated that patients should continue taking low-dose aspirin if they have already experienced a heart attack, stroke, episode of atrial fibrillation, or required a vascular stent.

Unless a patient with established CVD has intractable bleeding, “the aspirin is really for life,” Dr. Lloyd-Jones said. Patients who have a stent or who are at high risk for recurrence of stroke are more likely to experience thrombosis, and aspirin can decrease the risk.

“In our cardiology community, we don’t just strictly use the age of 70; the decision is always individualized,” Dr. Maqsood said.

Dr. Wong said primary care providers should focus on the USPSTF’s other recommendations that address CVD (Table), such as smoking cessation and screening for hypertension.

“I think our challenge is that we have so many of those A and B recommendations,” Dr. Wong said. “And I think part of the challenge for us is working with the patient to find out what’s most important to them.”

Discussing heart attacks and strokes often will strike a chord with patients because someone they know has been affected.

Dr. Maqsood emphasized the importance of behavioral interventions, such as helping patients decrease their body mass index and control their hyperlipidemia.

“The behavioral interventions are those which are the most cost-effective without any side effects,” he said.

His other piece of advice is to inquire with younger patients about a family history of heart attacks. Familial hypercholesteremia is unlikely to be controlled by diet and exercise and will need medical therapy.

Dr. Lloyd-Jones described the discussions he has with patients about preventing heart attacks as “the most important conversations we can have: Remember that cardiovascular disease is still the leading cause of death and disability in the world and in the United States.”

Dr. Wong, Dr. Lloyd-Jones, and Dr. Maqsood reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Experts say pediatricians and primary care clinicians should do more to prevent the toxic effects of lead in their young patients following a 2023 outbreak of elevated levels of lead in children associated with consumption of contaminated applesauce.

Federal legislation in the 1970s eliminated lead from gasoline, paints, and other consumer products, and resulted in significantly reduced blood lead levels (BLLs) in children throughout the United States.

But recently published studies highlight persistent issues with lead in drinking water and consumer products, suggesting that the fight is not over.
 

It’s in the Water

In 2014 the city of Flint, Michigan, changed its water supply and high levels of lead were later found in the municipal water supply.

Effects of that crisis still plague the city today. An initial study found that elevated BLLs had doubled among children between 2013 and 2015.

Lead exposure in young children is associated with several negative outcomes, including decreased cognitive ability, brain volume, and social mobility, and increased anxiety/depression and impulsivity, and higher rates of criminal offenses later in life. 

Many other water systems still contain lead pipes, despite a 1986 ban by the US Environmental Protection Agency on using them for installing or repairing public water systems. The mayor of Chicago announced a plan to start replacing lead service lines in 2020; however, 400,000 households are still served by these pipes, the most in the nation.

Benjamin Huynh, a native of Chicago, was curious about the impact of all those lead service lines. Now an assistant professor in the Department of Environmental Health and Engineering at Johns Hopkins University in Baltimore, Maryland, he and his colleagues researched how many children under the age of 6 years were exposed to contaminated water.

The results showed that lead contamination of water is widespread. 

“We’re estimating that 68% of kids under the age of 6 in Chicago were exposed to lead-contaminated drinking water,” Mr. Huynh said. 

He added that residents in predominantly Black and Latino neighborhoods had the highest risk for lead contamination in their water, but children living on these blocks were less likely to get tested, suggesting a need for more outreach to raise awareness.

Meanwhile, a little over one third of Chicago residents reported drinking bottled water as their main source of drinking water.

But even bottled water could contain lead. The US Food and Drug Administration (FDA) has set a limit for lead in bottled water to five parts per billion. The FDA threshold for taking action in public drinking water systems is 15 parts per billion. But the American Academy of Pediatrics states that no amount of lead in drinking water is considered safe for drinking. 

Mr. Huynh also pointed out that not all home water filters remove lead. Only devices that meet National Sanitation Foundation 53 standards are certified for lead removal. Consumers should verify that the filter package specifically lists the device as certified for removing contaminant lead.
 

Lead-tainted Cinnamon 

Last fall, the North Carolina Department of Health and Human Services identified several children with elevated levels of lead who had consumed WanaBana Apple Cinnamon Fruit Puree pouches.

An investigation by the FDA identified additional brands containing lead and issued a recall of applesauce pouches sold by retailers like Dollar Tree and Amazon.

According to the US Centers for Disease Control and Prevention, nearly 500 children were affected by the tainted applesauce. The FDA traced the source of the lead to cinnamon from a supplier in Ecuador.

An FDA spokesperson told this news organization the episode appears to have resulted from “economically motivated adulteration,” which occurs when a manufacturer leaves out or substitutes a valuable ingredient or part of a food. In the case of spices, lead may be added as a coloring agent or to increase the product weight.

“When we look at domestically made products from large, reputable companies, in general, they do a pretty good job of following safe product guidelines and regulations,” said Kevin Osterhoudt, MD, professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “But when we use third-party sellers and we import things from other countries that aren’t regulated as closely, we certainly take a lot more risk in the products that we receive.”

While the Food Safety Modernization Act of 2011 aimed to improve agency’s capacity to manage the ever-rising volume of food produced domestically and imported from overseas, the funding has stayed flat while the volume of inspections has increased. In the early 1990s, the number of shipments screened by the agency numbered in the thousands annually. Last year the FDA screened 15 million shipments from more than 200 countries, according to the agency.

Prompted by the finding of lead in applesauce, the FDA began a wider investigation into ground cinnamon by sampling the product from discount retail stores. It recalled an additional six brands of cinnamon sold in the United States containing lead.

Dr. Osterhoudt’s message to families who think their child might have been exposed to a contaminated product is to dispose of it as directed by FDA and CDC guidelines. 

In Philadelphia, where Dr. Osterhoudt practices as an emergency room physician, baseline rates of childhood lead poisoning are already high, so he advises families to “do a larger inventory of all the source potential sources of lead in their life and to reduce all the exposures as low as possible.” 

He also advises parents that a nutritious diet high in calcium and iron can protect their children from the deleterious effects of lead.
 

Current Standards for Lead Screening and Testing

Lead is ubiquitous. The common routes of exposure to humans include use of fossil fuels such as leaded gasoline, some types of industrial facilities, and past use of lead-based paint in homes. In addition to spices, lead has been found in a wide variety of products such as toys, jewelry, antiques, cosmetics, and dietary supplements imported from other countries.

Noah Buncher, DO, is a primary care pediatrician in South Philadelphia at Children’s Hospital of Pennsylvania and the former director of a lead clinic in Boston that provides care for children with lead poisoning. He follows guidelines from the American Academy of Pediatrics that define an elevated BLL as ≥ 3.5 µg/dL. The guidelines recommend screening children for lead exposures during well child visits starting at age 6 months up to 6 years and obtaining a BLL if risks for lead exposure are present. 

Dr. Buncher starts with a basic environmental history that covers items like the age, condition, zip code of home, parental occupations, or hobbies that might result in exposing family members to lead, and if another child in the home has a history of elevated BLLs. 

But a careful history for potential lead exposures can be time-consuming. 

“There’s a lot to cover in a routine well child visit,” Dr. Buncher said. “We have maybe 15-20 minutes to cover a lot.” 

Clinics also vary on whether lead screening questions are put into workflows in the electronic medical record. Although parents can complete a written questionnaire about possible lead exposures, they may have difficulty answering questions about the age of their home or not know whether their occupation is high risk.

Transportation to a clinic is often a barrier for families, and sometimes patients must travel to a separate lab to be tested for lead. 

Dr. Buncher also pointed to the patchwork of local and state requirements that can lead to confusion among providers. Massachusetts, where he formerly practiced, has a universal requirement to test all children at ages 1, 2, and 3 years. But in Pennsylvania, screening laws vary from county to county. 

“Pennsylvania should implement universal screening recommendations for all kids under 6 regardless of what county you live in,” Dr. Buncher said.
 

Protective Measures 

Alan Woolf, MD, a professor of pediatrics at Harvard Medical School, Boston, Massachusetts, and director of the Pediatric Environmental Health Center at Boston Children’s Hospital, has a few ideas about how providers can step up their lead game, including partnering with their local health department. 

The CDC funds Childhood Lead Poisoning Prevention Programs based in state and local health departments to work with clinicians to improve rates of blood lead testing, monitor the prevalence of lead in their jurisdictions, and ensure that a system of referral is available for treatment and lead remediation services in the home.

Dr. Woolf also suggested that clinicians refer patients under age 3 years with high BLLs to their local Early Intervention Program. 

“They’ll assess their child’s development, their speech, their motor skills, their social skills, and if they qualify, it’s free,” Dr. Woolf said. 

He cited research showing children with elevated lead levels who received early intervention services performed better in grade school than equally exposed children who did not access similar services.

Another key strategy for pediatric clinicians is to learn local or state regulations for testing children for lead and how to access lead surveillance data in their practice area. Children who reside in high-risk areas are automatic candidates for screening. 

Dr. Woolf pointed out that big cities are not the only localities with lead in the drinking water. If families are drawing water from their own well, they should collect that water annually to have it tested for lead and microbes.

At the clinic-wide level, Dr. Woolf recommends the use of blood lead testing as a quality improvement measure. For example, Akron Children’s Hospital developed a quality improvement initiative using a clinical decision support tool to raise screening rates in their network of 30 clinics. One year after beginning the project, lead screenings during 12-month well visits increased from 71% to 96%. 

“What we’re interested in as pediatric health professionals is eliminating all background sources of lead in a child’s environment,” Dr. Woolf said. “Whether that’s applesauce pouches, whether that’s lead-containing paint, lead in water, lead in spices, or lead in imported pottery or cookware — there are just a tremendous number of sources of lead that we can do something about.”

None of the subjects reported financial conflicts of interest.

A former pediatrician, Dr. Thomas is a freelance science writer living in Portland, Oregon.

A version of this article appeared on Medscape.com.

Experts say pediatricians and primary care clinicians should do more to prevent the toxic effects of lead in their young patients following a 2023 outbreak of elevated levels of lead in children associated with consumption of contaminated applesauce.

Federal legislation in the 1970s eliminated lead from gasoline, paints, and other consumer products, and resulted in significantly reduced blood lead levels (BLLs) in children throughout the United States.

But recently published studies highlight persistent issues with lead in drinking water and consumer products, suggesting that the fight is not over.
 

It’s in the Water

In 2014 the city of Flint, Michigan, changed its water supply and high levels of lead were later found in the municipal water supply.

Effects of that crisis still plague the city today. An initial study found that elevated BLLs had doubled among children between 2013 and 2015.

Lead exposure in young children is associated with several negative outcomes, including decreased cognitive ability, brain volume, and social mobility, and increased anxiety/depression and impulsivity, and higher rates of criminal offenses later in life. 

Many other water systems still contain lead pipes, despite a 1986 ban by the US Environmental Protection Agency on using them for installing or repairing public water systems. The mayor of Chicago announced a plan to start replacing lead service lines in 2020; however, 400,000 households are still served by these pipes, the most in the nation.

Benjamin Huynh, a native of Chicago, was curious about the impact of all those lead service lines. Now an assistant professor in the Department of Environmental Health and Engineering at Johns Hopkins University in Baltimore, Maryland, he and his colleagues researched how many children under the age of 6 years were exposed to contaminated water.

The results showed that lead contamination of water is widespread. 

“We’re estimating that 68% of kids under the age of 6 in Chicago were exposed to lead-contaminated drinking water,” Mr. Huynh said. 

He added that residents in predominantly Black and Latino neighborhoods had the highest risk for lead contamination in their water, but children living on these blocks were less likely to get tested, suggesting a need for more outreach to raise awareness.

Meanwhile, a little over one third of Chicago residents reported drinking bottled water as their main source of drinking water.

But even bottled water could contain lead. The US Food and Drug Administration (FDA) has set a limit for lead in bottled water to five parts per billion. The FDA threshold for taking action in public drinking water systems is 15 parts per billion. But the American Academy of Pediatrics states that no amount of lead in drinking water is considered safe for drinking. 

Mr. Huynh also pointed out that not all home water filters remove lead. Only devices that meet National Sanitation Foundation 53 standards are certified for lead removal. Consumers should verify that the filter package specifically lists the device as certified for removing contaminant lead.
 

Lead-tainted Cinnamon 

Last fall, the North Carolina Department of Health and Human Services identified several children with elevated levels of lead who had consumed WanaBana Apple Cinnamon Fruit Puree pouches.

An investigation by the FDA identified additional brands containing lead and issued a recall of applesauce pouches sold by retailers like Dollar Tree and Amazon.

According to the US Centers for Disease Control and Prevention, nearly 500 children were affected by the tainted applesauce. The FDA traced the source of the lead to cinnamon from a supplier in Ecuador.

An FDA spokesperson told this news organization the episode appears to have resulted from “economically motivated adulteration,” which occurs when a manufacturer leaves out or substitutes a valuable ingredient or part of a food. In the case of spices, lead may be added as a coloring agent or to increase the product weight.

“When we look at domestically made products from large, reputable companies, in general, they do a pretty good job of following safe product guidelines and regulations,” said Kevin Osterhoudt, MD, professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “But when we use third-party sellers and we import things from other countries that aren’t regulated as closely, we certainly take a lot more risk in the products that we receive.”

While the Food Safety Modernization Act of 2011 aimed to improve agency’s capacity to manage the ever-rising volume of food produced domestically and imported from overseas, the funding has stayed flat while the volume of inspections has increased. In the early 1990s, the number of shipments screened by the agency numbered in the thousands annually. Last year the FDA screened 15 million shipments from more than 200 countries, according to the agency.

Prompted by the finding of lead in applesauce, the FDA began a wider investigation into ground cinnamon by sampling the product from discount retail stores. It recalled an additional six brands of cinnamon sold in the United States containing lead.

Dr. Osterhoudt’s message to families who think their child might have been exposed to a contaminated product is to dispose of it as directed by FDA and CDC guidelines. 

In Philadelphia, where Dr. Osterhoudt practices as an emergency room physician, baseline rates of childhood lead poisoning are already high, so he advises families to “do a larger inventory of all the source potential sources of lead in their life and to reduce all the exposures as low as possible.” 

He also advises parents that a nutritious diet high in calcium and iron can protect their children from the deleterious effects of lead.
 

Current Standards for Lead Screening and Testing

Lead is ubiquitous. The common routes of exposure to humans include use of fossil fuels such as leaded gasoline, some types of industrial facilities, and past use of lead-based paint in homes. In addition to spices, lead has been found in a wide variety of products such as toys, jewelry, antiques, cosmetics, and dietary supplements imported from other countries.

Noah Buncher, DO, is a primary care pediatrician in South Philadelphia at Children’s Hospital of Pennsylvania and the former director of a lead clinic in Boston that provides care for children with lead poisoning. He follows guidelines from the American Academy of Pediatrics that define an elevated BLL as ≥ 3.5 µg/dL. The guidelines recommend screening children for lead exposures during well child visits starting at age 6 months up to 6 years and obtaining a BLL if risks for lead exposure are present. 

Dr. Buncher starts with a basic environmental history that covers items like the age, condition, zip code of home, parental occupations, or hobbies that might result in exposing family members to lead, and if another child in the home has a history of elevated BLLs. 

But a careful history for potential lead exposures can be time-consuming. 

“There’s a lot to cover in a routine well child visit,” Dr. Buncher said. “We have maybe 15-20 minutes to cover a lot.” 

Clinics also vary on whether lead screening questions are put into workflows in the electronic medical record. Although parents can complete a written questionnaire about possible lead exposures, they may have difficulty answering questions about the age of their home or not know whether their occupation is high risk.

Transportation to a clinic is often a barrier for families, and sometimes patients must travel to a separate lab to be tested for lead. 

Dr. Buncher also pointed to the patchwork of local and state requirements that can lead to confusion among providers. Massachusetts, where he formerly practiced, has a universal requirement to test all children at ages 1, 2, and 3 years. But in Pennsylvania, screening laws vary from county to county. 

“Pennsylvania should implement universal screening recommendations for all kids under 6 regardless of what county you live in,” Dr. Buncher said.
 

Protective Measures 

Alan Woolf, MD, a professor of pediatrics at Harvard Medical School, Boston, Massachusetts, and director of the Pediatric Environmental Health Center at Boston Children’s Hospital, has a few ideas about how providers can step up their lead game, including partnering with their local health department. 

The CDC funds Childhood Lead Poisoning Prevention Programs based in state and local health departments to work with clinicians to improve rates of blood lead testing, monitor the prevalence of lead in their jurisdictions, and ensure that a system of referral is available for treatment and lead remediation services in the home.

Dr. Woolf also suggested that clinicians refer patients under age 3 years with high BLLs to their local Early Intervention Program. 

“They’ll assess their child’s development, their speech, their motor skills, their social skills, and if they qualify, it’s free,” Dr. Woolf said. 

He cited research showing children with elevated lead levels who received early intervention services performed better in grade school than equally exposed children who did not access similar services.

Another key strategy for pediatric clinicians is to learn local or state regulations for testing children for lead and how to access lead surveillance data in their practice area. Children who reside in high-risk areas are automatic candidates for screening. 

Dr. Woolf pointed out that big cities are not the only localities with lead in the drinking water. If families are drawing water from their own well, they should collect that water annually to have it tested for lead and microbes.

At the clinic-wide level, Dr. Woolf recommends the use of blood lead testing as a quality improvement measure. For example, Akron Children’s Hospital developed a quality improvement initiative using a clinical decision support tool to raise screening rates in their network of 30 clinics. One year after beginning the project, lead screenings during 12-month well visits increased from 71% to 96%. 

“What we’re interested in as pediatric health professionals is eliminating all background sources of lead in a child’s environment,” Dr. Woolf said. “Whether that’s applesauce pouches, whether that’s lead-containing paint, lead in water, lead in spices, or lead in imported pottery or cookware — there are just a tremendous number of sources of lead that we can do something about.”

None of the subjects reported financial conflicts of interest.

A former pediatrician, Dr. Thomas is a freelance science writer living in Portland, Oregon.

A version of this article appeared on Medscape.com.

Experts say pediatricians and primary care clinicians should do more to prevent the toxic effects of lead in their young patients following a 2023 outbreak of elevated levels of lead in children associated with consumption of contaminated applesauce.

Federal legislation in the 1970s eliminated lead from gasoline, paints, and other consumer products, and resulted in significantly reduced blood lead levels (BLLs) in children throughout the United States.

But recently published studies highlight persistent issues with lead in drinking water and consumer products, suggesting that the fight is not over.
 

It’s in the Water

In 2014 the city of Flint, Michigan, changed its water supply and high levels of lead were later found in the municipal water supply.

Effects of that crisis still plague the city today. An initial study found that elevated BLLs had doubled among children between 2013 and 2015.

Lead exposure in young children is associated with several negative outcomes, including decreased cognitive ability, brain volume, and social mobility, and increased anxiety/depression and impulsivity, and higher rates of criminal offenses later in life. 

Many other water systems still contain lead pipes, despite a 1986 ban by the US Environmental Protection Agency on using them for installing or repairing public water systems. The mayor of Chicago announced a plan to start replacing lead service lines in 2020; however, 400,000 households are still served by these pipes, the most in the nation.

Benjamin Huynh, a native of Chicago, was curious about the impact of all those lead service lines. Now an assistant professor in the Department of Environmental Health and Engineering at Johns Hopkins University in Baltimore, Maryland, he and his colleagues researched how many children under the age of 6 years were exposed to contaminated water.

The results showed that lead contamination of water is widespread. 

“We’re estimating that 68% of kids under the age of 6 in Chicago were exposed to lead-contaminated drinking water,” Mr. Huynh said. 

He added that residents in predominantly Black and Latino neighborhoods had the highest risk for lead contamination in their water, but children living on these blocks were less likely to get tested, suggesting a need for more outreach to raise awareness.

Meanwhile, a little over one third of Chicago residents reported drinking bottled water as their main source of drinking water.

But even bottled water could contain lead. The US Food and Drug Administration (FDA) has set a limit for lead in bottled water to five parts per billion. The FDA threshold for taking action in public drinking water systems is 15 parts per billion. But the American Academy of Pediatrics states that no amount of lead in drinking water is considered safe for drinking. 

Mr. Huynh also pointed out that not all home water filters remove lead. Only devices that meet National Sanitation Foundation 53 standards are certified for lead removal. Consumers should verify that the filter package specifically lists the device as certified for removing contaminant lead.
 

Lead-tainted Cinnamon 

Last fall, the North Carolina Department of Health and Human Services identified several children with elevated levels of lead who had consumed WanaBana Apple Cinnamon Fruit Puree pouches.

An investigation by the FDA identified additional brands containing lead and issued a recall of applesauce pouches sold by retailers like Dollar Tree and Amazon.

According to the US Centers for Disease Control and Prevention, nearly 500 children were affected by the tainted applesauce. The FDA traced the source of the lead to cinnamon from a supplier in Ecuador.

An FDA spokesperson told this news organization the episode appears to have resulted from “economically motivated adulteration,” which occurs when a manufacturer leaves out or substitutes a valuable ingredient or part of a food. In the case of spices, lead may be added as a coloring agent or to increase the product weight.

“When we look at domestically made products from large, reputable companies, in general, they do a pretty good job of following safe product guidelines and regulations,” said Kevin Osterhoudt, MD, professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “But when we use third-party sellers and we import things from other countries that aren’t regulated as closely, we certainly take a lot more risk in the products that we receive.”

While the Food Safety Modernization Act of 2011 aimed to improve agency’s capacity to manage the ever-rising volume of food produced domestically and imported from overseas, the funding has stayed flat while the volume of inspections has increased. In the early 1990s, the number of shipments screened by the agency numbered in the thousands annually. Last year the FDA screened 15 million shipments from more than 200 countries, according to the agency.

Prompted by the finding of lead in applesauce, the FDA began a wider investigation into ground cinnamon by sampling the product from discount retail stores. It recalled an additional six brands of cinnamon sold in the United States containing lead.

Dr. Osterhoudt’s message to families who think their child might have been exposed to a contaminated product is to dispose of it as directed by FDA and CDC guidelines. 

In Philadelphia, where Dr. Osterhoudt practices as an emergency room physician, baseline rates of childhood lead poisoning are already high, so he advises families to “do a larger inventory of all the source potential sources of lead in their life and to reduce all the exposures as low as possible.” 

He also advises parents that a nutritious diet high in calcium and iron can protect their children from the deleterious effects of lead.
 

Current Standards for Lead Screening and Testing

Lead is ubiquitous. The common routes of exposure to humans include use of fossil fuels such as leaded gasoline, some types of industrial facilities, and past use of lead-based paint in homes. In addition to spices, lead has been found in a wide variety of products such as toys, jewelry, antiques, cosmetics, and dietary supplements imported from other countries.

Noah Buncher, DO, is a primary care pediatrician in South Philadelphia at Children’s Hospital of Pennsylvania and the former director of a lead clinic in Boston that provides care for children with lead poisoning. He follows guidelines from the American Academy of Pediatrics that define an elevated BLL as ≥ 3.5 µg/dL. The guidelines recommend screening children for lead exposures during well child visits starting at age 6 months up to 6 years and obtaining a BLL if risks for lead exposure are present. 

Dr. Buncher starts with a basic environmental history that covers items like the age, condition, zip code of home, parental occupations, or hobbies that might result in exposing family members to lead, and if another child in the home has a history of elevated BLLs. 

But a careful history for potential lead exposures can be time-consuming. 

“There’s a lot to cover in a routine well child visit,” Dr. Buncher said. “We have maybe 15-20 minutes to cover a lot.” 

Clinics also vary on whether lead screening questions are put into workflows in the electronic medical record. Although parents can complete a written questionnaire about possible lead exposures, they may have difficulty answering questions about the age of their home or not know whether their occupation is high risk.

Transportation to a clinic is often a barrier for families, and sometimes patients must travel to a separate lab to be tested for lead. 

Dr. Buncher also pointed to the patchwork of local and state requirements that can lead to confusion among providers. Massachusetts, where he formerly practiced, has a universal requirement to test all children at ages 1, 2, and 3 years. But in Pennsylvania, screening laws vary from county to county. 

“Pennsylvania should implement universal screening recommendations for all kids under 6 regardless of what county you live in,” Dr. Buncher said.
 

Protective Measures 

Alan Woolf, MD, a professor of pediatrics at Harvard Medical School, Boston, Massachusetts, and director of the Pediatric Environmental Health Center at Boston Children’s Hospital, has a few ideas about how providers can step up their lead game, including partnering with their local health department. 

The CDC funds Childhood Lead Poisoning Prevention Programs based in state and local health departments to work with clinicians to improve rates of blood lead testing, monitor the prevalence of lead in their jurisdictions, and ensure that a system of referral is available for treatment and lead remediation services in the home.

Dr. Woolf also suggested that clinicians refer patients under age 3 years with high BLLs to their local Early Intervention Program. 

“They’ll assess their child’s development, their speech, their motor skills, their social skills, and if they qualify, it’s free,” Dr. Woolf said. 

He cited research showing children with elevated lead levels who received early intervention services performed better in grade school than equally exposed children who did not access similar services.

Another key strategy for pediatric clinicians is to learn local or state regulations for testing children for lead and how to access lead surveillance data in their practice area. Children who reside in high-risk areas are automatic candidates for screening. 

Dr. Woolf pointed out that big cities are not the only localities with lead in the drinking water. If families are drawing water from their own well, they should collect that water annually to have it tested for lead and microbes.

At the clinic-wide level, Dr. Woolf recommends the use of blood lead testing as a quality improvement measure. For example, Akron Children’s Hospital developed a quality improvement initiative using a clinical decision support tool to raise screening rates in their network of 30 clinics. One year after beginning the project, lead screenings during 12-month well visits increased from 71% to 96%. 

“What we’re interested in as pediatric health professionals is eliminating all background sources of lead in a child’s environment,” Dr. Woolf said. “Whether that’s applesauce pouches, whether that’s lead-containing paint, lead in water, lead in spices, or lead in imported pottery or cookware — there are just a tremendous number of sources of lead that we can do something about.”

None of the subjects reported financial conflicts of interest.

A former pediatrician, Dr. Thomas is a freelance science writer living in Portland, Oregon.

A version of this article appeared on Medscape.com.

The Centers for Disease Control and Prevention (CDC) estimates that 1.1% of US adults have epilepsy. Although 89% report seeing a physician in the past year about their condition, only 62% of adults saw a neurologist or seizure specialist. 

These findings prompted Rosemary Kobau, MPH, the acting team lead for the CDC’s epilepsy program, to take a closer look at referral patterns by primary care providers in the United States. Using data from a 2018 online survey of US internists, pediatricians, family medicine physicians, and nurse practitioners, she found that 90% of providers would refer a patient with new-onset seizure to a neurologist.

She also noticed what she calls a “big red flag”: “We found that 40% of primary care providers did not indicate that they would refer their patient with epilepsy to a neurologist when their patient fails to respond to treatment, or if they have a change in seizure activity,” Dr. Kobau told this news organization. Individuals with uncontrolled seizures are at risk for multiple adverse health outcomes, along with emotional problems, social stigma, and decreased life expectancy. 

Factors that influenced primary care clinicians to refer to a neurologist included prompt availability of appointments, ability to talk to the neurologist, and whether a patient’s insurance covered specialty visits. Proximity of a specialist also was cited as a barrier, because neurologists can be hard to find outside of urban centers.

Wait lists for neurologist are not like to get shorter any time soon, according to a 2019 report from the American Academy of Neurology (AAN). A 2013 workforce report from the AAN found 35 US states, representing 62% of the US population, had fewer neurologists than needed to meet demand. By 2025, demand is projected to exceed supply in 41 states. 

Much of the increasing demand for adult neurologists is driven by aging of the population, resulting in higher rates of stroke, Parkinson’s disease, and dementia. But pediatric neurologists are also overwhelmed: Pediatric neurology is one of the top three pediatric subspecialties with the longest wait times. The shortage is exacerbated by difficulties in transitioning adolescents with epilepsy — many diagnosed early in life with neurodevelopmental and epileptic encephalopathy and problem lists that include learning disorders, behavioral issues, and other chronic medical problems — to adult epilepsy specialists. 

Although one of the solutions offered by the AAN is more training in epilepsy management for non-neurologists (such as CME programs developed by the American Epilepsy Society), many primary care providers are overwhelmed already. Still, primary care providers are well-positioned to help answer some of the most important questions about the management of patients with seizure disorders. 
 

How to Help

“There’s a lot the pediatrician can do when a child presents with seizures,” said Sucheta Joshi, MD, who serves as the medical director of the Neurological Institute Comprehensive Epilepsy Center at Children’s Hospital Los Angeles.

Step one is helping to allay the fears of family members who witness a seizure. “They can talk about seizure safety, they can talk about first aid when a seizure happens, they can talk about what to do, what not to do,” she advised. Clinicians who see children can find resources for families on the American Academy of Pediatrics (AAP) National Coordinating Center for Epilepsy website, including a 24/7 helpline, information about local chapters of the Epilepsy Foundation, and first aid training for seizures. 

Fred Lado, MD, PhD, a professor of neurology at the Zucker School of Medicine at Hofstra-Norwell in Hempstead, New York, said that primary care clinicians have several decision points when it comes to their patients with epilepsy.

The first is whether to initiate medication after the first episode of seizure. Studies show that the risk for a second seizure decreases in patients started on anticonvulsant therapy after a first event, but many clinicians don›t want to commit patients to long-term therapy without more evidence that the patient has epilepsy. Studies have shown that delaying therapy until a second seizure occurs doesn›t negatively affect quality of life and long-term prognosis. 

The International League Against Epilepsy (ILAE) advised treatment for patients with two or more unprovoked seizures but revised its recommendation in 2014 to begin treatment after a first seizure for individuals at high risk for a second seizure. History of a brain insult related to a stroke, mass lesion in the brain, or trauma are risk factors for a second seizure, whereas seizures provoked by a concussion, alcohol withdrawal, or exposure to toxins carry low risk for additional episodes.

Dr. Lado also raised the importance of taking a good history from a patient presenting for medical care for a new-onset seizure to determine whether the recent episode is really the first such incident.

Up to half of patients presenting to emergency departments for convulsive seizures have a history of a preceding nonmotor seizure that the patient or their family members have failed to identify. As many as 60% of people with epilepsy have focal seizures, but the majority of these are nonmotor seizures. As a result, these patients often go without a diagnosis until they develop bilateral tonic-clonic seizures — by which time they may already been injured during a seizure or had an accident while driving.

In terms of imaging and other workup that should be performed prior to the first appointment with a pediatric neurologist or epilepsy specialist, Dr. Joshi generally recommends EEG. She also prefers MRI over CT, which is better for finding lesions that tend to cause seizures in kids such as developmental abnormalities like a cortical malformation or a perinatal process. Obtaining an MRI prior to seeing the neurologist is elective, depending on whether the history and clinical presentation suggest a focal lesion.

For adults, Dr. Lado also recommends an EEG and MRI to start but rarely advises other laboratory studies. When patients present to the emergency department with a new-onset seizure, the workup commonly includes a chemistry panel to rule out hypoglycemia or electrolyte abnormalities. But in the outpatient setting, where a patient describes symptoms of a seizure that occurred a week ago or longer, Dr. Lado said the yield of such assessments is low. 

“I think the labs are often more useful as you’re thinking about an anticonvulsant,” Dr. Lado said. Particularly for a patient who is facing a long wait to see specialist, obtaining baseline liver enzymes and a complete blood cell count is worthwhile, because many antiseizure medications can cause anemia or liver damage.

Dr. Lado agreed that referral to a specialist is critical for patients with drug-resistant seizures, defined by the ILAE as seizures that persist despite the use of two or more anticonvulsants. 

“One of the great problems in epilepsy care is a sort of sense of complacency,” he said. Some of his own patients have become comfortable with their epilepsy diagnosis and profess to be untroubled by having a few seizures per year. In 2018, Dr. Kobau was a co-author on a study reporting that less than half of US adults taking seizure medications were seizure-free in the past year. 

This scenario is an opportunity for primary care providers to help determine whether their patients are taking their antiseizure medication correctly. A referral to a specialist might not be necessary if the seizures are occurring because the patient’s prescription ran out. Similarly, if a patient doesn’t take the medication because of unpleasant side effects, raising the dose won’t help. 

Dr. Lado’s advice is to explore why the patient’s management plan is not working and make adjustments tailored to their needs. The solution might be as simple as changing the patient to an extended-release formulation to lower the number of daily doses needed, he said.

But for patients who do have recurrent seizures despite good adherence, Dr. Lado strongly urges a referral to an epilepsy specialist. He serves as president of the National Association of Epilepsy Centers (NAEC), a network of more than 260 epilepsy centers in the United States that offer the services of epileptologists, neurosurgeons, neuropsychologists, nurse specialists, EEG technologists, social workers, and others with training and experience in epilepsy care. In addition to adjusting and monitoring medications, patients seen at an NAEC can be evaluated for surgery, neurostimulators, and ketogenic diets.
 

Improving Self-Management

Another role that primary care can play is promoting self-efficacy among patients with epilepsy.

“Providers have historically tended to focus on medication adherence alone, ignoring other health enhancing behaviors, even just sleep hygiene,” Dr. Kobau said. But adequate sleep, regular exercise, a healthy diet, avoidance of tobacco and excessive alcohol, and stress management are all important for seizure management. 

In 2007, CDC launched the Managing Epilepsy Well (MEW) Network, which has the mission of advancing self-management research in collaboration with patients with epilepsy as well as a broad range of healthcare providers. “It’s a patient-driven kind of approach consistent with community-based, participatory practice research,” said Dr. Kobau, who oversees the initiative.

The MEW network, which consists of six prevention research centers funded by CDC, has piloted and evaluated several evidence-based programs that can help patients better control their epilepsy. 

One such intervention is Project Uplift, which delivers mindfulness-based cognitive-behavioral therapy in a virtual group setting. Behavioral therapy is important for people with seizure disorders, whose risk for depression is more than twice that of the general population. The initial trial found the intervention was effective in reducing depressive symptoms in participants, and research since has focused on adapting the program to provide culturally appropriate care to underserved populations. The eight sessions, held weekly, are available in both English and Spanish.

Another program, HOBSCOTCH, allows patients to meet one-on-one virtually with a trained coach to work on skills for improving attention and memory, common problems among people with epilepsy.

MINDSET involves a tablet-based clinical decision tool that patients can use to track their self-management behaviors, such as taking their medications, seizure triggers, symptoms of depression, and keeping their clinic appointments. It also helps them monitor whether they are getting adequate sleep, reducing their stress, and maintaining social networks. The tool generates a printable action plan for patients to prompt discussion and shared decision-making between patient and clinician to prioritize behavioral issues, set goals, and monitor changes over time.

Clinicians can refer patients to any of the MEW interventions, or patients can enroll themselves online.

 

Emerging Approaches

The AAN’s 2019 report promoted use of technological solutions to bridge the gap between primary care providers and scarce — as well as distant — neurologists. Many health systems support e-consults between clinicians, allowing simple discussions about medications and advice about testing recommended prior to a neurology visit. Initially developed for treatment for infection with hepatitis C virus, Project Extension for Community Healthcare Outcomes (ECHO) uses a central hub of specialists to support primary care providers via teleconference to conduct case reviews and didactic sessions. 

Much of Dr. Joshi’s work has focused on ways to coordinate care to children who live far from a pediatric epilepsy center. In a previous position at the University of Michigan, her team was one of four sites funded by the AAP’s National Coordinating Center for Epilepsy to pilot an intervention using telehealth. Implemented in 2017-2019, the initiative used quality improvement methodology to explore a model where patients went to the office of their primary care provider so that both could participate in the call with a neurologist.

The strategy was successful, resulting in reduced out-of-pocket costs, missed school hours, and missed work hours. Patient satisfaction was high (97%), and more parents in the intervention group than the control group agreed that it was easier to obtain appointments with specialists (95% vs 65%, respectively).

And since the pandemic, in-home telehealth visits have become commonplace, adding to the potential convenience and cost savings of telemedicine. 

CDC has invested in Project ECHO as a training program for nonspecialist providers to manage epilepsy. Based at the University of Cincinnati, the initial pilot from 2017 to 2019 trained primary care providers in Ohio and neighboring states using monthly 1-hour sessions via Zoom. According to Dr. Kobau, “Of those 164 primary care providers, 97% reported higher interest in improving their care of patients with epilepsy, and at least 98% reported that they were more confident in treating their patients with epilepsy.” Since that time, over 900 providers have received the training, which now attracts participants from all over the country.

Although the current burden of managing epilepsy now seems to be falling heavily on primary care providers, Dr. Lado said he believes they can provide useful insight into their patients’ history and needs: “I think they are in a unique and impactful position, mostly to refer those patients who are still having seizures.”
 

Additional Resources for Patients and Providers

• American Academy of Pediatrics National Coordinating Center for Epilepsy 
• American Epilepsy Society  (CME courses designed to designed to increase knowledge about epilepsy diagnosis, treatment, and management; seizure first-aid; epilepsy stigma; and social determinants of health for people with epilepsy)  
• Centers for Disease Control and Prevention   .

Dr. Joshi, Dr. Kobau, and Dr. Lado report no relevant financial relationships. 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com .

The Centers for Disease Control and Prevention (CDC) estimates that 1.1% of US adults have epilepsy. Although 89% report seeing a physician in the past year about their condition, only 62% of adults saw a neurologist or seizure specialist. 

These findings prompted Rosemary Kobau, MPH, the acting team lead for the CDC’s epilepsy program, to take a closer look at referral patterns by primary care providers in the United States. Using data from a 2018 online survey of US internists, pediatricians, family medicine physicians, and nurse practitioners, she found that 90% of providers would refer a patient with new-onset seizure to a neurologist.

She also noticed what she calls a “big red flag”: “We found that 40% of primary care providers did not indicate that they would refer their patient with epilepsy to a neurologist when their patient fails to respond to treatment, or if they have a change in seizure activity,” Dr. Kobau told this news organization. Individuals with uncontrolled seizures are at risk for multiple adverse health outcomes, along with emotional problems, social stigma, and decreased life expectancy. 

Factors that influenced primary care clinicians to refer to a neurologist included prompt availability of appointments, ability to talk to the neurologist, and whether a patient’s insurance covered specialty visits. Proximity of a specialist also was cited as a barrier, because neurologists can be hard to find outside of urban centers.

Wait lists for neurologist are not like to get shorter any time soon, according to a 2019 report from the American Academy of Neurology (AAN). A 2013 workforce report from the AAN found 35 US states, representing 62% of the US population, had fewer neurologists than needed to meet demand. By 2025, demand is projected to exceed supply in 41 states. 

Much of the increasing demand for adult neurologists is driven by aging of the population, resulting in higher rates of stroke, Parkinson’s disease, and dementia. But pediatric neurologists are also overwhelmed: Pediatric neurology is one of the top three pediatric subspecialties with the longest wait times. The shortage is exacerbated by difficulties in transitioning adolescents with epilepsy — many diagnosed early in life with neurodevelopmental and epileptic encephalopathy and problem lists that include learning disorders, behavioral issues, and other chronic medical problems — to adult epilepsy specialists. 

Although one of the solutions offered by the AAN is more training in epilepsy management for non-neurologists (such as CME programs developed by the American Epilepsy Society), many primary care providers are overwhelmed already. Still, primary care providers are well-positioned to help answer some of the most important questions about the management of patients with seizure disorders. 
 

How to Help

“There’s a lot the pediatrician can do when a child presents with seizures,” said Sucheta Joshi, MD, who serves as the medical director of the Neurological Institute Comprehensive Epilepsy Center at Children’s Hospital Los Angeles.

Step one is helping to allay the fears of family members who witness a seizure. “They can talk about seizure safety, they can talk about first aid when a seizure happens, they can talk about what to do, what not to do,” she advised. Clinicians who see children can find resources for families on the American Academy of Pediatrics (AAP) National Coordinating Center for Epilepsy website, including a 24/7 helpline, information about local chapters of the Epilepsy Foundation, and first aid training for seizures. 

Fred Lado, MD, PhD, a professor of neurology at the Zucker School of Medicine at Hofstra-Norwell in Hempstead, New York, said that primary care clinicians have several decision points when it comes to their patients with epilepsy.

The first is whether to initiate medication after the first episode of seizure. Studies show that the risk for a second seizure decreases in patients started on anticonvulsant therapy after a first event, but many clinicians don›t want to commit patients to long-term therapy without more evidence that the patient has epilepsy. Studies have shown that delaying therapy until a second seizure occurs doesn›t negatively affect quality of life and long-term prognosis. 

The International League Against Epilepsy (ILAE) advised treatment for patients with two or more unprovoked seizures but revised its recommendation in 2014 to begin treatment after a first seizure for individuals at high risk for a second seizure. History of a brain insult related to a stroke, mass lesion in the brain, or trauma are risk factors for a second seizure, whereas seizures provoked by a concussion, alcohol withdrawal, or exposure to toxins carry low risk for additional episodes.

Dr. Lado also raised the importance of taking a good history from a patient presenting for medical care for a new-onset seizure to determine whether the recent episode is really the first such incident.

Up to half of patients presenting to emergency departments for convulsive seizures have a history of a preceding nonmotor seizure that the patient or their family members have failed to identify. As many as 60% of people with epilepsy have focal seizures, but the majority of these are nonmotor seizures. As a result, these patients often go without a diagnosis until they develop bilateral tonic-clonic seizures — by which time they may already been injured during a seizure or had an accident while driving.

In terms of imaging and other workup that should be performed prior to the first appointment with a pediatric neurologist or epilepsy specialist, Dr. Joshi generally recommends EEG. She also prefers MRI over CT, which is better for finding lesions that tend to cause seizures in kids such as developmental abnormalities like a cortical malformation or a perinatal process. Obtaining an MRI prior to seeing the neurologist is elective, depending on whether the history and clinical presentation suggest a focal lesion.

For adults, Dr. Lado also recommends an EEG and MRI to start but rarely advises other laboratory studies. When patients present to the emergency department with a new-onset seizure, the workup commonly includes a chemistry panel to rule out hypoglycemia or electrolyte abnormalities. But in the outpatient setting, where a patient describes symptoms of a seizure that occurred a week ago or longer, Dr. Lado said the yield of such assessments is low. 

“I think the labs are often more useful as you’re thinking about an anticonvulsant,” Dr. Lado said. Particularly for a patient who is facing a long wait to see specialist, obtaining baseline liver enzymes and a complete blood cell count is worthwhile, because many antiseizure medications can cause anemia or liver damage.

Dr. Lado agreed that referral to a specialist is critical for patients with drug-resistant seizures, defined by the ILAE as seizures that persist despite the use of two or more anticonvulsants. 

“One of the great problems in epilepsy care is a sort of sense of complacency,” he said. Some of his own patients have become comfortable with their epilepsy diagnosis and profess to be untroubled by having a few seizures per year. In 2018, Dr. Kobau was a co-author on a study reporting that less than half of US adults taking seizure medications were seizure-free in the past year. 

This scenario is an opportunity for primary care providers to help determine whether their patients are taking their antiseizure medication correctly. A referral to a specialist might not be necessary if the seizures are occurring because the patient’s prescription ran out. Similarly, if a patient doesn’t take the medication because of unpleasant side effects, raising the dose won’t help. 

Dr. Lado’s advice is to explore why the patient’s management plan is not working and make adjustments tailored to their needs. The solution might be as simple as changing the patient to an extended-release formulation to lower the number of daily doses needed, he said.

But for patients who do have recurrent seizures despite good adherence, Dr. Lado strongly urges a referral to an epilepsy specialist. He serves as president of the National Association of Epilepsy Centers (NAEC), a network of more than 260 epilepsy centers in the United States that offer the services of epileptologists, neurosurgeons, neuropsychologists, nurse specialists, EEG technologists, social workers, and others with training and experience in epilepsy care. In addition to adjusting and monitoring medications, patients seen at an NAEC can be evaluated for surgery, neurostimulators, and ketogenic diets.
 

Improving Self-Management

Another role that primary care can play is promoting self-efficacy among patients with epilepsy.

“Providers have historically tended to focus on medication adherence alone, ignoring other health enhancing behaviors, even just sleep hygiene,” Dr. Kobau said. But adequate sleep, regular exercise, a healthy diet, avoidance of tobacco and excessive alcohol, and stress management are all important for seizure management. 

In 2007, CDC launched the Managing Epilepsy Well (MEW) Network, which has the mission of advancing self-management research in collaboration with patients with epilepsy as well as a broad range of healthcare providers. “It’s a patient-driven kind of approach consistent with community-based, participatory practice research,” said Dr. Kobau, who oversees the initiative.

The MEW network, which consists of six prevention research centers funded by CDC, has piloted and evaluated several evidence-based programs that can help patients better control their epilepsy. 

One such intervention is Project Uplift, which delivers mindfulness-based cognitive-behavioral therapy in a virtual group setting. Behavioral therapy is important for people with seizure disorders, whose risk for depression is more than twice that of the general population. The initial trial found the intervention was effective in reducing depressive symptoms in participants, and research since has focused on adapting the program to provide culturally appropriate care to underserved populations. The eight sessions, held weekly, are available in both English and Spanish.

Another program, HOBSCOTCH, allows patients to meet one-on-one virtually with a trained coach to work on skills for improving attention and memory, common problems among people with epilepsy.

MINDSET involves a tablet-based clinical decision tool that patients can use to track their self-management behaviors, such as taking their medications, seizure triggers, symptoms of depression, and keeping their clinic appointments. It also helps them monitor whether they are getting adequate sleep, reducing their stress, and maintaining social networks. The tool generates a printable action plan for patients to prompt discussion and shared decision-making between patient and clinician to prioritize behavioral issues, set goals, and monitor changes over time.

Clinicians can refer patients to any of the MEW interventions, or patients can enroll themselves online.

 

Emerging Approaches

The AAN’s 2019 report promoted use of technological solutions to bridge the gap between primary care providers and scarce — as well as distant — neurologists. Many health systems support e-consults between clinicians, allowing simple discussions about medications and advice about testing recommended prior to a neurology visit. Initially developed for treatment for infection with hepatitis C virus, Project Extension for Community Healthcare Outcomes (ECHO) uses a central hub of specialists to support primary care providers via teleconference to conduct case reviews and didactic sessions. 

Much of Dr. Joshi’s work has focused on ways to coordinate care to children who live far from a pediatric epilepsy center. In a previous position at the University of Michigan, her team was one of four sites funded by the AAP’s National Coordinating Center for Epilepsy to pilot an intervention using telehealth. Implemented in 2017-2019, the initiative used quality improvement methodology to explore a model where patients went to the office of their primary care provider so that both could participate in the call with a neurologist.

The strategy was successful, resulting in reduced out-of-pocket costs, missed school hours, and missed work hours. Patient satisfaction was high (97%), and more parents in the intervention group than the control group agreed that it was easier to obtain appointments with specialists (95% vs 65%, respectively).

And since the pandemic, in-home telehealth visits have become commonplace, adding to the potential convenience and cost savings of telemedicine. 

CDC has invested in Project ECHO as a training program for nonspecialist providers to manage epilepsy. Based at the University of Cincinnati, the initial pilot from 2017 to 2019 trained primary care providers in Ohio and neighboring states using monthly 1-hour sessions via Zoom. According to Dr. Kobau, “Of those 164 primary care providers, 97% reported higher interest in improving their care of patients with epilepsy, and at least 98% reported that they were more confident in treating their patients with epilepsy.” Since that time, over 900 providers have received the training, which now attracts participants from all over the country.

Although the current burden of managing epilepsy now seems to be falling heavily on primary care providers, Dr. Lado said he believes they can provide useful insight into their patients’ history and needs: “I think they are in a unique and impactful position, mostly to refer those patients who are still having seizures.”
 

Additional Resources for Patients and Providers

• American Academy of Pediatrics National Coordinating Center for Epilepsy 
• American Epilepsy Society  (CME courses designed to designed to increase knowledge about epilepsy diagnosis, treatment, and management; seizure first-aid; epilepsy stigma; and social determinants of health for people with epilepsy)  
• Centers for Disease Control and Prevention   .

Dr. Joshi, Dr. Kobau, and Dr. Lado report no relevant financial relationships. 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com .

The Centers for Disease Control and Prevention (CDC) estimates that 1.1% of US adults have epilepsy. Although 89% report seeing a physician in the past year about their condition, only 62% of adults saw a neurologist or seizure specialist. 

These findings prompted Rosemary Kobau, MPH, the acting team lead for the CDC’s epilepsy program, to take a closer look at referral patterns by primary care providers in the United States. Using data from a 2018 online survey of US internists, pediatricians, family medicine physicians, and nurse practitioners, she found that 90% of providers would refer a patient with new-onset seizure to a neurologist.

She also noticed what she calls a “big red flag”: “We found that 40% of primary care providers did not indicate that they would refer their patient with epilepsy to a neurologist when their patient fails to respond to treatment, or if they have a change in seizure activity,” Dr. Kobau told this news organization. Individuals with uncontrolled seizures are at risk for multiple adverse health outcomes, along with emotional problems, social stigma, and decreased life expectancy. 

Factors that influenced primary care clinicians to refer to a neurologist included prompt availability of appointments, ability to talk to the neurologist, and whether a patient’s insurance covered specialty visits. Proximity of a specialist also was cited as a barrier, because neurologists can be hard to find outside of urban centers.

Wait lists for neurologist are not like to get shorter any time soon, according to a 2019 report from the American Academy of Neurology (AAN). A 2013 workforce report from the AAN found 35 US states, representing 62% of the US population, had fewer neurologists than needed to meet demand. By 2025, demand is projected to exceed supply in 41 states. 

Much of the increasing demand for adult neurologists is driven by aging of the population, resulting in higher rates of stroke, Parkinson’s disease, and dementia. But pediatric neurologists are also overwhelmed: Pediatric neurology is one of the top three pediatric subspecialties with the longest wait times. The shortage is exacerbated by difficulties in transitioning adolescents with epilepsy — many diagnosed early in life with neurodevelopmental and epileptic encephalopathy and problem lists that include learning disorders, behavioral issues, and other chronic medical problems — to adult epilepsy specialists. 

Although one of the solutions offered by the AAN is more training in epilepsy management for non-neurologists (such as CME programs developed by the American Epilepsy Society), many primary care providers are overwhelmed already. Still, primary care providers are well-positioned to help answer some of the most important questions about the management of patients with seizure disorders. 
 

How to Help

“There’s a lot the pediatrician can do when a child presents with seizures,” said Sucheta Joshi, MD, who serves as the medical director of the Neurological Institute Comprehensive Epilepsy Center at Children’s Hospital Los Angeles.

Step one is helping to allay the fears of family members who witness a seizure. “They can talk about seizure safety, they can talk about first aid when a seizure happens, they can talk about what to do, what not to do,” she advised. Clinicians who see children can find resources for families on the American Academy of Pediatrics (AAP) National Coordinating Center for Epilepsy website, including a 24/7 helpline, information about local chapters of the Epilepsy Foundation, and first aid training for seizures. 

Fred Lado, MD, PhD, a professor of neurology at the Zucker School of Medicine at Hofstra-Norwell in Hempstead, New York, said that primary care clinicians have several decision points when it comes to their patients with epilepsy.

The first is whether to initiate medication after the first episode of seizure. Studies show that the risk for a second seizure decreases in patients started on anticonvulsant therapy after a first event, but many clinicians don›t want to commit patients to long-term therapy without more evidence that the patient has epilepsy. Studies have shown that delaying therapy until a second seizure occurs doesn›t negatively affect quality of life and long-term prognosis. 

The International League Against Epilepsy (ILAE) advised treatment for patients with two or more unprovoked seizures but revised its recommendation in 2014 to begin treatment after a first seizure for individuals at high risk for a second seizure. History of a brain insult related to a stroke, mass lesion in the brain, or trauma are risk factors for a second seizure, whereas seizures provoked by a concussion, alcohol withdrawal, or exposure to toxins carry low risk for additional episodes.

Dr. Lado also raised the importance of taking a good history from a patient presenting for medical care for a new-onset seizure to determine whether the recent episode is really the first such incident.

Up to half of patients presenting to emergency departments for convulsive seizures have a history of a preceding nonmotor seizure that the patient or their family members have failed to identify. As many as 60% of people with epilepsy have focal seizures, but the majority of these are nonmotor seizures. As a result, these patients often go without a diagnosis until they develop bilateral tonic-clonic seizures — by which time they may already been injured during a seizure or had an accident while driving.

In terms of imaging and other workup that should be performed prior to the first appointment with a pediatric neurologist or epilepsy specialist, Dr. Joshi generally recommends EEG. She also prefers MRI over CT, which is better for finding lesions that tend to cause seizures in kids such as developmental abnormalities like a cortical malformation or a perinatal process. Obtaining an MRI prior to seeing the neurologist is elective, depending on whether the history and clinical presentation suggest a focal lesion.

For adults, Dr. Lado also recommends an EEG and MRI to start but rarely advises other laboratory studies. When patients present to the emergency department with a new-onset seizure, the workup commonly includes a chemistry panel to rule out hypoglycemia or electrolyte abnormalities. But in the outpatient setting, where a patient describes symptoms of a seizure that occurred a week ago or longer, Dr. Lado said the yield of such assessments is low. 

“I think the labs are often more useful as you’re thinking about an anticonvulsant,” Dr. Lado said. Particularly for a patient who is facing a long wait to see specialist, obtaining baseline liver enzymes and a complete blood cell count is worthwhile, because many antiseizure medications can cause anemia or liver damage.

Dr. Lado agreed that referral to a specialist is critical for patients with drug-resistant seizures, defined by the ILAE as seizures that persist despite the use of two or more anticonvulsants. 

“One of the great problems in epilepsy care is a sort of sense of complacency,” he said. Some of his own patients have become comfortable with their epilepsy diagnosis and profess to be untroubled by having a few seizures per year. In 2018, Dr. Kobau was a co-author on a study reporting that less than half of US adults taking seizure medications were seizure-free in the past year. 

This scenario is an opportunity for primary care providers to help determine whether their patients are taking their antiseizure medication correctly. A referral to a specialist might not be necessary if the seizures are occurring because the patient’s prescription ran out. Similarly, if a patient doesn’t take the medication because of unpleasant side effects, raising the dose won’t help. 

Dr. Lado’s advice is to explore why the patient’s management plan is not working and make adjustments tailored to their needs. The solution might be as simple as changing the patient to an extended-release formulation to lower the number of daily doses needed, he said.

But for patients who do have recurrent seizures despite good adherence, Dr. Lado strongly urges a referral to an epilepsy specialist. He serves as president of the National Association of Epilepsy Centers (NAEC), a network of more than 260 epilepsy centers in the United States that offer the services of epileptologists, neurosurgeons, neuropsychologists, nurse specialists, EEG technologists, social workers, and others with training and experience in epilepsy care. In addition to adjusting and monitoring medications, patients seen at an NAEC can be evaluated for surgery, neurostimulators, and ketogenic diets.
 

Improving Self-Management

Another role that primary care can play is promoting self-efficacy among patients with epilepsy.

“Providers have historically tended to focus on medication adherence alone, ignoring other health enhancing behaviors, even just sleep hygiene,” Dr. Kobau said. But adequate sleep, regular exercise, a healthy diet, avoidance of tobacco and excessive alcohol, and stress management are all important for seizure management. 

In 2007, CDC launched the Managing Epilepsy Well (MEW) Network, which has the mission of advancing self-management research in collaboration with patients with epilepsy as well as a broad range of healthcare providers. “It’s a patient-driven kind of approach consistent with community-based, participatory practice research,” said Dr. Kobau, who oversees the initiative.

The MEW network, which consists of six prevention research centers funded by CDC, has piloted and evaluated several evidence-based programs that can help patients better control their epilepsy. 

One such intervention is Project Uplift, which delivers mindfulness-based cognitive-behavioral therapy in a virtual group setting. Behavioral therapy is important for people with seizure disorders, whose risk for depression is more than twice that of the general population. The initial trial found the intervention was effective in reducing depressive symptoms in participants, and research since has focused on adapting the program to provide culturally appropriate care to underserved populations. The eight sessions, held weekly, are available in both English and Spanish.

Another program, HOBSCOTCH, allows patients to meet one-on-one virtually with a trained coach to work on skills for improving attention and memory, common problems among people with epilepsy.

MINDSET involves a tablet-based clinical decision tool that patients can use to track their self-management behaviors, such as taking their medications, seizure triggers, symptoms of depression, and keeping their clinic appointments. It also helps them monitor whether they are getting adequate sleep, reducing their stress, and maintaining social networks. The tool generates a printable action plan for patients to prompt discussion and shared decision-making between patient and clinician to prioritize behavioral issues, set goals, and monitor changes over time.

Clinicians can refer patients to any of the MEW interventions, or patients can enroll themselves online.

 

Emerging Approaches

The AAN’s 2019 report promoted use of technological solutions to bridge the gap between primary care providers and scarce — as well as distant — neurologists. Many health systems support e-consults between clinicians, allowing simple discussions about medications and advice about testing recommended prior to a neurology visit. Initially developed for treatment for infection with hepatitis C virus, Project Extension for Community Healthcare Outcomes (ECHO) uses a central hub of specialists to support primary care providers via teleconference to conduct case reviews and didactic sessions. 

Much of Dr. Joshi’s work has focused on ways to coordinate care to children who live far from a pediatric epilepsy center. In a previous position at the University of Michigan, her team was one of four sites funded by the AAP’s National Coordinating Center for Epilepsy to pilot an intervention using telehealth. Implemented in 2017-2019, the initiative used quality improvement methodology to explore a model where patients went to the office of their primary care provider so that both could participate in the call with a neurologist.

The strategy was successful, resulting in reduced out-of-pocket costs, missed school hours, and missed work hours. Patient satisfaction was high (97%), and more parents in the intervention group than the control group agreed that it was easier to obtain appointments with specialists (95% vs 65%, respectively).

And since the pandemic, in-home telehealth visits have become commonplace, adding to the potential convenience and cost savings of telemedicine. 

CDC has invested in Project ECHO as a training program for nonspecialist providers to manage epilepsy. Based at the University of Cincinnati, the initial pilot from 2017 to 2019 trained primary care providers in Ohio and neighboring states using monthly 1-hour sessions via Zoom. According to Dr. Kobau, “Of those 164 primary care providers, 97% reported higher interest in improving their care of patients with epilepsy, and at least 98% reported that they were more confident in treating their patients with epilepsy.” Since that time, over 900 providers have received the training, which now attracts participants from all over the country.

Although the current burden of managing epilepsy now seems to be falling heavily on primary care providers, Dr. Lado said he believes they can provide useful insight into their patients’ history and needs: “I think they are in a unique and impactful position, mostly to refer those patients who are still having seizures.”
 

Additional Resources for Patients and Providers

• American Academy of Pediatrics National Coordinating Center for Epilepsy 
• American Epilepsy Society  (CME courses designed to designed to increase knowledge about epilepsy diagnosis, treatment, and management; seizure first-aid; epilepsy stigma; and social determinants of health for people with epilepsy)  
• Centers for Disease Control and Prevention   .

Dr. Joshi, Dr. Kobau, and Dr. Lado report no relevant financial relationships. 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com .

As head of the clinical laboratory at the San Juan University Hospital in Alicante, Spain, Maria Salinas, PhD, is passionate about the role she and her colleagues can play in clinical decision-making.

Her mission is the identification of “hidden diseases,” as she calls them, chronic conditions for which early identification and intervention can change the course of the illness. Her lab has been a leader over the past decade in using technology to partner with clinicians to promote the appropriate use of testing and clinical decision-making.

An example of a disease ripe for this type of intervention is rheumatoid arthritis (RA), the most common form of autoimmune arthritis, affecting around 1.3 million people in the United States. The prognosis for patients is better the earlier treatment begins.

But the diagnosis is challenging because no single lab test can rule RA in or out. Current standards for diagnosis of RA take into account findings on the physical exam as well as nonspecific markers of inflammation and the presence of autoimmune antibodies.

Amy S. Kehl, MD, an attending rheumatologist at Cedars-Sinai Medical Center in Los Angeles, who also sees patients at Saint John’s Physician Partners in Santa Monica, California, recommends a workup for inflammatory arthritis for patients presenting with the new onset of joint pain and swelling, primarily of small joints, although larger joints can be involved. The workup includes markers of inflammation such as an erythrocyte sedimentation rate and C-reactive protein, which are typically elevated and can be used to monitor the progression of the disease. Similarly, the presence of anemia is consistent with RA and helpful in tracking response to treatment.

But pinning down the diagnosis requires the presence of autoimmune antibodies. Guidelines from the American College of Rheumatology require a positive result for either rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) antibody to definitively determine whether a patient has RA (Table).

166751_table_screengrab_web.jpg

• Reduced RF tests conducted by canceling 16% of tests ordered for patients with negative RF result in the previous 12 months
• Fewer unnecessary referrals, from 22% in the baseline period to 8% during the intervention period
• A smaller percentage of missed patients, from 21% to 16%

To be sure, pre- and post-implementation comparisons are difficult when the implementation period happens to coincide with the emergence of SARS-CoV-2.

Although fewer patients were seen and fewer lab tests were ordered overall in Alicante during the COVID-19 pandemic, the proportion of tests ordered for RF testing dropped, and all the patients identified with double positives for RF and anti-CCP antibodies were referred to rheumatology, suggesting evidence of benefit.

Dr. Kehl said the practice of using clinical decision support systems could be used in the United States. “I thought this was an important study,” she said. Electronic health records systems “have all these capabilities where we can include best practice alerts when you order a test to make sure that it’s clinically warranted and cost-effective.”

Dr. Salinas and Dr. Kehl reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

As head of the clinical laboratory at the San Juan University Hospital in Alicante, Spain, Maria Salinas, PhD, is passionate about the role she and her colleagues can play in clinical decision-making.

Her mission is the identification of “hidden diseases,” as she calls them, chronic conditions for which early identification and intervention can change the course of the illness. Her lab has been a leader over the past decade in using technology to partner with clinicians to promote the appropriate use of testing and clinical decision-making.

An example of a disease ripe for this type of intervention is rheumatoid arthritis (RA), the most common form of autoimmune arthritis, affecting around 1.3 million people in the United States. The prognosis for patients is better the earlier treatment begins.

But the diagnosis is challenging because no single lab test can rule RA in or out. Current standards for diagnosis of RA take into account findings on the physical exam as well as nonspecific markers of inflammation and the presence of autoimmune antibodies.

Amy S. Kehl, MD, an attending rheumatologist at Cedars-Sinai Medical Center in Los Angeles, who also sees patients at Saint John’s Physician Partners in Santa Monica, California, recommends a workup for inflammatory arthritis for patients presenting with the new onset of joint pain and swelling, primarily of small joints, although larger joints can be involved. The workup includes markers of inflammation such as an erythrocyte sedimentation rate and C-reactive protein, which are typically elevated and can be used to monitor the progression of the disease. Similarly, the presence of anemia is consistent with RA and helpful in tracking response to treatment.

But pinning down the diagnosis requires the presence of autoimmune antibodies. Guidelines from the American College of Rheumatology require a positive result for either rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) antibody to definitively determine whether a patient has RA (Table).

166751_table_screengrab_web.jpg

• Reduced RF tests conducted by canceling 16% of tests ordered for patients with negative RF result in the previous 12 months
• Fewer unnecessary referrals, from 22% in the baseline period to 8% during the intervention period
• A smaller percentage of missed patients, from 21% to 16%

To be sure, pre- and post-implementation comparisons are difficult when the implementation period happens to coincide with the emergence of SARS-CoV-2.

Although fewer patients were seen and fewer lab tests were ordered overall in Alicante during the COVID-19 pandemic, the proportion of tests ordered for RF testing dropped, and all the patients identified with double positives for RF and anti-CCP antibodies were referred to rheumatology, suggesting evidence of benefit.

Dr. Kehl said the practice of using clinical decision support systems could be used in the United States. “I thought this was an important study,” she said. Electronic health records systems “have all these capabilities where we can include best practice alerts when you order a test to make sure that it’s clinically warranted and cost-effective.”

Dr. Salinas and Dr. Kehl reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

As head of the clinical laboratory at the San Juan University Hospital in Alicante, Spain, Maria Salinas, PhD, is passionate about the role she and her colleagues can play in clinical decision-making.

Her mission is the identification of “hidden diseases,” as she calls them, chronic conditions for which early identification and intervention can change the course of the illness. Her lab has been a leader over the past decade in using technology to partner with clinicians to promote the appropriate use of testing and clinical decision-making.

An example of a disease ripe for this type of intervention is rheumatoid arthritis (RA), the most common form of autoimmune arthritis, affecting around 1.3 million people in the United States. The prognosis for patients is better the earlier treatment begins.

But the diagnosis is challenging because no single lab test can rule RA in or out. Current standards for diagnosis of RA take into account findings on the physical exam as well as nonspecific markers of inflammation and the presence of autoimmune antibodies.

Amy S. Kehl, MD, an attending rheumatologist at Cedars-Sinai Medical Center in Los Angeles, who also sees patients at Saint John’s Physician Partners in Santa Monica, California, recommends a workup for inflammatory arthritis for patients presenting with the new onset of joint pain and swelling, primarily of small joints, although larger joints can be involved. The workup includes markers of inflammation such as an erythrocyte sedimentation rate and C-reactive protein, which are typically elevated and can be used to monitor the progression of the disease. Similarly, the presence of anemia is consistent with RA and helpful in tracking response to treatment.

But pinning down the diagnosis requires the presence of autoimmune antibodies. Guidelines from the American College of Rheumatology require a positive result for either rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) antibody to definitively determine whether a patient has RA (Table).

166751_table_screengrab_web.jpg

• Reduced RF tests conducted by canceling 16% of tests ordered for patients with negative RF result in the previous 12 months
• Fewer unnecessary referrals, from 22% in the baseline period to 8% during the intervention period
• A smaller percentage of missed patients, from 21% to 16%

To be sure, pre- and post-implementation comparisons are difficult when the implementation period happens to coincide with the emergence of SARS-CoV-2.

Although fewer patients were seen and fewer lab tests were ordered overall in Alicante during the COVID-19 pandemic, the proportion of tests ordered for RF testing dropped, and all the patients identified with double positives for RF and anti-CCP antibodies were referred to rheumatology, suggesting evidence of benefit.

Dr. Kehl said the practice of using clinical decision support systems could be used in the United States. “I thought this was an important study,” she said. Electronic health records systems “have all these capabilities where we can include best practice alerts when you order a test to make sure that it’s clinically warranted and cost-effective.”

Dr. Salinas and Dr. Kehl reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Nearly 37 million Americans, or 15%, have chronic kidney disease (CKD), but 9 in 10 adults with the condition are not aware of their diagnosis. A recent study from Stanford University found that screening asymptomatic adults over the age of 35 years would be a cost-effective strategy for identifying patients with CKD before they develop severe illness. 

What should primary care providers be doing differently? 

The current standard of care is to screen people with underlying conditions that put them at higher risk of developing CKD, most commonly diabetes and hypertension. That’s why the American Diabetes Association recommends annual screening for CKD in patients with type 1 diabetes as well as those with type 2 diabetes. 

And the American Heart Association (AHA) released an advisory last year that defined cardiovascular-kidney-metabolic (CKM) syndrome, a constellation of conditions that often occur together: obesity, diabetes, CKD, and cardiovascular disease. They propose a staged approach to identifying and monitoring CKM throughout the lifespan, which includes regular monitoring of the urine albumin-creatinine ratio in patients who have developed diabetes, hypertension, metabolic syndrome, or any signs of kidney disease.

But despite recognition from the subspecialty professional societies of the importance of screening persons with risk factors — additional conditions are obesity and family history of CKD — real-world implementation lags. 

Sylvia Rosas, MD, is a nephrologist and associate professor of medicine at Harvard University in Cambridge, Massachusetts, who also serves as president of the National Kidney Foundation. In an interview with this news organization, she cited several alarming facts about the state of CKD screening in the United States. 

“Of people with diabetes who have insurance, only 40% get both the glomerular filtration rate (GFR) and the albumin performed, and for those who have hypertension, only 10%,” Dr. Rosas said. She is referring to a urine spot test that measures the amount of albumin in the urine, which is then paired with a serum measurement of creatinine to estimate the glomerular filtration rate. Both tests are needed to detect the asymptomatic stages of CKD, because the presence of albumin in the urine usually precedes drops in the GFR, which indicates more serious disease. 

Dr. Rosas said she is frustrated by the low rate of testing compared with other commonly recommended preventive screenings, given the low cost and simplicity of assessment. Serum creatinine often is obtained as part of a routine chemistry panel, and the albumin test requires a single spot urine test. Yet, in 2018, 61% of US adults aged 50-75 years had received a colonoscopy in the past 10 years. Compared with the high price and inconvenience of undergoing colonoscopy, Dr. Rosas has trouble believing that “we cannot get more than 40% of people [with diabetes] to pee in a cup.” 

But the biggest issue is that if people with risk factors don’t get screened before they develop symptoms of CKD, it is often too late to avoid dialysis or the need for transplantation. 

The early warning symptoms are few, according to Nisha Bansal, MD, a professor in the department of nephrology at the University of Washington in Seattle. “New hypertension is a really important early sign,” Dr. Bansal said. “We know kidney disease almost certainly causes hypertension, so I would definitely think about screening for kidney disease.” Other findings on exam are the appearance of new edema or signs of fluid retention in the hands or around the eyes, along with findings in the urine of albumin, protein, or blood. 

But most patients don’t have any symptoms in the early stages, and they can be nonspecific. “It is fatigue and some nausea,” Dr. Rosas said. “It’s only way at the end that you start vomiting, get itchy, or have hiccups.” Data from the Centers for Disease Control and Prevention have shown that over one third of patients at high risk for kidney failure are unaware of their disease. According to Dr. Rosas, these are patients who often receive the diagnosis of CKD and start dialysis the same day. 
 

Why Not Screen Everyone?

For many conditions, like HIV or different types of cancer, the US Preventive Services Task Force (USPSTF) recommends broad screening of asymptomatic individuals so that early treatment can improve outcomes. 

But when the USPSTF considered the question in 2012 of whether adults should be screened for CKD regardless of symptoms, it found little evidence that early detection could change the course of their illness. At that time, the standard of care for treating early stages of CKD generally focused on treating the comorbid conditions, such as diabetes, hypertension, and cardiovascular disease. 

But the equation has changed with the availability of new drugs to treat CKD, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).

“I consider these blockbuster drugs,” Dr. Bansal said. “For the first time in decades, we’re showing that this class of medications, the SGLT2 inhibitors, substantially reduce risk of loss of kidney function.”

Expressed in the lumen of the proximal renal tubules, SGLT2 reabsorbs filtered glucose from the tubular lumen. Inhibition of SGLT2 promotes urinary glucose excretion and reduces sodium reabsorption, increasing delivery of sodium to the distal tubule. The first SGLT2 inhibitor, canagliflozin, was approved in 2013 for use as an antihyperglycemic agent but subsequently was shown to have serendipitous benefits for the heart and kidneys. 

Clinical trials have documented reductions in the risk for cardiovascular events in patients with type 2 diabetes, as well as decreases in the risk for progression to end-stage renal disease, cardiovascular mortality, and hospitalization for heart failure. Updated international guidelines from 2022 recommend treating all patients with type 2 diabetes and CKD with an estimated GFR ≥ 20 mL/min/1.73 m2 with an SGLT2 inhibitor. 

But several trials of SGLT2 inhibitors also demonstrated benefits in reducing the risk for cardiovascular-related death or hospitalization for heart failure, even in patients without diabetes. Although initial approval from the US Food and Drug Administration was limited to patients with diabetes and heart failure, the agency has recently expanded its indications to include adults with CKD who do not have diabetes. 

Dr. Bansal said she was happy to see this widening of the indications, which makes more patients eligible to receive SGLT2 inhibitors. “I really think this early CKD group is a great group to consider for those medications,” she said. 

Dr. Bansal also pointed out that MRAs are another class of drugs with an interesting history. Earlier steroidal MRAs were found to have anti-inflammatory and antifibrotic properties, and in 1960 spironolactone was approved for use as a diuretic for the management of edema, primary aldosteronism, and hypertension. But even as their use in cardiology rose, MRAs had less utility for CKD, given adverse events such as hyperkalemia and hormonal effects like gynecomastia. 

But the latest generation of nonsteroidal MRAs (nsMRAs) has higher selectivity for the mineralocorticoid receptor than sex-steroid hormone receptors, reducing androgenic side effects and preventing elevated potassium. Finerenone, the only nsMRA approved in the United States, has been shown in clinical trials to reduce the incidence of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and CKD outcomes, including kidney failure, decrease in estimated GFR, or death from renal causes. 
 

EPIC Changes Coming?

In light of treatment advances that offer hope of preventing progression of CKD in patients identified early, both the National Kidney Foundation and the American Kidney Fund lobbied the USPSTF in 2022 to conduct a fresh review of recent data to evaluate the need for updated screening recommendations. 

The task force completed development of a research plan and collection of public comments in early 2023 and is now reviewing evidence before developing a draft recommendation. 

A team of health policy researchers from Stanford is hoping that some of their recently published work will attract the panel’s attention. The first study, published in 2022, evaluated the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor that has been shown to reduce mortality by 48% in CKD patients without diabetes. 

The Stanford team found that adding dapagliflozin to standard care for these patients improved life expectancy by 2 years and reduced the percentage of those who needed dialysis or kidney transplant from 17% to 11%. 

More recently, Marika Cusick, a doctoral candidate in health policy at the Stanford School of Medicine in Stanford, California, served as first author of an evaluation of the cost-effectiveness of screening asymptomatic adults. “We assessed screening for albuminuria in conjunction with conventional CKD therapy in addition to this new SGLT2 inhibitor class of drugs,” she said. They projected how this might change CKD progression in US adults who are aged 35 or older compared with standard therapy alone. 

The findings were favorable. “A one-time screening would result in a reduction of 398,000 cases of kidney replacement therapy [defined as needing either dialysis or renal transplant] among 158 million US adults who are currently aged 35-75 years,” Ms. Cusick told this news organization.

In terms of quality-adjusted life years (QALYs), a one-time screening at age 55 years yielded an incremental cost-effectiveness ratio of $86,300 per QALY. Screening every 10 years between the ages of 35 and 75 years cost less than $100,000 per QALY gained. 

According to Doug Owens, MD, professor and chair of the department of health policy at Stanford School of Medicine, “There’s a societal decision about how much are we willing to pay for additional length and quality of life. And this fits within what is generally considered reasonable for the US.” 

For example, in the United States, screening for breast cancer among women aged 40-64 years costs $51,000 per QALY, whereas screening for lung cancer using USPSTF guidelines ranges from $72,639 to $156,774 per QALY. 

A former member of the USPSTF, Owens predicted that the current review process would take at least another year. Meanwhile, he and Ms. Cusick are hoping that their work influences the USPSTF to recommend screening asymptomatic adults. “Increasing the awareness of these drugs and their effectiveness is a crucial first step,” he said. 

Although adherence to current recommendations for screening of people at risk is poor, Dr. Rosas suggested that the USPSTF guidelines would be more influential in changing practice among primary care physicians than subspecialty guidelines would. 

“When you have a recommendation like that, they’re putting it in the electronic health record,” she said. By adding best practice alerts to their electronic health record systems, health systems can make it easier for primary care doctors to check all the boxes. 

In line with the AHA’s holistic approach towards managing cardiovascular illnesses, CKD, and metabolic disease, Dr. Bansal suggested an additional strategy: “I think we’re moving toward more interdisciplinary care models, where primary care doctors, nephrologist, cardiologists, and endocrinologists — all of us — should be working together in a collaborative care model, to help break down some of these barriers in terms of screening as well as implementation of these therapies.”

Dr. Bansal, Ms. Cusick, and Dr. Owens reported no financial conflicts of interest. Dr. Rosas receives funding from AstraZeneca and Bayer for serving on advisory boards and clinical research funding, as well as funding from the National Institute of Diabetes and Digestive and Kidney Diseases for clinical trials. 
 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com.

Nearly 37 million Americans, or 15%, have chronic kidney disease (CKD), but 9 in 10 adults with the condition are not aware of their diagnosis. A recent study from Stanford University found that screening asymptomatic adults over the age of 35 years would be a cost-effective strategy for identifying patients with CKD before they develop severe illness. 

What should primary care providers be doing differently? 

The current standard of care is to screen people with underlying conditions that put them at higher risk of developing CKD, most commonly diabetes and hypertension. That’s why the American Diabetes Association recommends annual screening for CKD in patients with type 1 diabetes as well as those with type 2 diabetes. 

And the American Heart Association (AHA) released an advisory last year that defined cardiovascular-kidney-metabolic (CKM) syndrome, a constellation of conditions that often occur together: obesity, diabetes, CKD, and cardiovascular disease. They propose a staged approach to identifying and monitoring CKM throughout the lifespan, which includes regular monitoring of the urine albumin-creatinine ratio in patients who have developed diabetes, hypertension, metabolic syndrome, or any signs of kidney disease.

But despite recognition from the subspecialty professional societies of the importance of screening persons with risk factors — additional conditions are obesity and family history of CKD — real-world implementation lags. 

Sylvia Rosas, MD, is a nephrologist and associate professor of medicine at Harvard University in Cambridge, Massachusetts, who also serves as president of the National Kidney Foundation. In an interview with this news organization, she cited several alarming facts about the state of CKD screening in the United States. 

“Of people with diabetes who have insurance, only 40% get both the glomerular filtration rate (GFR) and the albumin performed, and for those who have hypertension, only 10%,” Dr. Rosas said. She is referring to a urine spot test that measures the amount of albumin in the urine, which is then paired with a serum measurement of creatinine to estimate the glomerular filtration rate. Both tests are needed to detect the asymptomatic stages of CKD, because the presence of albumin in the urine usually precedes drops in the GFR, which indicates more serious disease. 

Dr. Rosas said she is frustrated by the low rate of testing compared with other commonly recommended preventive screenings, given the low cost and simplicity of assessment. Serum creatinine often is obtained as part of a routine chemistry panel, and the albumin test requires a single spot urine test. Yet, in 2018, 61% of US adults aged 50-75 years had received a colonoscopy in the past 10 years. Compared with the high price and inconvenience of undergoing colonoscopy, Dr. Rosas has trouble believing that “we cannot get more than 40% of people [with diabetes] to pee in a cup.” 

But the biggest issue is that if people with risk factors don’t get screened before they develop symptoms of CKD, it is often too late to avoid dialysis or the need for transplantation. 

The early warning symptoms are few, according to Nisha Bansal, MD, a professor in the department of nephrology at the University of Washington in Seattle. “New hypertension is a really important early sign,” Dr. Bansal said. “We know kidney disease almost certainly causes hypertension, so I would definitely think about screening for kidney disease.” Other findings on exam are the appearance of new edema or signs of fluid retention in the hands or around the eyes, along with findings in the urine of albumin, protein, or blood. 

But most patients don’t have any symptoms in the early stages, and they can be nonspecific. “It is fatigue and some nausea,” Dr. Rosas said. “It’s only way at the end that you start vomiting, get itchy, or have hiccups.” Data from the Centers for Disease Control and Prevention have shown that over one third of patients at high risk for kidney failure are unaware of their disease. According to Dr. Rosas, these are patients who often receive the diagnosis of CKD and start dialysis the same day. 
 

Why Not Screen Everyone?

For many conditions, like HIV or different types of cancer, the US Preventive Services Task Force (USPSTF) recommends broad screening of asymptomatic individuals so that early treatment can improve outcomes. 

But when the USPSTF considered the question in 2012 of whether adults should be screened for CKD regardless of symptoms, it found little evidence that early detection could change the course of their illness. At that time, the standard of care for treating early stages of CKD generally focused on treating the comorbid conditions, such as diabetes, hypertension, and cardiovascular disease. 

But the equation has changed with the availability of new drugs to treat CKD, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).

“I consider these blockbuster drugs,” Dr. Bansal said. “For the first time in decades, we’re showing that this class of medications, the SGLT2 inhibitors, substantially reduce risk of loss of kidney function.”

Expressed in the lumen of the proximal renal tubules, SGLT2 reabsorbs filtered glucose from the tubular lumen. Inhibition of SGLT2 promotes urinary glucose excretion and reduces sodium reabsorption, increasing delivery of sodium to the distal tubule. The first SGLT2 inhibitor, canagliflozin, was approved in 2013 for use as an antihyperglycemic agent but subsequently was shown to have serendipitous benefits for the heart and kidneys. 

Clinical trials have documented reductions in the risk for cardiovascular events in patients with type 2 diabetes, as well as decreases in the risk for progression to end-stage renal disease, cardiovascular mortality, and hospitalization for heart failure. Updated international guidelines from 2022 recommend treating all patients with type 2 diabetes and CKD with an estimated GFR ≥ 20 mL/min/1.73 m2 with an SGLT2 inhibitor. 

But several trials of SGLT2 inhibitors also demonstrated benefits in reducing the risk for cardiovascular-related death or hospitalization for heart failure, even in patients without diabetes. Although initial approval from the US Food and Drug Administration was limited to patients with diabetes and heart failure, the agency has recently expanded its indications to include adults with CKD who do not have diabetes. 

Dr. Bansal said she was happy to see this widening of the indications, which makes more patients eligible to receive SGLT2 inhibitors. “I really think this early CKD group is a great group to consider for those medications,” she said. 

Dr. Bansal also pointed out that MRAs are another class of drugs with an interesting history. Earlier steroidal MRAs were found to have anti-inflammatory and antifibrotic properties, and in 1960 spironolactone was approved for use as a diuretic for the management of edema, primary aldosteronism, and hypertension. But even as their use in cardiology rose, MRAs had less utility for CKD, given adverse events such as hyperkalemia and hormonal effects like gynecomastia. 

But the latest generation of nonsteroidal MRAs (nsMRAs) has higher selectivity for the mineralocorticoid receptor than sex-steroid hormone receptors, reducing androgenic side effects and preventing elevated potassium. Finerenone, the only nsMRA approved in the United States, has been shown in clinical trials to reduce the incidence of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and CKD outcomes, including kidney failure, decrease in estimated GFR, or death from renal causes. 
 

EPIC Changes Coming?

In light of treatment advances that offer hope of preventing progression of CKD in patients identified early, both the National Kidney Foundation and the American Kidney Fund lobbied the USPSTF in 2022 to conduct a fresh review of recent data to evaluate the need for updated screening recommendations. 

The task force completed development of a research plan and collection of public comments in early 2023 and is now reviewing evidence before developing a draft recommendation. 

A team of health policy researchers from Stanford is hoping that some of their recently published work will attract the panel’s attention. The first study, published in 2022, evaluated the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor that has been shown to reduce mortality by 48% in CKD patients without diabetes. 

The Stanford team found that adding dapagliflozin to standard care for these patients improved life expectancy by 2 years and reduced the percentage of those who needed dialysis or kidney transplant from 17% to 11%. 

More recently, Marika Cusick, a doctoral candidate in health policy at the Stanford School of Medicine in Stanford, California, served as first author of an evaluation of the cost-effectiveness of screening asymptomatic adults. “We assessed screening for albuminuria in conjunction with conventional CKD therapy in addition to this new SGLT2 inhibitor class of drugs,” she said. They projected how this might change CKD progression in US adults who are aged 35 or older compared with standard therapy alone. 

The findings were favorable. “A one-time screening would result in a reduction of 398,000 cases of kidney replacement therapy [defined as needing either dialysis or renal transplant] among 158 million US adults who are currently aged 35-75 years,” Ms. Cusick told this news organization.

In terms of quality-adjusted life years (QALYs), a one-time screening at age 55 years yielded an incremental cost-effectiveness ratio of $86,300 per QALY. Screening every 10 years between the ages of 35 and 75 years cost less than $100,000 per QALY gained. 

According to Doug Owens, MD, professor and chair of the department of health policy at Stanford School of Medicine, “There’s a societal decision about how much are we willing to pay for additional length and quality of life. And this fits within what is generally considered reasonable for the US.” 

For example, in the United States, screening for breast cancer among women aged 40-64 years costs $51,000 per QALY, whereas screening for lung cancer using USPSTF guidelines ranges from $72,639 to $156,774 per QALY. 

A former member of the USPSTF, Owens predicted that the current review process would take at least another year. Meanwhile, he and Ms. Cusick are hoping that their work influences the USPSTF to recommend screening asymptomatic adults. “Increasing the awareness of these drugs and their effectiveness is a crucial first step,” he said. 

Although adherence to current recommendations for screening of people at risk is poor, Dr. Rosas suggested that the USPSTF guidelines would be more influential in changing practice among primary care physicians than subspecialty guidelines would. 

“When you have a recommendation like that, they’re putting it in the electronic health record,” she said. By adding best practice alerts to their electronic health record systems, health systems can make it easier for primary care doctors to check all the boxes. 

In line with the AHA’s holistic approach towards managing cardiovascular illnesses, CKD, and metabolic disease, Dr. Bansal suggested an additional strategy: “I think we’re moving toward more interdisciplinary care models, where primary care doctors, nephrologist, cardiologists, and endocrinologists — all of us — should be working together in a collaborative care model, to help break down some of these barriers in terms of screening as well as implementation of these therapies.”

Dr. Bansal, Ms. Cusick, and Dr. Owens reported no financial conflicts of interest. Dr. Rosas receives funding from AstraZeneca and Bayer for serving on advisory boards and clinical research funding, as well as funding from the National Institute of Diabetes and Digestive and Kidney Diseases for clinical trials. 
 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com.

Nearly 37 million Americans, or 15%, have chronic kidney disease (CKD), but 9 in 10 adults with the condition are not aware of their diagnosis. A recent study from Stanford University found that screening asymptomatic adults over the age of 35 years would be a cost-effective strategy for identifying patients with CKD before they develop severe illness. 

What should primary care providers be doing differently? 

The current standard of care is to screen people with underlying conditions that put them at higher risk of developing CKD, most commonly diabetes and hypertension. That’s why the American Diabetes Association recommends annual screening for CKD in patients with type 1 diabetes as well as those with type 2 diabetes. 

And the American Heart Association (AHA) released an advisory last year that defined cardiovascular-kidney-metabolic (CKM) syndrome, a constellation of conditions that often occur together: obesity, diabetes, CKD, and cardiovascular disease. They propose a staged approach to identifying and monitoring CKM throughout the lifespan, which includes regular monitoring of the urine albumin-creatinine ratio in patients who have developed diabetes, hypertension, metabolic syndrome, or any signs of kidney disease.

But despite recognition from the subspecialty professional societies of the importance of screening persons with risk factors — additional conditions are obesity and family history of CKD — real-world implementation lags. 

Sylvia Rosas, MD, is a nephrologist and associate professor of medicine at Harvard University in Cambridge, Massachusetts, who also serves as president of the National Kidney Foundation. In an interview with this news organization, she cited several alarming facts about the state of CKD screening in the United States. 

“Of people with diabetes who have insurance, only 40% get both the glomerular filtration rate (GFR) and the albumin performed, and for those who have hypertension, only 10%,” Dr. Rosas said. She is referring to a urine spot test that measures the amount of albumin in the urine, which is then paired with a serum measurement of creatinine to estimate the glomerular filtration rate. Both tests are needed to detect the asymptomatic stages of CKD, because the presence of albumin in the urine usually precedes drops in the GFR, which indicates more serious disease. 

Dr. Rosas said she is frustrated by the low rate of testing compared with other commonly recommended preventive screenings, given the low cost and simplicity of assessment. Serum creatinine often is obtained as part of a routine chemistry panel, and the albumin test requires a single spot urine test. Yet, in 2018, 61% of US adults aged 50-75 years had received a colonoscopy in the past 10 years. Compared with the high price and inconvenience of undergoing colonoscopy, Dr. Rosas has trouble believing that “we cannot get more than 40% of people [with diabetes] to pee in a cup.” 

But the biggest issue is that if people with risk factors don’t get screened before they develop symptoms of CKD, it is often too late to avoid dialysis or the need for transplantation. 

The early warning symptoms are few, according to Nisha Bansal, MD, a professor in the department of nephrology at the University of Washington in Seattle. “New hypertension is a really important early sign,” Dr. Bansal said. “We know kidney disease almost certainly causes hypertension, so I would definitely think about screening for kidney disease.” Other findings on exam are the appearance of new edema or signs of fluid retention in the hands or around the eyes, along with findings in the urine of albumin, protein, or blood. 

But most patients don’t have any symptoms in the early stages, and they can be nonspecific. “It is fatigue and some nausea,” Dr. Rosas said. “It’s only way at the end that you start vomiting, get itchy, or have hiccups.” Data from the Centers for Disease Control and Prevention have shown that over one third of patients at high risk for kidney failure are unaware of their disease. According to Dr. Rosas, these are patients who often receive the diagnosis of CKD and start dialysis the same day. 
 

Why Not Screen Everyone?

For many conditions, like HIV or different types of cancer, the US Preventive Services Task Force (USPSTF) recommends broad screening of asymptomatic individuals so that early treatment can improve outcomes. 

But when the USPSTF considered the question in 2012 of whether adults should be screened for CKD regardless of symptoms, it found little evidence that early detection could change the course of their illness. At that time, the standard of care for treating early stages of CKD generally focused on treating the comorbid conditions, such as diabetes, hypertension, and cardiovascular disease. 

But the equation has changed with the availability of new drugs to treat CKD, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).

“I consider these blockbuster drugs,” Dr. Bansal said. “For the first time in decades, we’re showing that this class of medications, the SGLT2 inhibitors, substantially reduce risk of loss of kidney function.”

Expressed in the lumen of the proximal renal tubules, SGLT2 reabsorbs filtered glucose from the tubular lumen. Inhibition of SGLT2 promotes urinary glucose excretion and reduces sodium reabsorption, increasing delivery of sodium to the distal tubule. The first SGLT2 inhibitor, canagliflozin, was approved in 2013 for use as an antihyperglycemic agent but subsequently was shown to have serendipitous benefits for the heart and kidneys. 

Clinical trials have documented reductions in the risk for cardiovascular events in patients with type 2 diabetes, as well as decreases in the risk for progression to end-stage renal disease, cardiovascular mortality, and hospitalization for heart failure. Updated international guidelines from 2022 recommend treating all patients with type 2 diabetes and CKD with an estimated GFR ≥ 20 mL/min/1.73 m2 with an SGLT2 inhibitor. 

But several trials of SGLT2 inhibitors also demonstrated benefits in reducing the risk for cardiovascular-related death or hospitalization for heart failure, even in patients without diabetes. Although initial approval from the US Food and Drug Administration was limited to patients with diabetes and heart failure, the agency has recently expanded its indications to include adults with CKD who do not have diabetes. 

Dr. Bansal said she was happy to see this widening of the indications, which makes more patients eligible to receive SGLT2 inhibitors. “I really think this early CKD group is a great group to consider for those medications,” she said. 

Dr. Bansal also pointed out that MRAs are another class of drugs with an interesting history. Earlier steroidal MRAs were found to have anti-inflammatory and antifibrotic properties, and in 1960 spironolactone was approved for use as a diuretic for the management of edema, primary aldosteronism, and hypertension. But even as their use in cardiology rose, MRAs had less utility for CKD, given adverse events such as hyperkalemia and hormonal effects like gynecomastia. 

But the latest generation of nonsteroidal MRAs (nsMRAs) has higher selectivity for the mineralocorticoid receptor than sex-steroid hormone receptors, reducing androgenic side effects and preventing elevated potassium. Finerenone, the only nsMRA approved in the United States, has been shown in clinical trials to reduce the incidence of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and CKD outcomes, including kidney failure, decrease in estimated GFR, or death from renal causes. 
 

EPIC Changes Coming?

In light of treatment advances that offer hope of preventing progression of CKD in patients identified early, both the National Kidney Foundation and the American Kidney Fund lobbied the USPSTF in 2022 to conduct a fresh review of recent data to evaluate the need for updated screening recommendations. 

The task force completed development of a research plan and collection of public comments in early 2023 and is now reviewing evidence before developing a draft recommendation. 

A team of health policy researchers from Stanford is hoping that some of their recently published work will attract the panel’s attention. The first study, published in 2022, evaluated the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor that has been shown to reduce mortality by 48% in CKD patients without diabetes. 

The Stanford team found that adding dapagliflozin to standard care for these patients improved life expectancy by 2 years and reduced the percentage of those who needed dialysis or kidney transplant from 17% to 11%. 

More recently, Marika Cusick, a doctoral candidate in health policy at the Stanford School of Medicine in Stanford, California, served as first author of an evaluation of the cost-effectiveness of screening asymptomatic adults. “We assessed screening for albuminuria in conjunction with conventional CKD therapy in addition to this new SGLT2 inhibitor class of drugs,” she said. They projected how this might change CKD progression in US adults who are aged 35 or older compared with standard therapy alone. 

The findings were favorable. “A one-time screening would result in a reduction of 398,000 cases of kidney replacement therapy [defined as needing either dialysis or renal transplant] among 158 million US adults who are currently aged 35-75 years,” Ms. Cusick told this news organization.

In terms of quality-adjusted life years (QALYs), a one-time screening at age 55 years yielded an incremental cost-effectiveness ratio of $86,300 per QALY. Screening every 10 years between the ages of 35 and 75 years cost less than $100,000 per QALY gained. 

According to Doug Owens, MD, professor and chair of the department of health policy at Stanford School of Medicine, “There’s a societal decision about how much are we willing to pay for additional length and quality of life. And this fits within what is generally considered reasonable for the US.” 

For example, in the United States, screening for breast cancer among women aged 40-64 years costs $51,000 per QALY, whereas screening for lung cancer using USPSTF guidelines ranges from $72,639 to $156,774 per QALY. 

A former member of the USPSTF, Owens predicted that the current review process would take at least another year. Meanwhile, he and Ms. Cusick are hoping that their work influences the USPSTF to recommend screening asymptomatic adults. “Increasing the awareness of these drugs and their effectiveness is a crucial first step,” he said. 

Although adherence to current recommendations for screening of people at risk is poor, Dr. Rosas suggested that the USPSTF guidelines would be more influential in changing practice among primary care physicians than subspecialty guidelines would. 

“When you have a recommendation like that, they’re putting it in the electronic health record,” she said. By adding best practice alerts to their electronic health record systems, health systems can make it easier for primary care doctors to check all the boxes. 

In line with the AHA’s holistic approach towards managing cardiovascular illnesses, CKD, and metabolic disease, Dr. Bansal suggested an additional strategy: “I think we’re moving toward more interdisciplinary care models, where primary care doctors, nephrologist, cardiologists, and endocrinologists — all of us — should be working together in a collaborative care model, to help break down some of these barriers in terms of screening as well as implementation of these therapies.”

Dr. Bansal, Ms. Cusick, and Dr. Owens reported no financial conflicts of interest. Dr. Rosas receives funding from AstraZeneca and Bayer for serving on advisory boards and clinical research funding, as well as funding from the National Institute of Diabetes and Digestive and Kidney Diseases for clinical trials. 
 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com.

In 2022, two colleagues from Johns Hopkins University, Baltimore, Bhuchitra Singh, MD, MPH, MS, MBA, and James Segars Jr., MD, reviewed the available literature to evaluate the effectiveness of newer minimally invasive therapies in reducing bleeding and improving the quality of life and control of symptoms linked to uterine fibroids. 

Their goal, according to Dr. Segars, a professor of obstetrics and gynecology and director of the division of women’s health research at Johns Hopkins, was to help guide clinicians and patients in making decisions about the use of the newer therapies, including radiofrequency ablation and ultrasound-guided removal of lesions. 

But he and Dr. Singh, the director of clinical research at the Howard W. and Georgeanna Seegar Jones Laboratory of Reproductive Sciences and Women’s Health Research, were surprised by their findings. “The outcomes were relatively the same,” Dr. Segars said. “All of the modalities lead to significant reduction in bleeding and other fibroid-related symptoms.” 

The data on long-term complications and risk for recurrence are sparse for some of the newer approaches, and not enough high-quality long-term studies have been conducted for the Food and Drug Administration to approve them as fertility-sparing treatments.

But perhaps, the biggest challenge now is to ensure that women can take advantage of these newer therapies, with large gaps in both the diagnosis of fibroids and geographic access to minimally invasive treatments.
 

A widespread condition widely underdiagnosed 

Uterine fibroids occur in most women (the incidence rises with age) and can be found in up to 70% of women by the time they reach menopause. Risk factors include family history, increasing interval since last birth, hypertension, and obesity. Increasing parity and use of oral contraceptives are protective.

But as many as 50% of cases go undiagnosed, and one reason for this is the failure of clinicians to dig deeply enough into women’s menstrual histories to diagnose fibroids. 

“The most common cause of anemia is heavy menstrual bleeding,” said Shannon Laughlin-Tommaso, MD, MPH, a professor of obstetrics and gynecology at Mayo Clinic in Rochester, Minn. She frequently sees patients who have already undergone colonoscopy to work-up the source of their anemia before anyone suspects that fibroids are the culprit. 

“When women tell us about their periods, what they’ve been told is normal [bleeding] – or what they’ve always had and considered normal – is actually kind of on the heavier spectrum,” she said. 

Ideally, treatment for uterine fibroids would fix abnormally prolonged or heavy menstrual bleeding, relieve pain, and ameliorate symptoms associated with an enlarged uterus, such as pelvic pressure, urinary frequency, and constipation. And the fibroids would never recur.

By those measures, hysterectomy fits the bill: Success rates in relieving symptoms are high, and the risk for recurrence is zero. But the procedure carries significant drawbacks: short-term complications of surgery, including infection, bleeding, and injury to the bowels and bladder along with potential long-term risks for cardiovascular disease, cancer, ovarian failure and premature menopause, depression, and decline in cognitive function. Those factors loom even larger for women who still hope to have children. 

For that reason, the American College of Obstetricians and Gynecologists recommends myomectomy, or surgical removal of individual fibroids, for women who desire uterine preservation or future pregnancy. And the literature here is solid, according to Dr. Singh, who found that 95% of myomectomy patients achieved control of their bleeding symptoms, whether it was via laparoscopy, hysteroscopy, or laparotomy. Up to 40% of women may develop new fibroids, or leiomyomas, within 3 years, although only 12.2% required a second surgery up to after 5 years. 

But myomectomy is invasive, requiring general anesthesia, incisions in the uterus, and stitches to close the organ. 

Newer techniques have emerged that can effectively treat symptoms of fibroids without requiring surgery. Uterine artery embolization (UAE), which involves passing a catheter into the femoral artery, or laparoscopic uterine artery occlusion can be used to cut off the blood supply of the fibroid. Other techniques, including focused ultrasound surgery and radiofrequency ablation (RFA), use various forms of energy to heat and ablate fibroids. The latter two can be performed in outpatient settings and often without general anesthesia.

Approved for use in 1994, UAE has the most data available, with reduction in the volume of fibroids and uterine tissue lasting up to 5 years, and rates of reintervention of 19%-38% between 2 and 5 years after the procedure. Dr. Singh’s review found that 79%-98.5% of recipients of the procedure reported declines in bleeding that persisted for several years, which is comparable to myomectomy. Quality of life and pain scores also showed good improvement, with follow-up in the different studies ranging from 12 months to over 5 years, the analysis showed.

UAE does have its drawbacks. In rare cases, embolization can deprive the entire uterus and ovaries of blood, which can cause ovarian dysfunction and potentially result in premature menopause, although this outcome is most common in women who are older than 45 years. The procedure can often also be painful enough that overnight hospitalization is required.

Focused ultrasound surgeries, which include magnetic resonance–guided focused ultrasound surgery (MRgFUS) and high-intensity focused ultrasound (HIFU), were approved by the FDA in 2004. Focused ultrasound waves pass through the abdominal wall and produce significant heating, causing a burn that destroys the targeted tissue without damaging surrounding tissue. As with UAE, improvements in fibroid-associated bleeding and measures of quality of life were similar to those after myomectomy up to 3 years later.

But Dr. Singh noted that both focused ultrasound and RFA can damage the skin or internal organs. “[As] always with the thermal interventions, there is the probability of skin as well as internal organs that might get the thermal energy if it’s not focused correctly on to the fibroid itself,” he said. In addition, MRgFUS is not an option for women who are not good candidates to undergo an MRI, such as those with claustrophobia or pacemakers.

Also, with focus ultrasound and RFA, “we do worry about that fibroid getting blood flow back,” which can lead to recurrence of heavy menstrual bleeding, Dr. Laughlin-Tommaso noted. 

Although data on RFA are limited to 12 months of follow-up, most women reported meaningful reductions in bleeding symptoms. Longer follow-up has been reported for bleeding symptoms after MRgFUS, with similar results up to 3 years later. 

For Leslie Hansen-Lindner, MD, chief of obstetrics and gynecology at Atrium Health in Charlotte, N.C., choosing the right procedure starts with a patient-centered conversation weighing the pros and cons of the options and the woman’s goals. 

“Is their goal to reduce the size and impact of their fibroid, bleed less, and have a better quality of life on their period?” Dr. Hansen-Lindner said. “Or is their goal to have the entire fibroid removed?” 

If the former, an RFA is appealing to many women. If the latter, laparoscopic or mini-laparotomy myomectomy might be a better choice. Although fewer than 10% of patients require surgical reintervention at 3 years of follow-up for RFA, myomectomy has more consistent long-term evidence showing that fewer women require re-intervention and preserve their fertility, she added. 

Age also plays a role in the decision: The closer a woman is to menopause, the less likely she is to experience a recurrence, so a less-invasive procedure is preferable. But for younger women hoping to become pregnant, the lower risk for recurrence and good prognosis for future fertility might sway the choice toward myomectomy.

The first laparoscopic RFA procedures were approved for uterine fibroids in 2012. Dr. Hansen-Lindner is a proponent of transcervical fibroid ablation (TFA), a newer RFA procedure that the FDA approved in 2018. Performed through the cervix, TFA requires no incisions and can generally be done without general anesthesia. Eligible candidates would be any woman with symptomatic fibroids, such as heavy menstrual bleeding, pain, or bulk symptoms. The contraindications are few.

“It’s going to come down to size and location of fibroids, and whether or not they would be accessible by the TFA,” Dr. Hansen-Lindner said. “I have to make sure that there isn’t a fibroid blocking their cervix and that the fibroids are accessible with this device.” 

TFA also is not suitable for removing most submucosal lesions, which typically must be removed by hysteroscopic myomectomy. Dr. Hansen-Lindner said that she often uses TFA in conjunction with hysteroscopic myomectomy for this scenario. Although data on pregnancy after RFA (including TFA), MRgFUS, and HIFU are lacking, Gynesonics, the manufacturer of the Sonata System (the device that delivers radiofrequency energy to shrink the fibroid) has documented 79 pregnancies among the 2,200 women who have undergone TFA in the United States since 2018.
 

Disparities hampering care

Uterine fibroids are a particular problem for Black women, whose symptoms are more likely to be ignored by clinicians, according to Jodie Katon, PhD, a core investigator at the Veterans Affairs Greater Los Angeles Center for the Study of Healthcare Innovation, Implementation and Policy. Dr. Katon cited studies in which Black women interviewed about their experiences reported a consistent theme: Clinicians dismissed their symptoms, told them these were nothing to worry about, and advised them to lose weight. Those interactions not only delayed diagnosis among Black women but also led many of them to mistrust clinicians and avoid the health care system altogether.

The failure of clinicians to take their complaints seriously is just one of the disparities affecting Black women. In reviewing the literature, Dr. Laughlin-Tommaso, who also serves as the associate dean for Education Diversity, Equity, and Inclusion at the Mayo Clinic, found that African American women experience two to three times the risk for fibroids, compared with White women, as well as earlier onset and more severe disease, as measured by number and size of the lesions. 

According to Dr. Katon, the etiology of fibroids is still poorly understood. “What we do know is that Black women are disproportionately exposed to a variety of factors that we have shown through observational studies are associated with increased risk of development of uterine fibroids.” 

The list includes factors like stress; interpersonal racism; early age at menarche; various indicators of poor diets, such as vitamin D deficiency; the use of certain beauty products, specifically hair straighteners; as well as exposure to air pollution and other environmental toxins.

Laughlin-Tommaso also pointed to historical disparities in management, citing a doubled risk for hysterectomy for Black women in a study published in 2007 despite survey data suggesting that Black women report being more interested in uterine-preserving therapies rather than a hysterectomy.
 

Breaking down barriers of access to new treatments

Dr. Laughlin-Tommaso looked at more recent trends in the management of fibroids using data from the multicenter COMPARE-UF study, which enrolled women between 2015 and 2020 undergoing fibroid treatment into a longitudinal registry to track their outcomes. She found that Black women underwent hysterectomies at a lower rate than did White women and were instead more likely to undergo myomectomy or UAE. 

Some of the change may reflect lack of approved minimally invasive procedures before 2000. “But now that we have expanded options, I think most women are opting not to have a hysterectomy,” Dr. Laughlin-Tommaso said.

Dr. Katon has research funding from the VA to look more closely at racial disparities in the treatment of fibroids. In a study published in April 2023, she reported some surprising trends. 

During the period from 2010 to 2018, she found that Black veterans diagnosed with fibroids were less likely than White veterans were to receive treatment, regardless of their age or the severity of their symptoms. This finding held even among women with anemia, which should have been a clear indication for treatment.

But, as in the COMPARE-UF study, the subset of Black veterans who received an interventional treatment were less likely than their White peers were to undergo hysterectomy in favor of a fertility-sparing treatment as their initial procedure. Dr. Katon called it a “welcome but unexpected finding.” 

But another significant barrier remains: The two newest types of procedures, RFA and guided focused ultrasound, are not commonly performed outside of tertiary care facilities. However, studies have found that all these procedures are cost effective (studies for myomectomy, UAE, MRgFUS, and TFA). The implementation of a category 1 billing code for laparoscopic RFA in 2017 has led more insurance companies to cover the service, and a category 1 code will be available for TFA effective January 2024. 

Although RFA does require investment in specialized equipment, which limits facilities from offering the procedure, any gynecologist who routinely performs hysteroscopy can easily learn to do TFA. And the VA, which is committed to eliminating disparities in women’s health, established a 2-year advanced fellowship in minimally invasive gynecologic surgery in 2022 to help expand their capacity to offer these procedures. 

The VA has been rapidly expanding their gynecology services, and Katon said that she is confident that ultrasound-guided procedures and RFA will become more available within the system. “I would say we’re keeping pace. And in some ways, you know, as a national system we may be positioned to actually outpace the rest of the U.S.”

Dr. Segars reported prior research funding for clinical trials from BioSpecifics Technologies, Bayer, Allergan, AbbVie, and ObsEva and currently receives funding from Myovant Sciences. Dr. Hansen-Lindner reported personal fees from Gynesonics. Dr. Singh, Dr. Laughlin-Tommaso, and Dr. Katon reported no financial conflicts of interest. 

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

In 2022, two colleagues from Johns Hopkins University, Baltimore, Bhuchitra Singh, MD, MPH, MS, MBA, and James Segars Jr., MD, reviewed the available literature to evaluate the effectiveness of newer minimally invasive therapies in reducing bleeding and improving the quality of life and control of symptoms linked to uterine fibroids. 

Their goal, according to Dr. Segars, a professor of obstetrics and gynecology and director of the division of women’s health research at Johns Hopkins, was to help guide clinicians and patients in making decisions about the use of the newer therapies, including radiofrequency ablation and ultrasound-guided removal of lesions. 

But he and Dr. Singh, the director of clinical research at the Howard W. and Georgeanna Seegar Jones Laboratory of Reproductive Sciences and Women’s Health Research, were surprised by their findings. “The outcomes were relatively the same,” Dr. Segars said. “All of the modalities lead to significant reduction in bleeding and other fibroid-related symptoms.” 

The data on long-term complications and risk for recurrence are sparse for some of the newer approaches, and not enough high-quality long-term studies have been conducted for the Food and Drug Administration to approve them as fertility-sparing treatments.

But perhaps, the biggest challenge now is to ensure that women can take advantage of these newer therapies, with large gaps in both the diagnosis of fibroids and geographic access to minimally invasive treatments.
 

A widespread condition widely underdiagnosed 

Uterine fibroids occur in most women (the incidence rises with age) and can be found in up to 70% of women by the time they reach menopause. Risk factors include family history, increasing interval since last birth, hypertension, and obesity. Increasing parity and use of oral contraceptives are protective.

But as many as 50% of cases go undiagnosed, and one reason for this is the failure of clinicians to dig deeply enough into women’s menstrual histories to diagnose fibroids. 

“The most common cause of anemia is heavy menstrual bleeding,” said Shannon Laughlin-Tommaso, MD, MPH, a professor of obstetrics and gynecology at Mayo Clinic in Rochester, Minn. She frequently sees patients who have already undergone colonoscopy to work-up the source of their anemia before anyone suspects that fibroids are the culprit. 

“When women tell us about their periods, what they’ve been told is normal [bleeding] – or what they’ve always had and considered normal – is actually kind of on the heavier spectrum,” she said. 

Ideally, treatment for uterine fibroids would fix abnormally prolonged or heavy menstrual bleeding, relieve pain, and ameliorate symptoms associated with an enlarged uterus, such as pelvic pressure, urinary frequency, and constipation. And the fibroids would never recur.

By those measures, hysterectomy fits the bill: Success rates in relieving symptoms are high, and the risk for recurrence is zero. But the procedure carries significant drawbacks: short-term complications of surgery, including infection, bleeding, and injury to the bowels and bladder along with potential long-term risks for cardiovascular disease, cancer, ovarian failure and premature menopause, depression, and decline in cognitive function. Those factors loom even larger for women who still hope to have children. 

For that reason, the American College of Obstetricians and Gynecologists recommends myomectomy, or surgical removal of individual fibroids, for women who desire uterine preservation or future pregnancy. And the literature here is solid, according to Dr. Singh, who found that 95% of myomectomy patients achieved control of their bleeding symptoms, whether it was via laparoscopy, hysteroscopy, or laparotomy. Up to 40% of women may develop new fibroids, or leiomyomas, within 3 years, although only 12.2% required a second surgery up to after 5 years. 

But myomectomy is invasive, requiring general anesthesia, incisions in the uterus, and stitches to close the organ. 

Newer techniques have emerged that can effectively treat symptoms of fibroids without requiring surgery. Uterine artery embolization (UAE), which involves passing a catheter into the femoral artery, or laparoscopic uterine artery occlusion can be used to cut off the blood supply of the fibroid. Other techniques, including focused ultrasound surgery and radiofrequency ablation (RFA), use various forms of energy to heat and ablate fibroids. The latter two can be performed in outpatient settings and often without general anesthesia.

Approved for use in 1994, UAE has the most data available, with reduction in the volume of fibroids and uterine tissue lasting up to 5 years, and rates of reintervention of 19%-38% between 2 and 5 years after the procedure. Dr. Singh’s review found that 79%-98.5% of recipients of the procedure reported declines in bleeding that persisted for several years, which is comparable to myomectomy. Quality of life and pain scores also showed good improvement, with follow-up in the different studies ranging from 12 months to over 5 years, the analysis showed.

UAE does have its drawbacks. In rare cases, embolization can deprive the entire uterus and ovaries of blood, which can cause ovarian dysfunction and potentially result in premature menopause, although this outcome is most common in women who are older than 45 years. The procedure can often also be painful enough that overnight hospitalization is required.

Focused ultrasound surgeries, which include magnetic resonance–guided focused ultrasound surgery (MRgFUS) and high-intensity focused ultrasound (HIFU), were approved by the FDA in 2004. Focused ultrasound waves pass through the abdominal wall and produce significant heating, causing a burn that destroys the targeted tissue without damaging surrounding tissue. As with UAE, improvements in fibroid-associated bleeding and measures of quality of life were similar to those after myomectomy up to 3 years later.

But Dr. Singh noted that both focused ultrasound and RFA can damage the skin or internal organs. “[As] always with the thermal interventions, there is the probability of skin as well as internal organs that might get the thermal energy if it’s not focused correctly on to the fibroid itself,” he said. In addition, MRgFUS is not an option for women who are not good candidates to undergo an MRI, such as those with claustrophobia or pacemakers.

Also, with focus ultrasound and RFA, “we do worry about that fibroid getting blood flow back,” which can lead to recurrence of heavy menstrual bleeding, Dr. Laughlin-Tommaso noted. 

Although data on RFA are limited to 12 months of follow-up, most women reported meaningful reductions in bleeding symptoms. Longer follow-up has been reported for bleeding symptoms after MRgFUS, with similar results up to 3 years later. 

For Leslie Hansen-Lindner, MD, chief of obstetrics and gynecology at Atrium Health in Charlotte, N.C., choosing the right procedure starts with a patient-centered conversation weighing the pros and cons of the options and the woman’s goals. 

“Is their goal to reduce the size and impact of their fibroid, bleed less, and have a better quality of life on their period?” Dr. Hansen-Lindner said. “Or is their goal to have the entire fibroid removed?” 

If the former, an RFA is appealing to many women. If the latter, laparoscopic or mini-laparotomy myomectomy might be a better choice. Although fewer than 10% of patients require surgical reintervention at 3 years of follow-up for RFA, myomectomy has more consistent long-term evidence showing that fewer women require re-intervention and preserve their fertility, she added. 

Age also plays a role in the decision: The closer a woman is to menopause, the less likely she is to experience a recurrence, so a less-invasive procedure is preferable. But for younger women hoping to become pregnant, the lower risk for recurrence and good prognosis for future fertility might sway the choice toward myomectomy.

The first laparoscopic RFA procedures were approved for uterine fibroids in 2012. Dr. Hansen-Lindner is a proponent of transcervical fibroid ablation (TFA), a newer RFA procedure that the FDA approved in 2018. Performed through the cervix, TFA requires no incisions and can generally be done without general anesthesia. Eligible candidates would be any woman with symptomatic fibroids, such as heavy menstrual bleeding, pain, or bulk symptoms. The contraindications are few.

“It’s going to come down to size and location of fibroids, and whether or not they would be accessible by the TFA,” Dr. Hansen-Lindner said. “I have to make sure that there isn’t a fibroid blocking their cervix and that the fibroids are accessible with this device.” 

TFA also is not suitable for removing most submucosal lesions, which typically must be removed by hysteroscopic myomectomy. Dr. Hansen-Lindner said that she often uses TFA in conjunction with hysteroscopic myomectomy for this scenario. Although data on pregnancy after RFA (including TFA), MRgFUS, and HIFU are lacking, Gynesonics, the manufacturer of the Sonata System (the device that delivers radiofrequency energy to shrink the fibroid) has documented 79 pregnancies among the 2,200 women who have undergone TFA in the United States since 2018.
 

Disparities hampering care

Uterine fibroids are a particular problem for Black women, whose symptoms are more likely to be ignored by clinicians, according to Jodie Katon, PhD, a core investigator at the Veterans Affairs Greater Los Angeles Center for the Study of Healthcare Innovation, Implementation and Policy. Dr. Katon cited studies in which Black women interviewed about their experiences reported a consistent theme: Clinicians dismissed their symptoms, told them these were nothing to worry about, and advised them to lose weight. Those interactions not only delayed diagnosis among Black women but also led many of them to mistrust clinicians and avoid the health care system altogether.

The failure of clinicians to take their complaints seriously is just one of the disparities affecting Black women. In reviewing the literature, Dr. Laughlin-Tommaso, who also serves as the associate dean for Education Diversity, Equity, and Inclusion at the Mayo Clinic, found that African American women experience two to three times the risk for fibroids, compared with White women, as well as earlier onset and more severe disease, as measured by number and size of the lesions. 

According to Dr. Katon, the etiology of fibroids is still poorly understood. “What we do know is that Black women are disproportionately exposed to a variety of factors that we have shown through observational studies are associated with increased risk of development of uterine fibroids.” 

The list includes factors like stress; interpersonal racism; early age at menarche; various indicators of poor diets, such as vitamin D deficiency; the use of certain beauty products, specifically hair straighteners; as well as exposure to air pollution and other environmental toxins.

Laughlin-Tommaso also pointed to historical disparities in management, citing a doubled risk for hysterectomy for Black women in a study published in 2007 despite survey data suggesting that Black women report being more interested in uterine-preserving therapies rather than a hysterectomy.
 

Breaking down barriers of access to new treatments

Dr. Laughlin-Tommaso looked at more recent trends in the management of fibroids using data from the multicenter COMPARE-UF study, which enrolled women between 2015 and 2020 undergoing fibroid treatment into a longitudinal registry to track their outcomes. She found that Black women underwent hysterectomies at a lower rate than did White women and were instead more likely to undergo myomectomy or UAE. 

Some of the change may reflect lack of approved minimally invasive procedures before 2000. “But now that we have expanded options, I think most women are opting not to have a hysterectomy,” Dr. Laughlin-Tommaso said.

Dr. Katon has research funding from the VA to look more closely at racial disparities in the treatment of fibroids. In a study published in April 2023, she reported some surprising trends. 

During the period from 2010 to 2018, she found that Black veterans diagnosed with fibroids were less likely than White veterans were to receive treatment, regardless of their age or the severity of their symptoms. This finding held even among women with anemia, which should have been a clear indication for treatment.

But, as in the COMPARE-UF study, the subset of Black veterans who received an interventional treatment were less likely than their White peers were to undergo hysterectomy in favor of a fertility-sparing treatment as their initial procedure. Dr. Katon called it a “welcome but unexpected finding.” 

But another significant barrier remains: The two newest types of procedures, RFA and guided focused ultrasound, are not commonly performed outside of tertiary care facilities. However, studies have found that all these procedures are cost effective (studies for myomectomy, UAE, MRgFUS, and TFA). The implementation of a category 1 billing code for laparoscopic RFA in 2017 has led more insurance companies to cover the service, and a category 1 code will be available for TFA effective January 2024. 

Although RFA does require investment in specialized equipment, which limits facilities from offering the procedure, any gynecologist who routinely performs hysteroscopy can easily learn to do TFA. And the VA, which is committed to eliminating disparities in women’s health, established a 2-year advanced fellowship in minimally invasive gynecologic surgery in 2022 to help expand their capacity to offer these procedures. 

The VA has been rapidly expanding their gynecology services, and Katon said that she is confident that ultrasound-guided procedures and RFA will become more available within the system. “I would say we’re keeping pace. And in some ways, you know, as a national system we may be positioned to actually outpace the rest of the U.S.”

Dr. Segars reported prior research funding for clinical trials from BioSpecifics Technologies, Bayer, Allergan, AbbVie, and ObsEva and currently receives funding from Myovant Sciences. Dr. Hansen-Lindner reported personal fees from Gynesonics. Dr. Singh, Dr. Laughlin-Tommaso, and Dr. Katon reported no financial conflicts of interest. 

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

In 2022, two colleagues from Johns Hopkins University, Baltimore, Bhuchitra Singh, MD, MPH, MS, MBA, and James Segars Jr., MD, reviewed the available literature to evaluate the effectiveness of newer minimally invasive therapies in reducing bleeding and improving the quality of life and control of symptoms linked to uterine fibroids. 

Their goal, according to Dr. Segars, a professor of obstetrics and gynecology and director of the division of women’s health research at Johns Hopkins, was to help guide clinicians and patients in making decisions about the use of the newer therapies, including radiofrequency ablation and ultrasound-guided removal of lesions. 

But he and Dr. Singh, the director of clinical research at the Howard W. and Georgeanna Seegar Jones Laboratory of Reproductive Sciences and Women’s Health Research, were surprised by their findings. “The outcomes were relatively the same,” Dr. Segars said. “All of the modalities lead to significant reduction in bleeding and other fibroid-related symptoms.” 

The data on long-term complications and risk for recurrence are sparse for some of the newer approaches, and not enough high-quality long-term studies have been conducted for the Food and Drug Administration to approve them as fertility-sparing treatments.

But perhaps, the biggest challenge now is to ensure that women can take advantage of these newer therapies, with large gaps in both the diagnosis of fibroids and geographic access to minimally invasive treatments.
 

A widespread condition widely underdiagnosed 

Uterine fibroids occur in most women (the incidence rises with age) and can be found in up to 70% of women by the time they reach menopause. Risk factors include family history, increasing interval since last birth, hypertension, and obesity. Increasing parity and use of oral contraceptives are protective.

But as many as 50% of cases go undiagnosed, and one reason for this is the failure of clinicians to dig deeply enough into women’s menstrual histories to diagnose fibroids. 

“The most common cause of anemia is heavy menstrual bleeding,” said Shannon Laughlin-Tommaso, MD, MPH, a professor of obstetrics and gynecology at Mayo Clinic in Rochester, Minn. She frequently sees patients who have already undergone colonoscopy to work-up the source of their anemia before anyone suspects that fibroids are the culprit. 

“When women tell us about their periods, what they’ve been told is normal [bleeding] – or what they’ve always had and considered normal – is actually kind of on the heavier spectrum,” she said. 

Ideally, treatment for uterine fibroids would fix abnormally prolonged or heavy menstrual bleeding, relieve pain, and ameliorate symptoms associated with an enlarged uterus, such as pelvic pressure, urinary frequency, and constipation. And the fibroids would never recur.

By those measures, hysterectomy fits the bill: Success rates in relieving symptoms are high, and the risk for recurrence is zero. But the procedure carries significant drawbacks: short-term complications of surgery, including infection, bleeding, and injury to the bowels and bladder along with potential long-term risks for cardiovascular disease, cancer, ovarian failure and premature menopause, depression, and decline in cognitive function. Those factors loom even larger for women who still hope to have children. 

For that reason, the American College of Obstetricians and Gynecologists recommends myomectomy, or surgical removal of individual fibroids, for women who desire uterine preservation or future pregnancy. And the literature here is solid, according to Dr. Singh, who found that 95% of myomectomy patients achieved control of their bleeding symptoms, whether it was via laparoscopy, hysteroscopy, or laparotomy. Up to 40% of women may develop new fibroids, or leiomyomas, within 3 years, although only 12.2% required a second surgery up to after 5 years. 

But myomectomy is invasive, requiring general anesthesia, incisions in the uterus, and stitches to close the organ. 

Newer techniques have emerged that can effectively treat symptoms of fibroids without requiring surgery. Uterine artery embolization (UAE), which involves passing a catheter into the femoral artery, or laparoscopic uterine artery occlusion can be used to cut off the blood supply of the fibroid. Other techniques, including focused ultrasound surgery and radiofrequency ablation (RFA), use various forms of energy to heat and ablate fibroids. The latter two can be performed in outpatient settings and often without general anesthesia.

Approved for use in 1994, UAE has the most data available, with reduction in the volume of fibroids and uterine tissue lasting up to 5 years, and rates of reintervention of 19%-38% between 2 and 5 years after the procedure. Dr. Singh’s review found that 79%-98.5% of recipients of the procedure reported declines in bleeding that persisted for several years, which is comparable to myomectomy. Quality of life and pain scores also showed good improvement, with follow-up in the different studies ranging from 12 months to over 5 years, the analysis showed.

UAE does have its drawbacks. In rare cases, embolization can deprive the entire uterus and ovaries of blood, which can cause ovarian dysfunction and potentially result in premature menopause, although this outcome is most common in women who are older than 45 years. The procedure can often also be painful enough that overnight hospitalization is required.

Focused ultrasound surgeries, which include magnetic resonance–guided focused ultrasound surgery (MRgFUS) and high-intensity focused ultrasound (HIFU), were approved by the FDA in 2004. Focused ultrasound waves pass through the abdominal wall and produce significant heating, causing a burn that destroys the targeted tissue without damaging surrounding tissue. As with UAE, improvements in fibroid-associated bleeding and measures of quality of life were similar to those after myomectomy up to 3 years later.

But Dr. Singh noted that both focused ultrasound and RFA can damage the skin or internal organs. “[As] always with the thermal interventions, there is the probability of skin as well as internal organs that might get the thermal energy if it’s not focused correctly on to the fibroid itself,” he said. In addition, MRgFUS is not an option for women who are not good candidates to undergo an MRI, such as those with claustrophobia or pacemakers.

Also, with focus ultrasound and RFA, “we do worry about that fibroid getting blood flow back,” which can lead to recurrence of heavy menstrual bleeding, Dr. Laughlin-Tommaso noted. 

Although data on RFA are limited to 12 months of follow-up, most women reported meaningful reductions in bleeding symptoms. Longer follow-up has been reported for bleeding symptoms after MRgFUS, with similar results up to 3 years later. 

For Leslie Hansen-Lindner, MD, chief of obstetrics and gynecology at Atrium Health in Charlotte, N.C., choosing the right procedure starts with a patient-centered conversation weighing the pros and cons of the options and the woman’s goals. 

“Is their goal to reduce the size and impact of their fibroid, bleed less, and have a better quality of life on their period?” Dr. Hansen-Lindner said. “Or is their goal to have the entire fibroid removed?” 

If the former, an RFA is appealing to many women. If the latter, laparoscopic or mini-laparotomy myomectomy might be a better choice. Although fewer than 10% of patients require surgical reintervention at 3 years of follow-up for RFA, myomectomy has more consistent long-term evidence showing that fewer women require re-intervention and preserve their fertility, she added. 

Age also plays a role in the decision: The closer a woman is to menopause, the less likely she is to experience a recurrence, so a less-invasive procedure is preferable. But for younger women hoping to become pregnant, the lower risk for recurrence and good prognosis for future fertility might sway the choice toward myomectomy.

The first laparoscopic RFA procedures were approved for uterine fibroids in 2012. Dr. Hansen-Lindner is a proponent of transcervical fibroid ablation (TFA), a newer RFA procedure that the FDA approved in 2018. Performed through the cervix, TFA requires no incisions and can generally be done without general anesthesia. Eligible candidates would be any woman with symptomatic fibroids, such as heavy menstrual bleeding, pain, or bulk symptoms. The contraindications are few.

“It’s going to come down to size and location of fibroids, and whether or not they would be accessible by the TFA,” Dr. Hansen-Lindner said. “I have to make sure that there isn’t a fibroid blocking their cervix and that the fibroids are accessible with this device.” 

TFA also is not suitable for removing most submucosal lesions, which typically must be removed by hysteroscopic myomectomy. Dr. Hansen-Lindner said that she often uses TFA in conjunction with hysteroscopic myomectomy for this scenario. Although data on pregnancy after RFA (including TFA), MRgFUS, and HIFU are lacking, Gynesonics, the manufacturer of the Sonata System (the device that delivers radiofrequency energy to shrink the fibroid) has documented 79 pregnancies among the 2,200 women who have undergone TFA in the United States since 2018.
 

Disparities hampering care

Uterine fibroids are a particular problem for Black women, whose symptoms are more likely to be ignored by clinicians, according to Jodie Katon, PhD, a core investigator at the Veterans Affairs Greater Los Angeles Center for the Study of Healthcare Innovation, Implementation and Policy. Dr. Katon cited studies in which Black women interviewed about their experiences reported a consistent theme: Clinicians dismissed their symptoms, told them these were nothing to worry about, and advised them to lose weight. Those interactions not only delayed diagnosis among Black women but also led many of them to mistrust clinicians and avoid the health care system altogether.

The failure of clinicians to take their complaints seriously is just one of the disparities affecting Black women. In reviewing the literature, Dr. Laughlin-Tommaso, who also serves as the associate dean for Education Diversity, Equity, and Inclusion at the Mayo Clinic, found that African American women experience two to three times the risk for fibroids, compared with White women, as well as earlier onset and more severe disease, as measured by number and size of the lesions. 

According to Dr. Katon, the etiology of fibroids is still poorly understood. “What we do know is that Black women are disproportionately exposed to a variety of factors that we have shown through observational studies are associated with increased risk of development of uterine fibroids.” 

The list includes factors like stress; interpersonal racism; early age at menarche; various indicators of poor diets, such as vitamin D deficiency; the use of certain beauty products, specifically hair straighteners; as well as exposure to air pollution and other environmental toxins.

Laughlin-Tommaso also pointed to historical disparities in management, citing a doubled risk for hysterectomy for Black women in a study published in 2007 despite survey data suggesting that Black women report being more interested in uterine-preserving therapies rather than a hysterectomy.
 

Breaking down barriers of access to new treatments

Dr. Laughlin-Tommaso looked at more recent trends in the management of fibroids using data from the multicenter COMPARE-UF study, which enrolled women between 2015 and 2020 undergoing fibroid treatment into a longitudinal registry to track their outcomes. She found that Black women underwent hysterectomies at a lower rate than did White women and were instead more likely to undergo myomectomy or UAE. 

Some of the change may reflect lack of approved minimally invasive procedures before 2000. “But now that we have expanded options, I think most women are opting not to have a hysterectomy,” Dr. Laughlin-Tommaso said.

Dr. Katon has research funding from the VA to look more closely at racial disparities in the treatment of fibroids. In a study published in April 2023, she reported some surprising trends. 

During the period from 2010 to 2018, she found that Black veterans diagnosed with fibroids were less likely than White veterans were to receive treatment, regardless of their age or the severity of their symptoms. This finding held even among women with anemia, which should have been a clear indication for treatment.

But, as in the COMPARE-UF study, the subset of Black veterans who received an interventional treatment were less likely than their White peers were to undergo hysterectomy in favor of a fertility-sparing treatment as their initial procedure. Dr. Katon called it a “welcome but unexpected finding.” 

But another significant barrier remains: The two newest types of procedures, RFA and guided focused ultrasound, are not commonly performed outside of tertiary care facilities. However, studies have found that all these procedures are cost effective (studies for myomectomy, UAE, MRgFUS, and TFA). The implementation of a category 1 billing code for laparoscopic RFA in 2017 has led more insurance companies to cover the service, and a category 1 code will be available for TFA effective January 2024. 

Although RFA does require investment in specialized equipment, which limits facilities from offering the procedure, any gynecologist who routinely performs hysteroscopy can easily learn to do TFA. And the VA, which is committed to eliminating disparities in women’s health, established a 2-year advanced fellowship in minimally invasive gynecologic surgery in 2022 to help expand their capacity to offer these procedures. 

The VA has been rapidly expanding their gynecology services, and Katon said that she is confident that ultrasound-guided procedures and RFA will become more available within the system. “I would say we’re keeping pace. And in some ways, you know, as a national system we may be positioned to actually outpace the rest of the U.S.”

Dr. Segars reported prior research funding for clinical trials from BioSpecifics Technologies, Bayer, Allergan, AbbVie, and ObsEva and currently receives funding from Myovant Sciences. Dr. Hansen-Lindner reported personal fees from Gynesonics. Dr. Singh, Dr. Laughlin-Tommaso, and Dr. Katon reported no financial conflicts of interest. 

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

Before he attended medical school, Thomas O’Connor, MD, had a not-very-well-kept secret: As a competitive powerlifter, he had used steroids to build strength.

Now an internist and clinical instructor of medicine at the University of Connecticut, Farmington, Dr. O’Connor’s practice focuses on the needs of men taking testosterone and other anabolic steroids – a group he feels is poorly understood and largely neglected by conventional medical care, perceptions borne out by a 2020 study of steroid users he helped conduct.

“They felt discriminated against, they did not feel comfortable working with their physicians, and they felt that the doctors did not know what they were doing,” Dr. O’Connor said in an interview. His patients often express anger and frustration with doctors they had seen previously.
 

Patients turning to home tests

Not surprisingly, then, many users of illegal anabolic-androgenic steroids (AAS) have adopted a DIY approach to monitoring the side effects of the drugs, turning to direct-to-consumer laboratory tests. Clients can order a panel of labs designed to screen for health conditions commonly associated with use of AAS, such as dyslipidemia, renal and hepatic dysfunction, polycythemia, thrombosis, and insulin resistance. The panels also include tests for levels of different hormones.

Sales of direct-to-consumer tests topped $3.6 billion in the United States in 2022 and are predicted to grow. Some of that spending is coming from people, mostly men, using illegally obtained steroids to build muscle. Although published data on the size of the bodybuilder market are unavailable, the Internet is a ready source of relatively inexpensive tests aimed at helping individuals monitor their health.  

While clinicians may have their doubts about allowing patients to pick and choose tests and interpret their results, proponents claim they empower consumers to take control of their health – and save themselves money in the process.

But a test panel designed to help the user monitor the effects of banned substances is a bit unnerving to many clinicians, including Dr. O’Connor.

“People using anabolic steroids should be aware of the health risks associated with such use and that laboratory analysis is an important step toward improving health outcomes,” he said, “I’m all about open education, but not self-diagnosis and treatment.” 

Testosterone and other AAS such as nandrolone, trenbolone, and boldenone are Schedule III controlled substances that have been banned by numerous athletic governing bodies. Yet recreational users can easily obtain them from online international pharmacies without a prescription. Should they be monitoring themselves for side effects?

A basic problem is that few primary care clinicians routinely ask their patients about the use of AAS or feel competent to manage the complications or withdrawal symptoms associated with the agents. And they may have no idea what the average AAS user looks like.

The American College of Sports Medicine updated its statement on the use of AAS in 2021. The statement warned of a growing new segment of users – up to 70% of people who take the drugs do so recreationally in pursuit of a more muscular appearance, rather than competitive athletes seeking enhanced performance.

The ACSM highlighted the syndrome of muscle dysmorphia, also known as “megarexia” or “bigorexia” (think of it as “reverse anorexia”), as a major risk factor for illicit use of AAS.

Stuart Phillips, PhD, professor and director of the department of kinesiology at McMaster University, Hamilton, Ont., coauthored the ACSM guidelines. 

“The prince in Snow White circa 1950s was a guy with nice hair,” said Dr. Phillips, pointing to a change in cultural expectations for the male body. “But then fast forward to the prince or hero in any other Disney movie recently – and the guy is jacked.”

Since the last guidelines were published in 1987, Dr. Phillips has seen some cultural shifts. Testosterone has gone from a banned substance no one talked about to a mainstream medical therapy for men with low androgen levels, as any television viewer of primetime sports can attest. “But the other thing that’s changed,” he added, “is that we’ve seen the proliferation of illicit anabolic steroid use solely for the purpose of aesthetics.”

As an adolescent medicine physician who specializes in eating disorders, Jason Nagata, MD, MSc, sees many young men in his practice who engage in different behaviors to increase their muscle mass – from exercising, consuming high protein diets or taking protein supplements, even injecting AAS.

“A third of teenage boys across the U.S. report they’re trying to gain weight to bulk up and gain muscle,” said Dr. Nagata, an associate professor of pediatrics at the University of California, San Francisco.

In a 2020 study published in JAMA Pediatrics, Dr. Nagata and colleagues found that use of legal performance-enhancing substances in young men aged 18-26 years was associated with a higher odds of using AAS 7 years later (adjusted odds ratio, 3.18; 95% confidence interval, 1.90-5.32). “Some of the legal performance-enhancing substances like the protein powders or creatine may serve as a gateway to use of AAS,” Dr. Nagata said.  

Another important factor is exposure to AAS use on social media, where muscular influencers gain huge followings. Dr. Nagata said most of the research on eating disorders and social media has examined the role of media on weight loss in girls.

“Although there’s less research on the social media impact on boys and men, a few studies have shown links between more Instagram use and muscle dissatisfaction, as well as thinking about using steroids,” he said.

The number of people using AAS is not trivial. In a longitudinal study (led by Nagata) of young U.S. adults surveyed multiple times between 1994 and 2002, a total of 2.7% of 18- to 26-year-old men and 0.4% of women reported using AAS. In a more recent cohort of adolescents in Minnesota aged 14-22 years followed between 2010 and 2018, a total of 2.2% of males and 1% of females initiated AAS use. 

The Endocrine Society has estimated that between 2.9 and 4 million Americans have used an AAS at some point in their lives. Given that use is illegal without a prescription, a limitation of any survey is that participants may not be willing to disclose their AAS habit, leading to an underestimate of the actual number.

Nor are the complications of AAS use negligible. The drugs can have wide-ranging effects on the body, potentially affecting the brain, heart, liver, kidneys, musculoskeletal system, immune system, and reproductive systems. And individuals might unknowingly expose themselves to AAS: A recent literature review found that over a quarter of dietary supplements tested were found to contain undeclared substances that are on the World Anti-Doping Agency’s list of banned agents.
 

Alarming mistrust of MDs

Dr. O’Connor’s study shed some light on why AAS users might resort to surfing the Internet looking for a way to diagnose their own complications from steroid use. The web-based survey of nearly 2,400 men who said they took the drugs found that participants considered physicians to be the worst source of information, ranking them below coaches, online bodybuilding forums and sites, other AAS users, and bodybuilding books or magazines. The majority (56%) did not reveal AAS use to their clinicians. Of those who did, 55% reported feeling discriminated against for the admission.

Dr. O’Connor said physicians receive scant education on the many different drugs and regimens used by bodybuilders and have no idea how to a manage withdrawal syndrome for people trying to get off steroids. He urged the medical community to develop an educational campaign for clinicians, similar to those from public health officials aimed at combating the opioid epidemic: “Let’s educate med students and the residents. Let’s put [steroid use] on our agenda.”
 

Consumer testing evangelist ... or physician nemesis?

Nelson Vergel, BSChE, MBA, is on a mission to make medical lab testing affordable and accessible to everyone. The chemical engineer founded Discounted Labs 8 years ago, offering commonly ordered tests, such as complete blood counts, liver function tests, and cholesterol levels.

Mr. Vergel has advocated for the use of hormones to treat HIV-wasting disease for nearly 40 years, after his own diagnosis of the infection in 1986. After losing 40 pounds, steroids saved his life, he said.

Mr. Vergel said he was shocked to learn about the lack of continuing medical education on AAS for physicians and agreed with Dr. O’Connor that more training is needed for the medical profession. He also recognized that stigma on the part of clinicians is a huge barrier for many AAS users.

“We have to accept the fact that people are using them instead of demonizing them,” Mr. Vergel said. “What I was seeing is that there was so much stigma – and patients would not even talk to their doctors about their use.”

After reviewing Google analytics for his lab’s website and seeing how often “bodybuilder” came up as a search term, he added a panel of labs a year ago that allows AAS users to monitor themselves for adverse events.

Although he doesn’t condone the use of AAS without a medical indication and advises customers to discuss their results with a doctor, “we have to make sure people are reducing their harm or risk,” he said. “That’s really my goal.”

Many health care professionals would disagree with that statement. Dr. Nagata said he was concerned that management of side effects is too complicated. “There are a lot of nuances in the interpretation of these tests.” Arriving at the correct interpretation of the results requires a clinician’s thorough review of each patient’s health history, family history, and mental health history along with lab results. 
 

‘I’m concerned’

In a second article outlining harm-reduction strategies designed to improve care for patients using AAS, Dr. O’Connor and colleagues outlined an approach for talking with patients who are concerned about their health and are seeking guidance from a clinician.

The first step is to work on developing a rapport, and not to demand that patients stop their use of AAS. His recommended opening line is: “I want to be honest with you – I’m concerned.”

The initial interaction is an opportunity to find out why the person uses AAS, what health concerns they have at present, and why they are seeking care. Open-ended questions may reveal concerns that the patient has about fertility or side effects.

Consistent with harm-reduction approaches used for other public health epidemics – such as opioid abuse and blood-borne pathogens among people who inject drugs – follow-up visits can include nonjudgmental discussions about decreasing or stopping their use.

Ultimately, minimizing the harms of AAS use can serve as a bridge to their cessation, but the medical community needs to build up trust with a community of users who currently rely more on each other and the Internet for guidance than their primary care physicians. “We need more education. We’re going to need resources to do it,” Dr. O’Connell said. “And we’re going to have to do it.”

Dr. Phillips and Dr. Nagata have no financial disclosures. Mr. Vergel is the owner and founder of Discounted Labs but reported no other financial conflicts. Dr. O’Connor owns Anabolic Doc but has no additional financial disclosures.

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

Before he attended medical school, Thomas O’Connor, MD, had a not-very-well-kept secret: As a competitive powerlifter, he had used steroids to build strength.

Now an internist and clinical instructor of medicine at the University of Connecticut, Farmington, Dr. O’Connor’s practice focuses on the needs of men taking testosterone and other anabolic steroids – a group he feels is poorly understood and largely neglected by conventional medical care, perceptions borne out by a 2020 study of steroid users he helped conduct.

“They felt discriminated against, they did not feel comfortable working with their physicians, and they felt that the doctors did not know what they were doing,” Dr. O’Connor said in an interview. His patients often express anger and frustration with doctors they had seen previously.
 

Patients turning to home tests

Not surprisingly, then, many users of illegal anabolic-androgenic steroids (AAS) have adopted a DIY approach to monitoring the side effects of the drugs, turning to direct-to-consumer laboratory tests. Clients can order a panel of labs designed to screen for health conditions commonly associated with use of AAS, such as dyslipidemia, renal and hepatic dysfunction, polycythemia, thrombosis, and insulin resistance. The panels also include tests for levels of different hormones.

Sales of direct-to-consumer tests topped $3.6 billion in the United States in 2022 and are predicted to grow. Some of that spending is coming from people, mostly men, using illegally obtained steroids to build muscle. Although published data on the size of the bodybuilder market are unavailable, the Internet is a ready source of relatively inexpensive tests aimed at helping individuals monitor their health.  

While clinicians may have their doubts about allowing patients to pick and choose tests and interpret their results, proponents claim they empower consumers to take control of their health – and save themselves money in the process.

But a test panel designed to help the user monitor the effects of banned substances is a bit unnerving to many clinicians, including Dr. O’Connor.

“People using anabolic steroids should be aware of the health risks associated with such use and that laboratory analysis is an important step toward improving health outcomes,” he said, “I’m all about open education, but not self-diagnosis and treatment.” 

Testosterone and other AAS such as nandrolone, trenbolone, and boldenone are Schedule III controlled substances that have been banned by numerous athletic governing bodies. Yet recreational users can easily obtain them from online international pharmacies without a prescription. Should they be monitoring themselves for side effects?

A basic problem is that few primary care clinicians routinely ask their patients about the use of AAS or feel competent to manage the complications or withdrawal symptoms associated with the agents. And they may have no idea what the average AAS user looks like.

The American College of Sports Medicine updated its statement on the use of AAS in 2021. The statement warned of a growing new segment of users – up to 70% of people who take the drugs do so recreationally in pursuit of a more muscular appearance, rather than competitive athletes seeking enhanced performance.

The ACSM highlighted the syndrome of muscle dysmorphia, also known as “megarexia” or “bigorexia” (think of it as “reverse anorexia”), as a major risk factor for illicit use of AAS.

Stuart Phillips, PhD, professor and director of the department of kinesiology at McMaster University, Hamilton, Ont., coauthored the ACSM guidelines. 

“The prince in Snow White circa 1950s was a guy with nice hair,” said Dr. Phillips, pointing to a change in cultural expectations for the male body. “But then fast forward to the prince or hero in any other Disney movie recently – and the guy is jacked.”

Since the last guidelines were published in 1987, Dr. Phillips has seen some cultural shifts. Testosterone has gone from a banned substance no one talked about to a mainstream medical therapy for men with low androgen levels, as any television viewer of primetime sports can attest. “But the other thing that’s changed,” he added, “is that we’ve seen the proliferation of illicit anabolic steroid use solely for the purpose of aesthetics.”

As an adolescent medicine physician who specializes in eating disorders, Jason Nagata, MD, MSc, sees many young men in his practice who engage in different behaviors to increase their muscle mass – from exercising, consuming high protein diets or taking protein supplements, even injecting AAS.

“A third of teenage boys across the U.S. report they’re trying to gain weight to bulk up and gain muscle,” said Dr. Nagata, an associate professor of pediatrics at the University of California, San Francisco.

In a 2020 study published in JAMA Pediatrics, Dr. Nagata and colleagues found that use of legal performance-enhancing substances in young men aged 18-26 years was associated with a higher odds of using AAS 7 years later (adjusted odds ratio, 3.18; 95% confidence interval, 1.90-5.32). “Some of the legal performance-enhancing substances like the protein powders or creatine may serve as a gateway to use of AAS,” Dr. Nagata said.  

Another important factor is exposure to AAS use on social media, where muscular influencers gain huge followings. Dr. Nagata said most of the research on eating disorders and social media has examined the role of media on weight loss in girls.

“Although there’s less research on the social media impact on boys and men, a few studies have shown links between more Instagram use and muscle dissatisfaction, as well as thinking about using steroids,” he said.

The number of people using AAS is not trivial. In a longitudinal study (led by Nagata) of young U.S. adults surveyed multiple times between 1994 and 2002, a total of 2.7% of 18- to 26-year-old men and 0.4% of women reported using AAS. In a more recent cohort of adolescents in Minnesota aged 14-22 years followed between 2010 and 2018, a total of 2.2% of males and 1% of females initiated AAS use. 

The Endocrine Society has estimated that between 2.9 and 4 million Americans have used an AAS at some point in their lives. Given that use is illegal without a prescription, a limitation of any survey is that participants may not be willing to disclose their AAS habit, leading to an underestimate of the actual number.

Nor are the complications of AAS use negligible. The drugs can have wide-ranging effects on the body, potentially affecting the brain, heart, liver, kidneys, musculoskeletal system, immune system, and reproductive systems. And individuals might unknowingly expose themselves to AAS: A recent literature review found that over a quarter of dietary supplements tested were found to contain undeclared substances that are on the World Anti-Doping Agency’s list of banned agents.
 

Alarming mistrust of MDs

Dr. O’Connor’s study shed some light on why AAS users might resort to surfing the Internet looking for a way to diagnose their own complications from steroid use. The web-based survey of nearly 2,400 men who said they took the drugs found that participants considered physicians to be the worst source of information, ranking them below coaches, online bodybuilding forums and sites, other AAS users, and bodybuilding books or magazines. The majority (56%) did not reveal AAS use to their clinicians. Of those who did, 55% reported feeling discriminated against for the admission.

Dr. O’Connor said physicians receive scant education on the many different drugs and regimens used by bodybuilders and have no idea how to a manage withdrawal syndrome for people trying to get off steroids. He urged the medical community to develop an educational campaign for clinicians, similar to those from public health officials aimed at combating the opioid epidemic: “Let’s educate med students and the residents. Let’s put [steroid use] on our agenda.”
 

Consumer testing evangelist ... or physician nemesis?

Nelson Vergel, BSChE, MBA, is on a mission to make medical lab testing affordable and accessible to everyone. The chemical engineer founded Discounted Labs 8 years ago, offering commonly ordered tests, such as complete blood counts, liver function tests, and cholesterol levels.

Mr. Vergel has advocated for the use of hormones to treat HIV-wasting disease for nearly 40 years, after his own diagnosis of the infection in 1986. After losing 40 pounds, steroids saved his life, he said.

Mr. Vergel said he was shocked to learn about the lack of continuing medical education on AAS for physicians and agreed with Dr. O’Connor that more training is needed for the medical profession. He also recognized that stigma on the part of clinicians is a huge barrier for many AAS users.

“We have to accept the fact that people are using them instead of demonizing them,” Mr. Vergel said. “What I was seeing is that there was so much stigma – and patients would not even talk to their doctors about their use.”

After reviewing Google analytics for his lab’s website and seeing how often “bodybuilder” came up as a search term, he added a panel of labs a year ago that allows AAS users to monitor themselves for adverse events.

Although he doesn’t condone the use of AAS without a medical indication and advises customers to discuss their results with a doctor, “we have to make sure people are reducing their harm or risk,” he said. “That’s really my goal.”

Many health care professionals would disagree with that statement. Dr. Nagata said he was concerned that management of side effects is too complicated. “There are a lot of nuances in the interpretation of these tests.” Arriving at the correct interpretation of the results requires a clinician’s thorough review of each patient’s health history, family history, and mental health history along with lab results. 
 

‘I’m concerned’

In a second article outlining harm-reduction strategies designed to improve care for patients using AAS, Dr. O’Connor and colleagues outlined an approach for talking with patients who are concerned about their health and are seeking guidance from a clinician.

The first step is to work on developing a rapport, and not to demand that patients stop their use of AAS. His recommended opening line is: “I want to be honest with you – I’m concerned.”

The initial interaction is an opportunity to find out why the person uses AAS, what health concerns they have at present, and why they are seeking care. Open-ended questions may reveal concerns that the patient has about fertility or side effects.

Consistent with harm-reduction approaches used for other public health epidemics – such as opioid abuse and blood-borne pathogens among people who inject drugs – follow-up visits can include nonjudgmental discussions about decreasing or stopping their use.

Ultimately, minimizing the harms of AAS use can serve as a bridge to their cessation, but the medical community needs to build up trust with a community of users who currently rely more on each other and the Internet for guidance than their primary care physicians. “We need more education. We’re going to need resources to do it,” Dr. O’Connell said. “And we’re going to have to do it.”

Dr. Phillips and Dr. Nagata have no financial disclosures. Mr. Vergel is the owner and founder of Discounted Labs but reported no other financial conflicts. Dr. O’Connor owns Anabolic Doc but has no additional financial disclosures.

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

Before he attended medical school, Thomas O’Connor, MD, had a not-very-well-kept secret: As a competitive powerlifter, he had used steroids to build strength.

Now an internist and clinical instructor of medicine at the University of Connecticut, Farmington, Dr. O’Connor’s practice focuses on the needs of men taking testosterone and other anabolic steroids – a group he feels is poorly understood and largely neglected by conventional medical care, perceptions borne out by a 2020 study of steroid users he helped conduct.

“They felt discriminated against, they did not feel comfortable working with their physicians, and they felt that the doctors did not know what they were doing,” Dr. O’Connor said in an interview. His patients often express anger and frustration with doctors they had seen previously.
 

Patients turning to home tests

Not surprisingly, then, many users of illegal anabolic-androgenic steroids (AAS) have adopted a DIY approach to monitoring the side effects of the drugs, turning to direct-to-consumer laboratory tests. Clients can order a panel of labs designed to screen for health conditions commonly associated with use of AAS, such as dyslipidemia, renal and hepatic dysfunction, polycythemia, thrombosis, and insulin resistance. The panels also include tests for levels of different hormones.

Sales of direct-to-consumer tests topped $3.6 billion in the United States in 2022 and are predicted to grow. Some of that spending is coming from people, mostly men, using illegally obtained steroids to build muscle. Although published data on the size of the bodybuilder market are unavailable, the Internet is a ready source of relatively inexpensive tests aimed at helping individuals monitor their health.  

While clinicians may have their doubts about allowing patients to pick and choose tests and interpret their results, proponents claim they empower consumers to take control of their health – and save themselves money in the process.

But a test panel designed to help the user monitor the effects of banned substances is a bit unnerving to many clinicians, including Dr. O’Connor.

“People using anabolic steroids should be aware of the health risks associated with such use and that laboratory analysis is an important step toward improving health outcomes,” he said, “I’m all about open education, but not self-diagnosis and treatment.” 

Testosterone and other AAS such as nandrolone, trenbolone, and boldenone are Schedule III controlled substances that have been banned by numerous athletic governing bodies. Yet recreational users can easily obtain them from online international pharmacies without a prescription. Should they be monitoring themselves for side effects?

A basic problem is that few primary care clinicians routinely ask their patients about the use of AAS or feel competent to manage the complications or withdrawal symptoms associated with the agents. And they may have no idea what the average AAS user looks like.

The American College of Sports Medicine updated its statement on the use of AAS in 2021. The statement warned of a growing new segment of users – up to 70% of people who take the drugs do so recreationally in pursuit of a more muscular appearance, rather than competitive athletes seeking enhanced performance.

The ACSM highlighted the syndrome of muscle dysmorphia, also known as “megarexia” or “bigorexia” (think of it as “reverse anorexia”), as a major risk factor for illicit use of AAS.

Stuart Phillips, PhD, professor and director of the department of kinesiology at McMaster University, Hamilton, Ont., coauthored the ACSM guidelines. 

“The prince in Snow White circa 1950s was a guy with nice hair,” said Dr. Phillips, pointing to a change in cultural expectations for the male body. “But then fast forward to the prince or hero in any other Disney movie recently – and the guy is jacked.”

Since the last guidelines were published in 1987, Dr. Phillips has seen some cultural shifts. Testosterone has gone from a banned substance no one talked about to a mainstream medical therapy for men with low androgen levels, as any television viewer of primetime sports can attest. “But the other thing that’s changed,” he added, “is that we’ve seen the proliferation of illicit anabolic steroid use solely for the purpose of aesthetics.”

As an adolescent medicine physician who specializes in eating disorders, Jason Nagata, MD, MSc, sees many young men in his practice who engage in different behaviors to increase their muscle mass – from exercising, consuming high protein diets or taking protein supplements, even injecting AAS.

“A third of teenage boys across the U.S. report they’re trying to gain weight to bulk up and gain muscle,” said Dr. Nagata, an associate professor of pediatrics at the University of California, San Francisco.

In a 2020 study published in JAMA Pediatrics, Dr. Nagata and colleagues found that use of legal performance-enhancing substances in young men aged 18-26 years was associated with a higher odds of using AAS 7 years later (adjusted odds ratio, 3.18; 95% confidence interval, 1.90-5.32). “Some of the legal performance-enhancing substances like the protein powders or creatine may serve as a gateway to use of AAS,” Dr. Nagata said.  

Another important factor is exposure to AAS use on social media, where muscular influencers gain huge followings. Dr. Nagata said most of the research on eating disorders and social media has examined the role of media on weight loss in girls.

“Although there’s less research on the social media impact on boys and men, a few studies have shown links between more Instagram use and muscle dissatisfaction, as well as thinking about using steroids,” he said.

The number of people using AAS is not trivial. In a longitudinal study (led by Nagata) of young U.S. adults surveyed multiple times between 1994 and 2002, a total of 2.7% of 18- to 26-year-old men and 0.4% of women reported using AAS. In a more recent cohort of adolescents in Minnesota aged 14-22 years followed between 2010 and 2018, a total of 2.2% of males and 1% of females initiated AAS use. 

The Endocrine Society has estimated that between 2.9 and 4 million Americans have used an AAS at some point in their lives. Given that use is illegal without a prescription, a limitation of any survey is that participants may not be willing to disclose their AAS habit, leading to an underestimate of the actual number.

Nor are the complications of AAS use negligible. The drugs can have wide-ranging effects on the body, potentially affecting the brain, heart, liver, kidneys, musculoskeletal system, immune system, and reproductive systems. And individuals might unknowingly expose themselves to AAS: A recent literature review found that over a quarter of dietary supplements tested were found to contain undeclared substances that are on the World Anti-Doping Agency’s list of banned agents.
 

Alarming mistrust of MDs

Dr. O’Connor’s study shed some light on why AAS users might resort to surfing the Internet looking for a way to diagnose their own complications from steroid use. The web-based survey of nearly 2,400 men who said they took the drugs found that participants considered physicians to be the worst source of information, ranking them below coaches, online bodybuilding forums and sites, other AAS users, and bodybuilding books or magazines. The majority (56%) did not reveal AAS use to their clinicians. Of those who did, 55% reported feeling discriminated against for the admission.

Dr. O’Connor said physicians receive scant education on the many different drugs and regimens used by bodybuilders and have no idea how to a manage withdrawal syndrome for people trying to get off steroids. He urged the medical community to develop an educational campaign for clinicians, similar to those from public health officials aimed at combating the opioid epidemic: “Let’s educate med students and the residents. Let’s put [steroid use] on our agenda.”
 

Consumer testing evangelist ... or physician nemesis?

Nelson Vergel, BSChE, MBA, is on a mission to make medical lab testing affordable and accessible to everyone. The chemical engineer founded Discounted Labs 8 years ago, offering commonly ordered tests, such as complete blood counts, liver function tests, and cholesterol levels.

Mr. Vergel has advocated for the use of hormones to treat HIV-wasting disease for nearly 40 years, after his own diagnosis of the infection in 1986. After losing 40 pounds, steroids saved his life, he said.

Mr. Vergel said he was shocked to learn about the lack of continuing medical education on AAS for physicians and agreed with Dr. O’Connor that more training is needed for the medical profession. He also recognized that stigma on the part of clinicians is a huge barrier for many AAS users.

“We have to accept the fact that people are using them instead of demonizing them,” Mr. Vergel said. “What I was seeing is that there was so much stigma – and patients would not even talk to their doctors about their use.”

After reviewing Google analytics for his lab’s website and seeing how often “bodybuilder” came up as a search term, he added a panel of labs a year ago that allows AAS users to monitor themselves for adverse events.

Although he doesn’t condone the use of AAS without a medical indication and advises customers to discuss their results with a doctor, “we have to make sure people are reducing their harm or risk,” he said. “That’s really my goal.”

Many health care professionals would disagree with that statement. Dr. Nagata said he was concerned that management of side effects is too complicated. “There are a lot of nuances in the interpretation of these tests.” Arriving at the correct interpretation of the results requires a clinician’s thorough review of each patient’s health history, family history, and mental health history along with lab results. 
 

‘I’m concerned’

In a second article outlining harm-reduction strategies designed to improve care for patients using AAS, Dr. O’Connor and colleagues outlined an approach for talking with patients who are concerned about their health and are seeking guidance from a clinician.

The first step is to work on developing a rapport, and not to demand that patients stop their use of AAS. His recommended opening line is: “I want to be honest with you – I’m concerned.”

The initial interaction is an opportunity to find out why the person uses AAS, what health concerns they have at present, and why they are seeking care. Open-ended questions may reveal concerns that the patient has about fertility or side effects.

Consistent with harm-reduction approaches used for other public health epidemics – such as opioid abuse and blood-borne pathogens among people who inject drugs – follow-up visits can include nonjudgmental discussions about decreasing or stopping their use.

Ultimately, minimizing the harms of AAS use can serve as a bridge to their cessation, but the medical community needs to build up trust with a community of users who currently rely more on each other and the Internet for guidance than their primary care physicians. “We need more education. We’re going to need resources to do it,” Dr. O’Connell said. “And we’re going to have to do it.”

Dr. Phillips and Dr. Nagata have no financial disclosures. Mr. Vergel is the owner and founder of Discounted Labs but reported no other financial conflicts. Dr. O’Connor owns Anabolic Doc but has no additional financial disclosures.

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

A century ago, pediatricians began prescribing for children with intractable seizures the “keto diet,” which they also used to treat diabetes in children and adults. The low-carbohydrate, high-fat meals were designed to induce a near hypoglycemic state, forcing the body to use ketones for fuel instead of glucose.

The strategy fell out of favor after the discovery of insulin in the 1920s and the development of better antiseizure medications. But the epidemics of obesity and diabetes in the United States have revived interest in low-carbohydrate, high-fat diets. The global market for the ketogenic diet topped $11 billion in 2022.

Is it just a fad, or has the public – and science – caught up with the 100-year-old approach?

Although scientists still don’t know why the ketogenic diet was effective for controlling seizures, they have documented the effectiveness of ketogenic diets for the treatment of diabetes and metabolic syndrome. An extensive body of literature has documented their use in athletes, but less is known regarding conditions such as heart disease and dementia.

Although the data are promising, much of the research has been conducted with mice or has come from trials of short-term use in humans. But recently, the National Institutes of Health awarded a $3.5 million federal grant for a double-blind, randomized, placebo-controlled clinical trial to understand the effects of the long-term use of ketone ester supplementation on frailty. Developed 20 years ago, ketone esters are precursor molecules that the body quickly breaks down into ketone bodies when carbohydrates aren’t available.

“We’ve learned so much recently about how ketone bodies interact with aging biology,” John Newman, MD, PhD, of the Buck Institute for Research on Aging in Novato, Calif., and the study’s principal investigator, said in an interview. “And we’re only just starting to translate that out of the laboratory and into human studies to see how we can take advantage of ketone bodies to improve people’s health.”

Researchers from the Ohio State University and the University of Connecticut will also participate in the TAKEOFF (Targeting Aging With Ketone Ester in Older Adults for Function in Frailty) trial, which seeks to recruit a total of 180 people across the three sites.

Dr. Newman, assistant professor at the Buck Institute and associate professor in the division of geriatrics at the University of California, San Francisco, said ketone bodies might have helpful applications in a variety of conditions of aging.

One of the common things that happen during aging is that tissues – such as of the heart, brain, and muscle – lose the ability to metabolize glucose effectively. Over time, resistance to insulin can develop.

Researchers can map out areas of the brain affected by Alzheimer’s disease, for example, by assessing where patients’ glucose uptake drops. In heart failure, the heart has difficulty obtaining enough energy from glucose and instead burns fats and ketone bodies.

How might ketones affect frailty in the elderly?

As a practicing geriatrician, Dr. Newman measures frailty by evaluating patients’ strength, endurance, and how they react to stresses. He and his colleagues believe certain molecular and cellular changes may make patients more likely to fall, to recover more slowly from surgery, or to lose mobility.

The main hypothesis of the TAKEOFF study is “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”

Dr. Newman and Brianna Stubbs, DPhil, lead translational scientist at the Buck Institute, are still finishing up the BIKE (Buck Institute Ketone Ester) pilot study, which was the first double-blind, randomized, placebo-controlled study to evaluate the use of ketone ester supplements in adults older than 65 years. “The BIKE study is 12 weeks long. That’s actually the longest that anyone has studied ketone ester supplements in humans,” Dr. Stubbs said. The results will help them firm up the protocol for the TAKEOFF trial, which will likely treat patients for up to 24 weeks.

The primary outcome measure at all three study sites will be leg press strength. Researchers will also assess a variety of secondary outcomes that cover geriatric and cognitive function – measures such as gait speed and walking endurance, cognitive tests, and quality of life. And at the Buck, Dr. Newman and Dr. Stubbs will be evaluating the use of biomarkers that are often available in clinical labs – insulin, C-reactive protein, cystatin, and natriuretic peptide tests – for use as outcome measures that are responsive to treatment interventions and that can be used to track outcomes in future research on aging.

To achieve the goal of looking broadly at different organ systems likely to be affected by ketogenic supplements, they have assembled a team of coinvestigators with wide-ranging expertise in ketone and aging research.

Jeff Volek, PhD, professor in the department of human sciences at the Ohio State University, in Columbus, has contributed extensively to the literature on the use of ketogenic diets and supplements in a variety of populations, such as endurance athletes and patients with insulin resistance or diabetes.

Dr. Volek has demonstrated that ketones can have an anticatabolic effect on muscle tissue. “They could help offset some of the muscle loss with aging, which would in turn improve their physical functioning and ability to do daily activities,” he said.

The anti-inflammatory property of ketones may provide another benefit to older people. They can reduce oxidative stress, which is considered one of the chief pathologic mechanisms responsible for conditions such as heart disease, Alzheimer’s disease, asthma, and arthritis.

In addition to the main study outcomes, Dr. Volek’s lab will study muscle physiology by performing biopsies at baseline and after consumption of ketogenic supplements to assess metabolic changes in muscle cells as they consume energy. Study participants will also undergo MRIs to detect subtle changes in muscle size before and after treatment.
 

From elite athletes to everyday agers

As a graduate student in Dr. Volek’s lab, Jenna Bartley, PhD, studied the effects of a ketogenic diet on elite athletes. But her work has taken a turn. Now an assistant professor in the department of immunology and the center on aging at the University of Connecticut in Farmington, she focuses on how immune responses and physical function decline with age.

“Ketogenic diets and the main ketone bodies – mainly beta-hydroxybutyrate – have been shown to have really powerful influences on a lot of things that go wrong with aging,” Dr. Bartley said. The decline in immune function in the elderly is not isolated to one cell type or even one arm of the immune system. There is reason to believe ketone supplementation could improve immune function.

“T cells really love ketones for energy,” Dr. Bartley said. Some data show that production of ketone bodies is impaired in individuals with severe SARS-CoV-2 infection. Mouse models of SARS-CoV-2 infection have found that ketogenic diets led to improvement in the response to antiviral therapy.

In her lab, she’ll assess serum markers of inflammation in patients, as well as cytokine secretion following stimulation of T cells. T cells in culture from older people produce more inflammatory cytokines than those from younger people, leading to a dysfunctional immune response. Dr. Bartley is curious to see whether ketones can fix that. Additional work will include single-cell RNA sequencing of different classes of immune cells to investigate how ketones might change metabolic pathways.

Why use ketogenic supplements instead of having people consume ketogenic diets? “There are no cheat days in the keto diet,” Dr. Bartley said. Administering the diet requires intense supervision of research participants to enforce adherence. Use of supplements will improve compliance and likely make any findings translatable to more of the population, she said.

Drawbacks of the initial formulations of ketone esters, first developed 20 years ago, included high cost and terrible taste. Dr, Stubbs, a former world class rowing champion who competed in the Ironman World Championship last year, has firsthand experience with them as a research participant.

“It tasted like drinking nail polish,” she said. Recent advances in manufacturing have made them cheaper – roughly $5 per day – and more palatable, enabling research studies such as TAKEOFF.

For Dr. Newman, the studies are early building blocks in the emerging field of geroscience, which aims to translate fundamental mechanisms of aging into therapies to treat disease.

“We’re hoping that this will be an example of a proof-of-concept geroscience study that will really help to translate ketone body biology out of the laboratory and hopefully into a diversity of clinical applications,” he said. “There’s a lot we don’t understand still about the molecular mechanisms of frailty.”

Dr. Newman and Dr. Stubbs own stock in BHB Therapeutics Ltd, the company providing the product being studied, and are inventors on patents that relate to the product being studied. The Buck Institute has an ownership interest in BHB Therapeutics. Dr. Bartley and Dr. Volek report no relevant financial relationships.

A version of this article appeared on Medscape.com .

A century ago, pediatricians began prescribing for children with intractable seizures the “keto diet,” which they also used to treat diabetes in children and adults. The low-carbohydrate, high-fat meals were designed to induce a near hypoglycemic state, forcing the body to use ketones for fuel instead of glucose.

The strategy fell out of favor after the discovery of insulin in the 1920s and the development of better antiseizure medications. But the epidemics of obesity and diabetes in the United States have revived interest in low-carbohydrate, high-fat diets. The global market for the ketogenic diet topped $11 billion in 2022.

Is it just a fad, or has the public – and science – caught up with the 100-year-old approach?

Although scientists still don’t know why the ketogenic diet was effective for controlling seizures, they have documented the effectiveness of ketogenic diets for the treatment of diabetes and metabolic syndrome. An extensive body of literature has documented their use in athletes, but less is known regarding conditions such as heart disease and dementia.

Although the data are promising, much of the research has been conducted with mice or has come from trials of short-term use in humans. But recently, the National Institutes of Health awarded a $3.5 million federal grant for a double-blind, randomized, placebo-controlled clinical trial to understand the effects of the long-term use of ketone ester supplementation on frailty. Developed 20 years ago, ketone esters are precursor molecules that the body quickly breaks down into ketone bodies when carbohydrates aren’t available.

“We’ve learned so much recently about how ketone bodies interact with aging biology,” John Newman, MD, PhD, of the Buck Institute for Research on Aging in Novato, Calif., and the study’s principal investigator, said in an interview. “And we’re only just starting to translate that out of the laboratory and into human studies to see how we can take advantage of ketone bodies to improve people’s health.”

Researchers from the Ohio State University and the University of Connecticut will also participate in the TAKEOFF (Targeting Aging With Ketone Ester in Older Adults for Function in Frailty) trial, which seeks to recruit a total of 180 people across the three sites.

Dr. Newman, assistant professor at the Buck Institute and associate professor in the division of geriatrics at the University of California, San Francisco, said ketone bodies might have helpful applications in a variety of conditions of aging.

One of the common things that happen during aging is that tissues – such as of the heart, brain, and muscle – lose the ability to metabolize glucose effectively. Over time, resistance to insulin can develop.

Researchers can map out areas of the brain affected by Alzheimer’s disease, for example, by assessing where patients’ glucose uptake drops. In heart failure, the heart has difficulty obtaining enough energy from glucose and instead burns fats and ketone bodies.

How might ketones affect frailty in the elderly?

As a practicing geriatrician, Dr. Newman measures frailty by evaluating patients’ strength, endurance, and how they react to stresses. He and his colleagues believe certain molecular and cellular changes may make patients more likely to fall, to recover more slowly from surgery, or to lose mobility.

The main hypothesis of the TAKEOFF study is “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”

Dr. Newman and Brianna Stubbs, DPhil, lead translational scientist at the Buck Institute, are still finishing up the BIKE (Buck Institute Ketone Ester) pilot study, which was the first double-blind, randomized, placebo-controlled study to evaluate the use of ketone ester supplements in adults older than 65 years. “The BIKE study is 12 weeks long. That’s actually the longest that anyone has studied ketone ester supplements in humans,” Dr. Stubbs said. The results will help them firm up the protocol for the TAKEOFF trial, which will likely treat patients for up to 24 weeks.

The primary outcome measure at all three study sites will be leg press strength. Researchers will also assess a variety of secondary outcomes that cover geriatric and cognitive function – measures such as gait speed and walking endurance, cognitive tests, and quality of life. And at the Buck, Dr. Newman and Dr. Stubbs will be evaluating the use of biomarkers that are often available in clinical labs – insulin, C-reactive protein, cystatin, and natriuretic peptide tests – for use as outcome measures that are responsive to treatment interventions and that can be used to track outcomes in future research on aging.

To achieve the goal of looking broadly at different organ systems likely to be affected by ketogenic supplements, they have assembled a team of coinvestigators with wide-ranging expertise in ketone and aging research.

Jeff Volek, PhD, professor in the department of human sciences at the Ohio State University, in Columbus, has contributed extensively to the literature on the use of ketogenic diets and supplements in a variety of populations, such as endurance athletes and patients with insulin resistance or diabetes.

Dr. Volek has demonstrated that ketones can have an anticatabolic effect on muscle tissue. “They could help offset some of the muscle loss with aging, which would in turn improve their physical functioning and ability to do daily activities,” he said.

The anti-inflammatory property of ketones may provide another benefit to older people. They can reduce oxidative stress, which is considered one of the chief pathologic mechanisms responsible for conditions such as heart disease, Alzheimer’s disease, asthma, and arthritis.

In addition to the main study outcomes, Dr. Volek’s lab will study muscle physiology by performing biopsies at baseline and after consumption of ketogenic supplements to assess metabolic changes in muscle cells as they consume energy. Study participants will also undergo MRIs to detect subtle changes in muscle size before and after treatment.
 

From elite athletes to everyday agers

As a graduate student in Dr. Volek’s lab, Jenna Bartley, PhD, studied the effects of a ketogenic diet on elite athletes. But her work has taken a turn. Now an assistant professor in the department of immunology and the center on aging at the University of Connecticut in Farmington, she focuses on how immune responses and physical function decline with age.

“Ketogenic diets and the main ketone bodies – mainly beta-hydroxybutyrate – have been shown to have really powerful influences on a lot of things that go wrong with aging,” Dr. Bartley said. The decline in immune function in the elderly is not isolated to one cell type or even one arm of the immune system. There is reason to believe ketone supplementation could improve immune function.

“T cells really love ketones for energy,” Dr. Bartley said. Some data show that production of ketone bodies is impaired in individuals with severe SARS-CoV-2 infection. Mouse models of SARS-CoV-2 infection have found that ketogenic diets led to improvement in the response to antiviral therapy.

In her lab, she’ll assess serum markers of inflammation in patients, as well as cytokine secretion following stimulation of T cells. T cells in culture from older people produce more inflammatory cytokines than those from younger people, leading to a dysfunctional immune response. Dr. Bartley is curious to see whether ketones can fix that. Additional work will include single-cell RNA sequencing of different classes of immune cells to investigate how ketones might change metabolic pathways.

Why use ketogenic supplements instead of having people consume ketogenic diets? “There are no cheat days in the keto diet,” Dr. Bartley said. Administering the diet requires intense supervision of research participants to enforce adherence. Use of supplements will improve compliance and likely make any findings translatable to more of the population, she said.

Drawbacks of the initial formulations of ketone esters, first developed 20 years ago, included high cost and terrible taste. Dr, Stubbs, a former world class rowing champion who competed in the Ironman World Championship last year, has firsthand experience with them as a research participant.

“It tasted like drinking nail polish,” she said. Recent advances in manufacturing have made them cheaper – roughly $5 per day – and more palatable, enabling research studies such as TAKEOFF.

For Dr. Newman, the studies are early building blocks in the emerging field of geroscience, which aims to translate fundamental mechanisms of aging into therapies to treat disease.

“We’re hoping that this will be an example of a proof-of-concept geroscience study that will really help to translate ketone body biology out of the laboratory and hopefully into a diversity of clinical applications,” he said. “There’s a lot we don’t understand still about the molecular mechanisms of frailty.”

Dr. Newman and Dr. Stubbs own stock in BHB Therapeutics Ltd, the company providing the product being studied, and are inventors on patents that relate to the product being studied. The Buck Institute has an ownership interest in BHB Therapeutics. Dr. Bartley and Dr. Volek report no relevant financial relationships.

A version of this article appeared on Medscape.com .

A century ago, pediatricians began prescribing for children with intractable seizures the “keto diet,” which they also used to treat diabetes in children and adults. The low-carbohydrate, high-fat meals were designed to induce a near hypoglycemic state, forcing the body to use ketones for fuel instead of glucose.

The strategy fell out of favor after the discovery of insulin in the 1920s and the development of better antiseizure medications. But the epidemics of obesity and diabetes in the United States have revived interest in low-carbohydrate, high-fat diets. The global market for the ketogenic diet topped $11 billion in 2022.

Is it just a fad, or has the public – and science – caught up with the 100-year-old approach?

Although scientists still don’t know why the ketogenic diet was effective for controlling seizures, they have documented the effectiveness of ketogenic diets for the treatment of diabetes and metabolic syndrome. An extensive body of literature has documented their use in athletes, but less is known regarding conditions such as heart disease and dementia.

Although the data are promising, much of the research has been conducted with mice or has come from trials of short-term use in humans. But recently, the National Institutes of Health awarded a $3.5 million federal grant for a double-blind, randomized, placebo-controlled clinical trial to understand the effects of the long-term use of ketone ester supplementation on frailty. Developed 20 years ago, ketone esters are precursor molecules that the body quickly breaks down into ketone bodies when carbohydrates aren’t available.

“We’ve learned so much recently about how ketone bodies interact with aging biology,” John Newman, MD, PhD, of the Buck Institute for Research on Aging in Novato, Calif., and the study’s principal investigator, said in an interview. “And we’re only just starting to translate that out of the laboratory and into human studies to see how we can take advantage of ketone bodies to improve people’s health.”

Researchers from the Ohio State University and the University of Connecticut will also participate in the TAKEOFF (Targeting Aging With Ketone Ester in Older Adults for Function in Frailty) trial, which seeks to recruit a total of 180 people across the three sites.

Dr. Newman, assistant professor at the Buck Institute and associate professor in the division of geriatrics at the University of California, San Francisco, said ketone bodies might have helpful applications in a variety of conditions of aging.

One of the common things that happen during aging is that tissues – such as of the heart, brain, and muscle – lose the ability to metabolize glucose effectively. Over time, resistance to insulin can develop.

Researchers can map out areas of the brain affected by Alzheimer’s disease, for example, by assessing where patients’ glucose uptake drops. In heart failure, the heart has difficulty obtaining enough energy from glucose and instead burns fats and ketone bodies.

How might ketones affect frailty in the elderly?

As a practicing geriatrician, Dr. Newman measures frailty by evaluating patients’ strength, endurance, and how they react to stresses. He and his colleagues believe certain molecular and cellular changes may make patients more likely to fall, to recover more slowly from surgery, or to lose mobility.

The main hypothesis of the TAKEOFF study is “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”

Dr. Newman and Brianna Stubbs, DPhil, lead translational scientist at the Buck Institute, are still finishing up the BIKE (Buck Institute Ketone Ester) pilot study, which was the first double-blind, randomized, placebo-controlled study to evaluate the use of ketone ester supplements in adults older than 65 years. “The BIKE study is 12 weeks long. That’s actually the longest that anyone has studied ketone ester supplements in humans,” Dr. Stubbs said. The results will help them firm up the protocol for the TAKEOFF trial, which will likely treat patients for up to 24 weeks.

The primary outcome measure at all three study sites will be leg press strength. Researchers will also assess a variety of secondary outcomes that cover geriatric and cognitive function – measures such as gait speed and walking endurance, cognitive tests, and quality of life. And at the Buck, Dr. Newman and Dr. Stubbs will be evaluating the use of biomarkers that are often available in clinical labs – insulin, C-reactive protein, cystatin, and natriuretic peptide tests – for use as outcome measures that are responsive to treatment interventions and that can be used to track outcomes in future research on aging.

To achieve the goal of looking broadly at different organ systems likely to be affected by ketogenic supplements, they have assembled a team of coinvestigators with wide-ranging expertise in ketone and aging research.

Jeff Volek, PhD, professor in the department of human sciences at the Ohio State University, in Columbus, has contributed extensively to the literature on the use of ketogenic diets and supplements in a variety of populations, such as endurance athletes and patients with insulin resistance or diabetes.

Dr. Volek has demonstrated that ketones can have an anticatabolic effect on muscle tissue. “They could help offset some of the muscle loss with aging, which would in turn improve their physical functioning and ability to do daily activities,” he said.

The anti-inflammatory property of ketones may provide another benefit to older people. They can reduce oxidative stress, which is considered one of the chief pathologic mechanisms responsible for conditions such as heart disease, Alzheimer’s disease, asthma, and arthritis.

In addition to the main study outcomes, Dr. Volek’s lab will study muscle physiology by performing biopsies at baseline and after consumption of ketogenic supplements to assess metabolic changes in muscle cells as they consume energy. Study participants will also undergo MRIs to detect subtle changes in muscle size before and after treatment.
 

From elite athletes to everyday agers

As a graduate student in Dr. Volek’s lab, Jenna Bartley, PhD, studied the effects of a ketogenic diet on elite athletes. But her work has taken a turn. Now an assistant professor in the department of immunology and the center on aging at the University of Connecticut in Farmington, she focuses on how immune responses and physical function decline with age.

“Ketogenic diets and the main ketone bodies – mainly beta-hydroxybutyrate – have been shown to have really powerful influences on a lot of things that go wrong with aging,” Dr. Bartley said. The decline in immune function in the elderly is not isolated to one cell type or even one arm of the immune system. There is reason to believe ketone supplementation could improve immune function.

“T cells really love ketones for energy,” Dr. Bartley said. Some data show that production of ketone bodies is impaired in individuals with severe SARS-CoV-2 infection. Mouse models of SARS-CoV-2 infection have found that ketogenic diets led to improvement in the response to antiviral therapy.

In her lab, she’ll assess serum markers of inflammation in patients, as well as cytokine secretion following stimulation of T cells. T cells in culture from older people produce more inflammatory cytokines than those from younger people, leading to a dysfunctional immune response. Dr. Bartley is curious to see whether ketones can fix that. Additional work will include single-cell RNA sequencing of different classes of immune cells to investigate how ketones might change metabolic pathways.

Why use ketogenic supplements instead of having people consume ketogenic diets? “There are no cheat days in the keto diet,” Dr. Bartley said. Administering the diet requires intense supervision of research participants to enforce adherence. Use of supplements will improve compliance and likely make any findings translatable to more of the population, she said.

Drawbacks of the initial formulations of ketone esters, first developed 20 years ago, included high cost and terrible taste. Dr, Stubbs, a former world class rowing champion who competed in the Ironman World Championship last year, has firsthand experience with them as a research participant.

“It tasted like drinking nail polish,” she said. Recent advances in manufacturing have made them cheaper – roughly $5 per day – and more palatable, enabling research studies such as TAKEOFF.

For Dr. Newman, the studies are early building blocks in the emerging field of geroscience, which aims to translate fundamental mechanisms of aging into therapies to treat disease.

“We’re hoping that this will be an example of a proof-of-concept geroscience study that will really help to translate ketone body biology out of the laboratory and hopefully into a diversity of clinical applications,” he said. “There’s a lot we don’t understand still about the molecular mechanisms of frailty.”

Dr. Newman and Dr. Stubbs own stock in BHB Therapeutics Ltd, the company providing the product being studied, and are inventors on patents that relate to the product being studied. The Buck Institute has an ownership interest in BHB Therapeutics. Dr. Bartley and Dr. Volek report no relevant financial relationships.

A version of this article appeared on Medscape.com .

In 1927, American gynecologist John Sampson published his theory of the etiology of endometriosis, postulating that retrograde flow of endometrial debris flows backward through the fallopian tubes during menses into the peritoneal cavity. Dr. Sampson’s notion remains the main paradigm today, mentioned still in recent articles on the topic, but it has a flaw: Although the theory may account for how endometrial tissue escapes the uterus, a 1984 study revealed that this phenomenon occurs in 90% of women. Why, then, do only 10% of women suffer from endometriosis?

Endometriosis describes a condition in which endometrial tissue lining the uterus is found outside the uterus. The disease can be painful, even crippling. As many as 30% of women in their reproductive years who have endometriosis are infertile as a consequence. The hallmarks of the condition are superficial peritoneal lesions of varying color, cysts in the ovaries, deeper nodules accompanied by scarring and adhesion, primarily in the pelvis but sometimes appearing outside the pelvis. The syndrome can be challenging to identify, requiring laparoscopy for definitive diagnosis.

John Sampson aside, scientists have struggled for the past century to identify the cause, or causes, of endometriosis. Hormones clearly play a role in its development, and women with endometriosis have an elevated risk of clear-cell and endometrioid ovarian cancer and autoimmune diseases. Immunodeficiency also could be to blame, if a faulty immune system fails to find and remove endometrial tissue outside of the uterus. A class of chemicals known as endocrine disruptors have been linked to endometriosis, but not definitively. Twin studies have demonstrated that as many as 50% of cases have a genetic basis, while mice with surgically induced endometriosis have been found to have a higher ratio of harmful to beneficial bacteria in their gut.

Several studies published this year point to new insights into the old mystery – with possible implications for ways to treat the disorder.

Perhaps the most surprising came out earlier this year in Science Translational Medicine, as a team of researchers in Japan reported that invasive infection by bacteria of the genus Fusobacterium may cause at least some cases of endometriosis.

Is Fusobacterium the new Helicobacter pylori?

The researchers, from Nagoya University, are the first to suggest that not only might a single bacterial genus cause endometriosis, but that antibiotic treatment could prevent progression of the disease. Using endometrial tissue obtained from 79 women undergoing hysterectomy for endometriosis and 76 women undergoing hysterectomy for other reasons (such as cervical cancer), the team started with gene expression profiling to explore differences between the two sets of samples. 

They uncovered an interesting chain of cellular events:  macrophages found in endometriotic lesions were secreting transforming growth factor-beta (TGF-beta). TGF-beta in turn stimulated high levels of expression of a gene called TAGLN in fibroblast cells from women with endometriosis but not in fibroblasts from women without endometriosis. 

Turning on TAGLN transformed these previously inactive cells into active myofibroblasts, leading to increased proliferation, mobility, and attachment to mesothelial cells, the layer of cells that line body cavities and internal organs. In short, they identified some key players in an environment that seemed very favorable to the development of endometriosis.

“So, the question is: Why are macrophages activated?” said Yutaka Kondo, MD, PhD, the senior author of the study and a professor in the division of cancer biology at the Nagoya (Japan) University Graduate School of Medicine. “We think that there are always bacteria in the endometrium.”

After reviewing data from a previously published study, they used quantitative polymerase chain reaction to rule out one candidate, Erysipelothrix, but scored on their next attempt, identifying Fusobacterium species in endometrial tissue from 64% of the women with endometriosis, compared with fewer than 10% of the controls.

To confirm that the bacteria could cause disease and were not simply bystanders, Dr. Kondo’s team turned to a mouse model for endometriosis, in which endometrial cells are surgically removed from the uteri of mice and injected into the peritoneum of recipient mice, leading to the formation of endometriotic lesions. When mice received further injections of uterine tissue from mice that were infected with F. nucleatum, their lesions were more numerous when compared with mice that received injections of uninfected uterine tissue. Furthermore, antibiotic treatment with metronidazole or chloramphenicol immediately after surgery largely prevented progression to endometriosis, Dr. Kondo and his colleagues reported.

Dr. Kondo likened this relationship between Fusobacterium and endometriosis to that of the link between Helicobacter pylori and peptic ulcers but acknowledged that he doesn’t have all the answers.

“We need more clinical trials, and also we have to know what kind of treatment might be the most effective for the treatment of endometriosis,” Dr. Kondo said, pointing out that other therapies should still be pursued in addition to antibiotics, as not all the samples from women with endometriosis harbored Fusobacterium. “It might be possible that other mechanisms are also involved.”

Don’t write off gut microbiota

Ramakrishna Kommagani, PhD, associate professor of pathology and immunology at Baylor College of Medicine in Houston, agreed. “Endometriosis is a complex disease, which appears to be impacted by many factors, including genetic, epigenetic, and environmental factors,” Dr. Kommagani said.

Kommagani_Ramakrishna_TX_web.jpg

Clues in genetic variants

Krina Zondervan, DPhil, professor and head of the department of reproductive and genomic epidemiology at the University of Oxford (England), focuses on genomic, molecular, and epidemiologic approaches to understanding endometriosis.

Zondervan_Krina_UK_web.jpg

What’s next?

The chief limitation of human studies looking at mechanisms of endometriosis is that they are correlational: Tissue samples are collected from women with and without endometriosis, often through an invasive procedure such as laparoscopy or biopsy, at one point in time. If a researcher identifies a factor that is more common in women with endometriosis – a particular bacterium or environmental exposure – proving causality is difficult. Currently, the best tools for proving causation are animal models of endometriosis, such as the those used by Dr. Kondo’s and Dr. Kommagani’s teams.

Better diagnostic tools would solve that problem. The ultimate goal is a noninvasive test for endometriosis that would allow clinicians to follow women over time and permit the monitoring of disease progression, or regression, without the need for painful procedures. Such a diagnostic tool would facilitate rigorous longitudinal studies evaluating mechanisms of disease, as well as monitoring outcomes of clinical trials of new treatments.

Could stool samples be the answer?

The Japanese team found that women harboring Fusobacterium in endometrial tissue also had Fusobacterium in vaginal samples taken at the time of their hysterectomy – and stool samples can pick up changes in the gut microbiome.

“Vaginal swab or stool tests are probably the best and easiest for noninvasive early detection,” Dr. Kommagani said. 

Spit tests for DNA would be even easier to obtain. Polygenic risk scores could be developed to estimate an individual’s risk of disease based on the number of variants, but Dr. Zondervan cautioned that not all the genes that account for endometriosis are known.

“The things that we found altogether explain about 5% of disease variability, basically – which is still not an awful lot,” she said.

Dr. Kondo’s work was supported by the Grant-in-Aid for Scientific Research, the Japan Society for the Promotion of Science, and the Research Grant of the Princess Takamatsu Cancer Research Fund. A patent method for detecting bacteria of genus Fusobacterium in order to diagnose endometriosis (WO2023/ 042714), was submitted (international publication date, March 23, 2023).

Dr. Kommagani’s work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742. He has no other conflicts of interest. Dr. Zondervan received funding from the Wellcome Trust (216767; 104036; 084766; 212904; 076113 and 085475) and also reported grants from Bayer AG, AbbVie, Volition Rx, MDNA Life Sciences, and Roche Diagnostics outside the submitted work.

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Ore.

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

In 1927, American gynecologist John Sampson published his theory of the etiology of endometriosis, postulating that retrograde flow of endometrial debris flows backward through the fallopian tubes during menses into the peritoneal cavity. Dr. Sampson’s notion remains the main paradigm today, mentioned still in recent articles on the topic, but it has a flaw: Although the theory may account for how endometrial tissue escapes the uterus, a 1984 study revealed that this phenomenon occurs in 90% of women. Why, then, do only 10% of women suffer from endometriosis?

Endometriosis describes a condition in which endometrial tissue lining the uterus is found outside the uterus. The disease can be painful, even crippling. As many as 30% of women in their reproductive years who have endometriosis are infertile as a consequence. The hallmarks of the condition are superficial peritoneal lesions of varying color, cysts in the ovaries, deeper nodules accompanied by scarring and adhesion, primarily in the pelvis but sometimes appearing outside the pelvis. The syndrome can be challenging to identify, requiring laparoscopy for definitive diagnosis.

John Sampson aside, scientists have struggled for the past century to identify the cause, or causes, of endometriosis. Hormones clearly play a role in its development, and women with endometriosis have an elevated risk of clear-cell and endometrioid ovarian cancer and autoimmune diseases. Immunodeficiency also could be to blame, if a faulty immune system fails to find and remove endometrial tissue outside of the uterus. A class of chemicals known as endocrine disruptors have been linked to endometriosis, but not definitively. Twin studies have demonstrated that as many as 50% of cases have a genetic basis, while mice with surgically induced endometriosis have been found to have a higher ratio of harmful to beneficial bacteria in their gut.

Several studies published this year point to new insights into the old mystery – with possible implications for ways to treat the disorder.

Perhaps the most surprising came out earlier this year in Science Translational Medicine, as a team of researchers in Japan reported that invasive infection by bacteria of the genus Fusobacterium may cause at least some cases of endometriosis.

Is Fusobacterium the new Helicobacter pylori?

The researchers, from Nagoya University, are the first to suggest that not only might a single bacterial genus cause endometriosis, but that antibiotic treatment could prevent progression of the disease. Using endometrial tissue obtained from 79 women undergoing hysterectomy for endometriosis and 76 women undergoing hysterectomy for other reasons (such as cervical cancer), the team started with gene expression profiling to explore differences between the two sets of samples. 

They uncovered an interesting chain of cellular events:  macrophages found in endometriotic lesions were secreting transforming growth factor-beta (TGF-beta). TGF-beta in turn stimulated high levels of expression of a gene called TAGLN in fibroblast cells from women with endometriosis but not in fibroblasts from women without endometriosis. 

Turning on TAGLN transformed these previously inactive cells into active myofibroblasts, leading to increased proliferation, mobility, and attachment to mesothelial cells, the layer of cells that line body cavities and internal organs. In short, they identified some key players in an environment that seemed very favorable to the development of endometriosis.

“So, the question is: Why are macrophages activated?” said Yutaka Kondo, MD, PhD, the senior author of the study and a professor in the division of cancer biology at the Nagoya (Japan) University Graduate School of Medicine. “We think that there are always bacteria in the endometrium.”

After reviewing data from a previously published study, they used quantitative polymerase chain reaction to rule out one candidate, Erysipelothrix, but scored on their next attempt, identifying Fusobacterium species in endometrial tissue from 64% of the women with endometriosis, compared with fewer than 10% of the controls.

To confirm that the bacteria could cause disease and were not simply bystanders, Dr. Kondo’s team turned to a mouse model for endometriosis, in which endometrial cells are surgically removed from the uteri of mice and injected into the peritoneum of recipient mice, leading to the formation of endometriotic lesions. When mice received further injections of uterine tissue from mice that were infected with F. nucleatum, their lesions were more numerous when compared with mice that received injections of uninfected uterine tissue. Furthermore, antibiotic treatment with metronidazole or chloramphenicol immediately after surgery largely prevented progression to endometriosis, Dr. Kondo and his colleagues reported.

Dr. Kondo likened this relationship between Fusobacterium and endometriosis to that of the link between Helicobacter pylori and peptic ulcers but acknowledged that he doesn’t have all the answers.

“We need more clinical trials, and also we have to know what kind of treatment might be the most effective for the treatment of endometriosis,” Dr. Kondo said, pointing out that other therapies should still be pursued in addition to antibiotics, as not all the samples from women with endometriosis harbored Fusobacterium. “It might be possible that other mechanisms are also involved.”

Don’t write off gut microbiota

Ramakrishna Kommagani, PhD, associate professor of pathology and immunology at Baylor College of Medicine in Houston, agreed. “Endometriosis is a complex disease, which appears to be impacted by many factors, including genetic, epigenetic, and environmental factors,” Dr. Kommagani said.

Kommagani_Ramakrishna_TX_web.jpg

Clues in genetic variants

Krina Zondervan, DPhil, professor and head of the department of reproductive and genomic epidemiology at the University of Oxford (England), focuses on genomic, molecular, and epidemiologic approaches to understanding endometriosis.

Zondervan_Krina_UK_web.jpg

What’s next?

The chief limitation of human studies looking at mechanisms of endometriosis is that they are correlational: Tissue samples are collected from women with and without endometriosis, often through an invasive procedure such as laparoscopy or biopsy, at one point in time. If a researcher identifies a factor that is more common in women with endometriosis – a particular bacterium or environmental exposure – proving causality is difficult. Currently, the best tools for proving causation are animal models of endometriosis, such as the those used by Dr. Kondo’s and Dr. Kommagani’s teams.

Better diagnostic tools would solve that problem. The ultimate goal is a noninvasive test for endometriosis that would allow clinicians to follow women over time and permit the monitoring of disease progression, or regression, without the need for painful procedures. Such a diagnostic tool would facilitate rigorous longitudinal studies evaluating mechanisms of disease, as well as monitoring outcomes of clinical trials of new treatments.

Could stool samples be the answer?

The Japanese team found that women harboring Fusobacterium in endometrial tissue also had Fusobacterium in vaginal samples taken at the time of their hysterectomy – and stool samples can pick up changes in the gut microbiome.

“Vaginal swab or stool tests are probably the best and easiest for noninvasive early detection,” Dr. Kommagani said. 

Spit tests for DNA would be even easier to obtain. Polygenic risk scores could be developed to estimate an individual’s risk of disease based on the number of variants, but Dr. Zondervan cautioned that not all the genes that account for endometriosis are known.

“The things that we found altogether explain about 5% of disease variability, basically – which is still not an awful lot,” she said.

Dr. Kondo’s work was supported by the Grant-in-Aid for Scientific Research, the Japan Society for the Promotion of Science, and the Research Grant of the Princess Takamatsu Cancer Research Fund. A patent method for detecting bacteria of genus Fusobacterium in order to diagnose endometriosis (WO2023/ 042714), was submitted (international publication date, March 23, 2023).

Dr. Kommagani’s work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742. He has no other conflicts of interest. Dr. Zondervan received funding from the Wellcome Trust (216767; 104036; 084766; 212904; 076113 and 085475) and also reported grants from Bayer AG, AbbVie, Volition Rx, MDNA Life Sciences, and Roche Diagnostics outside the submitted work.

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Ore.

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

In 1927, American gynecologist John Sampson published his theory of the etiology of endometriosis, postulating that retrograde flow of endometrial debris flows backward through the fallopian tubes during menses into the peritoneal cavity. Dr. Sampson’s notion remains the main paradigm today, mentioned still in recent articles on the topic, but it has a flaw: Although the theory may account for how endometrial tissue escapes the uterus, a 1984 study revealed that this phenomenon occurs in 90% of women. Why, then, do only 10% of women suffer from endometriosis?

Endometriosis describes a condition in which endometrial tissue lining the uterus is found outside the uterus. The disease can be painful, even crippling. As many as 30% of women in their reproductive years who have endometriosis are infertile as a consequence. The hallmarks of the condition are superficial peritoneal lesions of varying color, cysts in the ovaries, deeper nodules accompanied by scarring and adhesion, primarily in the pelvis but sometimes appearing outside the pelvis. The syndrome can be challenging to identify, requiring laparoscopy for definitive diagnosis.

John Sampson aside, scientists have struggled for the past century to identify the cause, or causes, of endometriosis. Hormones clearly play a role in its development, and women with endometriosis have an elevated risk of clear-cell and endometrioid ovarian cancer and autoimmune diseases. Immunodeficiency also could be to blame, if a faulty immune system fails to find and remove endometrial tissue outside of the uterus. A class of chemicals known as endocrine disruptors have been linked to endometriosis, but not definitively. Twin studies have demonstrated that as many as 50% of cases have a genetic basis, while mice with surgically induced endometriosis have been found to have a higher ratio of harmful to beneficial bacteria in their gut.

Several studies published this year point to new insights into the old mystery – with possible implications for ways to treat the disorder.

Perhaps the most surprising came out earlier this year in Science Translational Medicine, as a team of researchers in Japan reported that invasive infection by bacteria of the genus Fusobacterium may cause at least some cases of endometriosis.

Is Fusobacterium the new Helicobacter pylori?

The researchers, from Nagoya University, are the first to suggest that not only might a single bacterial genus cause endometriosis, but that antibiotic treatment could prevent progression of the disease. Using endometrial tissue obtained from 79 women undergoing hysterectomy for endometriosis and 76 women undergoing hysterectomy for other reasons (such as cervical cancer), the team started with gene expression profiling to explore differences between the two sets of samples. 

They uncovered an interesting chain of cellular events:  macrophages found in endometriotic lesions were secreting transforming growth factor-beta (TGF-beta). TGF-beta in turn stimulated high levels of expression of a gene called TAGLN in fibroblast cells from women with endometriosis but not in fibroblasts from women without endometriosis. 

Turning on TAGLN transformed these previously inactive cells into active myofibroblasts, leading to increased proliferation, mobility, and attachment to mesothelial cells, the layer of cells that line body cavities and internal organs. In short, they identified some key players in an environment that seemed very favorable to the development of endometriosis.

“So, the question is: Why are macrophages activated?” said Yutaka Kondo, MD, PhD, the senior author of the study and a professor in the division of cancer biology at the Nagoya (Japan) University Graduate School of Medicine. “We think that there are always bacteria in the endometrium.”

After reviewing data from a previously published study, they used quantitative polymerase chain reaction to rule out one candidate, Erysipelothrix, but scored on their next attempt, identifying Fusobacterium species in endometrial tissue from 64% of the women with endometriosis, compared with fewer than 10% of the controls.

To confirm that the bacteria could cause disease and were not simply bystanders, Dr. Kondo’s team turned to a mouse model for endometriosis, in which endometrial cells are surgically removed from the uteri of mice and injected into the peritoneum of recipient mice, leading to the formation of endometriotic lesions. When mice received further injections of uterine tissue from mice that were infected with F. nucleatum, their lesions were more numerous when compared with mice that received injections of uninfected uterine tissue. Furthermore, antibiotic treatment with metronidazole or chloramphenicol immediately after surgery largely prevented progression to endometriosis, Dr. Kondo and his colleagues reported.

Dr. Kondo likened this relationship between Fusobacterium and endometriosis to that of the link between Helicobacter pylori and peptic ulcers but acknowledged that he doesn’t have all the answers.

“We need more clinical trials, and also we have to know what kind of treatment might be the most effective for the treatment of endometriosis,” Dr. Kondo said, pointing out that other therapies should still be pursued in addition to antibiotics, as not all the samples from women with endometriosis harbored Fusobacterium. “It might be possible that other mechanisms are also involved.”

Don’t write off gut microbiota

Ramakrishna Kommagani, PhD, associate professor of pathology and immunology at Baylor College of Medicine in Houston, agreed. “Endometriosis is a complex disease, which appears to be impacted by many factors, including genetic, epigenetic, and environmental factors,” Dr. Kommagani said.

Kommagani_Ramakrishna_TX_web.jpg

Clues in genetic variants

Krina Zondervan, DPhil, professor and head of the department of reproductive and genomic epidemiology at the University of Oxford (England), focuses on genomic, molecular, and epidemiologic approaches to understanding endometriosis.

Zondervan_Krina_UK_web.jpg

What’s next?

The chief limitation of human studies looking at mechanisms of endometriosis is that they are correlational: Tissue samples are collected from women with and without endometriosis, often through an invasive procedure such as laparoscopy or biopsy, at one point in time. If a researcher identifies a factor that is more common in women with endometriosis – a particular bacterium or environmental exposure – proving causality is difficult. Currently, the best tools for proving causation are animal models of endometriosis, such as the those used by Dr. Kondo’s and Dr. Kommagani’s teams.

Better diagnostic tools would solve that problem. The ultimate goal is a noninvasive test for endometriosis that would allow clinicians to follow women over time and permit the monitoring of disease progression, or regression, without the need for painful procedures. Such a diagnostic tool would facilitate rigorous longitudinal studies evaluating mechanisms of disease, as well as monitoring outcomes of clinical trials of new treatments.

Could stool samples be the answer?

The Japanese team found that women harboring Fusobacterium in endometrial tissue also had Fusobacterium in vaginal samples taken at the time of their hysterectomy – and stool samples can pick up changes in the gut microbiome.

“Vaginal swab or stool tests are probably the best and easiest for noninvasive early detection,” Dr. Kommagani said. 

Spit tests for DNA would be even easier to obtain. Polygenic risk scores could be developed to estimate an individual’s risk of disease based on the number of variants, but Dr. Zondervan cautioned that not all the genes that account for endometriosis are known.

“The things that we found altogether explain about 5% of disease variability, basically – which is still not an awful lot,” she said.

Dr. Kondo’s work was supported by the Grant-in-Aid for Scientific Research, the Japan Society for the Promotion of Science, and the Research Grant of the Princess Takamatsu Cancer Research Fund. A patent method for detecting bacteria of genus Fusobacterium in order to diagnose endometriosis (WO2023/ 042714), was submitted (international publication date, March 23, 2023).

Dr. Kommagani’s work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742. He has no other conflicts of interest. Dr. Zondervan received funding from the Wellcome Trust (216767; 104036; 084766; 212904; 076113 and 085475) and also reported grants from Bayer AG, AbbVie, Volition Rx, MDNA Life Sciences, and Roche Diagnostics outside the submitted work.

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Ore.

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