The U.S. Preventive Services Task Force reaffirmed its recommendations for screening patients for HIV infection.

According to the task force, screening is recommended for all patients aged 15-65 years. Screening also is recommended for adolescents and older adults at increased risk for acquiring HIV infection and for all pregnant patients, including those in labor whose HIV status is unknown (JAMA. 2019. doi: 10.1001/jama.2019.6587).

Patients who are considered at increased risk for acquiring HIV include the following: Men who have sex with men, those who inject drugs, those who have receptive sex without a condom, those with at least one partner whose HIV status is positive or unknown, those who have transactional sex, and those who request testing for sexually transmitted infection, including HIV. All recommendations are A-level, meaning the task force recommends the service,with high certainty that the net benefit is substantial.

In a systematic review created for the task force, Roger Chou, MD, of Oregon Health & Science University, Portland, and colleagues found there continued to be no studies that examined the benefits and harms of HIV screening for HIV infections, compared with no screening, but new evidence found beginning antiretroviral therapy (ART) for patients with CD4 cell counts greater than 500/mm³ who are otherwise asymptomatic was associated with a reduced risk of mortality, compared with waiting for ART in cases of CD4 cell counts less than 350/mm³ (JAMA. 2019. doi: 10.1001/jama.2019.2592).

A second systematic review of pregnant patients by Shelley S. Selph, MD, also of Oregon Health & Science University, Portland, and colleagues found no studies examining the effectiveness of prenatal screening on mother-to-child HIV transmission, but combination ART was significantly effective at reducing transmission between mother and child, while ART that includes a boosted protease inhibitor may result in preterm delivery (JAMA. 2019. doi: 10.1001/jama.2019.2593).

Although no studies have been conducted that compare the benefits of screening with not screening for HIV, the task force concluded with “high certainty” that early HIV detection and treatment has “substantial benefits.”

“Clinicians can make a real difference toward reducing the burden of HIV in the United States,” Douglas K. Owens, MD, task force chairman, said in a statement. “HIV screening and HIV prevention work to reduce new HIV infections and ultimately save lives.”

The USPSTF is a voluntary, independent body, with operations supported by the U.S. Agency for Healthcare Research and Quality. Task force members received travel reimbursement and an honorarium for attending meetings. Dr. Owens reports financial disclosures with relation to HIV infection screening, preexposure prophylaxis for HIV prevention, and hepatitis C screening. Other task force members reported no relevant conflicts of interest.

SOURCE: JAMA. 2019. doi: 10.1001/jama.2019.6587.

The U.S. Preventive Services Task Force reaffirmed its recommendations for screening patients for HIV infection.

According to the task force, screening is recommended for all patients aged 15-65 years. Screening also is recommended for adolescents and older adults at increased risk for acquiring HIV infection and for all pregnant patients, including those in labor whose HIV status is unknown (JAMA. 2019. doi: 10.1001/jama.2019.6587).

Patients who are considered at increased risk for acquiring HIV include the following: Men who have sex with men, those who inject drugs, those who have receptive sex without a condom, those with at least one partner whose HIV status is positive or unknown, those who have transactional sex, and those who request testing for sexually transmitted infection, including HIV. All recommendations are A-level, meaning the task force recommends the service,with high certainty that the net benefit is substantial.

In a systematic review created for the task force, Roger Chou, MD, of Oregon Health & Science University, Portland, and colleagues found there continued to be no studies that examined the benefits and harms of HIV screening for HIV infections, compared with no screening, but new evidence found beginning antiretroviral therapy (ART) for patients with CD4 cell counts greater than 500/mm³ who are otherwise asymptomatic was associated with a reduced risk of mortality, compared with waiting for ART in cases of CD4 cell counts less than 350/mm³ (JAMA. 2019. doi: 10.1001/jama.2019.2592).

A second systematic review of pregnant patients by Shelley S. Selph, MD, also of Oregon Health & Science University, Portland, and colleagues found no studies examining the effectiveness of prenatal screening on mother-to-child HIV transmission, but combination ART was significantly effective at reducing transmission between mother and child, while ART that includes a boosted protease inhibitor may result in preterm delivery (JAMA. 2019. doi: 10.1001/jama.2019.2593).

Although no studies have been conducted that compare the benefits of screening with not screening for HIV, the task force concluded with “high certainty” that early HIV detection and treatment has “substantial benefits.”

“Clinicians can make a real difference toward reducing the burden of HIV in the United States,” Douglas K. Owens, MD, task force chairman, said in a statement. “HIV screening and HIV prevention work to reduce new HIV infections and ultimately save lives.”

The USPSTF is a voluntary, independent body, with operations supported by the U.S. Agency for Healthcare Research and Quality. Task force members received travel reimbursement and an honorarium for attending meetings. Dr. Owens reports financial disclosures with relation to HIV infection screening, preexposure prophylaxis for HIV prevention, and hepatitis C screening. Other task force members reported no relevant conflicts of interest.

SOURCE: JAMA. 2019. doi: 10.1001/jama.2019.6587.

The U.S. Preventive Services Task Force reaffirmed its recommendations for screening patients for HIV infection.

According to the task force, screening is recommended for all patients aged 15-65 years. Screening also is recommended for adolescents and older adults at increased risk for acquiring HIV infection and for all pregnant patients, including those in labor whose HIV status is unknown (JAMA. 2019. doi: 10.1001/jama.2019.6587).

Patients who are considered at increased risk for acquiring HIV include the following: Men who have sex with men, those who inject drugs, those who have receptive sex without a condom, those with at least one partner whose HIV status is positive or unknown, those who have transactional sex, and those who request testing for sexually transmitted infection, including HIV. All recommendations are A-level, meaning the task force recommends the service,with high certainty that the net benefit is substantial.

In a systematic review created for the task force, Roger Chou, MD, of Oregon Health & Science University, Portland, and colleagues found there continued to be no studies that examined the benefits and harms of HIV screening for HIV infections, compared with no screening, but new evidence found beginning antiretroviral therapy (ART) for patients with CD4 cell counts greater than 500/mm³ who are otherwise asymptomatic was associated with a reduced risk of mortality, compared with waiting for ART in cases of CD4 cell counts less than 350/mm³ (JAMA. 2019. doi: 10.1001/jama.2019.2592).

A second systematic review of pregnant patients by Shelley S. Selph, MD, also of Oregon Health & Science University, Portland, and colleagues found no studies examining the effectiveness of prenatal screening on mother-to-child HIV transmission, but combination ART was significantly effective at reducing transmission between mother and child, while ART that includes a boosted protease inhibitor may result in preterm delivery (JAMA. 2019. doi: 10.1001/jama.2019.2593).

Although no studies have been conducted that compare the benefits of screening with not screening for HIV, the task force concluded with “high certainty” that early HIV detection and treatment has “substantial benefits.”

“Clinicians can make a real difference toward reducing the burden of HIV in the United States,” Douglas K. Owens, MD, task force chairman, said in a statement. “HIV screening and HIV prevention work to reduce new HIV infections and ultimately save lives.”

The USPSTF is a voluntary, independent body, with operations supported by the U.S. Agency for Healthcare Research and Quality. Task force members received travel reimbursement and an honorarium for attending meetings. Dr. Owens reports financial disclosures with relation to HIV infection screening, preexposure prophylaxis for HIV prevention, and hepatitis C screening. Other task force members reported no relevant conflicts of interest.

SOURCE: JAMA. 2019. doi: 10.1001/jama.2019.6587.

Hypertension is one of the most common reasons for patient visits.¹ According to the US Preventive Services Task Force, more than 70 million individuals older than 20 have hypertension, which is defined as a blood pressure (BP) of ≥ 130/85 mm Hg.² Essential hypertension is the most common form of this condition; most affected patients will show improvement with evidence-based pharmacologic treatment, lifestyle modifications, and risk factor reductions.

For patients with refractory hypertension, however, identifying what steps to take in screening and diagnosis can be daunting for clinicians. It is important to identify cases of secondary hypertension, because if it is left undiagnosed and untreated, serious complications—such as cardiovascular and renal disease—are likely to occur.^3,4

Secondary hypertension can be caused by myriad disease states and disorders, including endocrine ­disorders, renal disease, neurologic disorders, acute stress, and drug-induced hypertension.⁵ Endocrine hypertension is most commonly caused by adrenal gland disorders, including primary aldosteronism, Cushing syndrome, and pheochromocytoma. (Of note, Cushing syndrome is caused by glucocorticoid-secreting adrenal tumors, while Cushing disease is a condition in which there is glucocorticoid excess caused by oversecretion of pituitary adrenocorticotropic hormone.⁶ Cushing disease is more common than Cushing syndrome, which is rare.⁷) While nonadrenal endocrine disorders are not as common, they pose significant health issues, including growth hormone excess or deficiency, thyroid disorders, testosterone deficiency, obesity, insulin resistance, and metabolic syndrome.⁸

Understanding the endocrine causes of hypertension is a valuable resource for clinicians to have in their toolbox. Although the negative consequences of endocrine disorders are significant, these conditions are often recognizable, and pharmacologic treatment and/or surgical interventions can potentially resolve or improve hypertension and reduce risk for other comorbidities. This article summarizes screening and diagnosis guidelines for several possible causes of endocrine hypertension: primary aldosteronism, Cushing syndrome, and pheochromocytoma.

PRIMARY ALDOSTERONISM

Primary aldosteronism occurs in 5% to 10% of all hypertensive patients and is a common cause of secondary and endocrine hypertension (although in younger—particularly female—patients, it most commonly causes renal artery stenosis).^9,10 Historically, primary aldosteronism was considered rare and not generally included in a differential diagnosis for patients presenting with resistant hypertension. However, clinical investigations have indicated that primary aldosteronism is more prevalent than previously thought.¹¹

Patients develop this condition when there is increased aldosterone production independent of the renin-angiotensin system. The resulting sodium retention can lead to hypertension, hypokalemia, and high plasma aldosterone/renin ratio (ARR).¹² Clinical findings and symptoms can be vague, increasing the difficulty in identifying primary aldosteronism as the diagnosis. Patients may be asymptomatic, with the only abnormal lab finding being hypokalemia (an infrequent finding, affecting < 25% of patients).¹³ If hypokalemia is present, symptoms can include nocturia, polyuria, muscle weakness, cramps, paresthesias, and palpitations.¹¹

The Endocrine Society has identified 8 characteristics that increase the likelihood of primary aldosteronism. Patients require further screening if they

1. Have a sustained elevated BP (≥ 150 mm Hg [systolic] and/or 100 mm Hg [diastolic])
2. Have hypertension (BP > 140/90 mm Hg) that is resistant to 3 conventional antihypertensive drugs, including a diuretic
3. Have controlled BP (BP < 140/90 mm Hg) with ≥ 4 antihypertensive drugs
4. Have hypertension and spontaneous or diuretic-induced hypokalemia
5. Have hypertension and adrenal incidentaloma
6. Have hypertension and obstructive sleep apnea
7. Have hypertension and a family history of early-onset hypertension or a cerebrovascular accident at a young age (< 40 years)
8. Are hypertensive and a first-degree relative of a patient with primary aldosteronism.¹⁴

Continue to: The most reliable screening test...

The most reliable screening test for primary aldosterone is the ARR, although false-negative and false-positive results are possible.¹¹ False-negative results can be caused by dietary salt restriction, hypokalemia, and use of medications including diuretics, calcium channel blockers, ACE inhibitors, and angiotensin receptor antagonists. Use of ß-adrenergic blockers, α-methyldopa, or NSAIDs can cause false-positive results.¹⁵ Patients should be encouraged to follow a liberal sodium diet before ARR testing, and efforts to correct hypokalemia should be implemented. Before ARR is measured, diuretics (specifically spironolactone) should be stopped for at least 4 weeks; other possible interfering medications should be stopped for at least 2 weeks.¹⁶

The ARR should be obtained multiple times to confirm elevated readings.¹⁶ Reference ranges vary, but generally plasma aldosterone concentrations > 20 ng/dL and plasma renin activity < 1 ng/mL/h indicate whether confirmatory testing should be completed.¹⁴ Further confirmatory testing can be achieved with efforts to suppress plasma aldosterone to < 10 ng/dL after an IV infusion of 2 L isotonic saline over 4 hours.¹² Oral sodium load is used as well and usually before IV infusion.

CUSHING SYNDROME

Cushing syndrome is caused by excess circulating levels of glucocorticoids and affects < 0.1% of the world population.¹⁷ Signs and symptoms include centripetal obesity, moon facies, facial plethora, easy bruising, buffalo hump (or posterior cervical fat pad), hirsutism, and wide-purple striae.¹⁸ Up to 80% of these patients also have hypertension.¹⁹ If these patients have chronic exposure to high levels of glucocorticoid (the most common source being therapeutic administration of exogenous glucocorticoids), multiple complications can occur.^6,20

The Endocrine Society Clinical Practice Guideline recommends the following patient groups be tested for Cushing syndrome:

1. Young patients with unusual medical conditions, such as osteoporosis and resistant hypertension
2. Patients with classic signs and symptoms, such as easy bruising, weight gain, facial plethora, and purple striae
3. Children with decreasing height percentile and increasing weight
4. Patients with adrenal incidentaloma compatible with adenoma.¹⁸

If Cushing syndrome is suspected, 1 of the following 3 initial tests can be completed: 24-hour, urine-free cortisol and creatinine; late-night salivary cortisol; or 1-mg overnight dexamethasone suppression test. Two of these tests must have abnormal results for confirmation before appropriate pituitary or adrenal imaging. If a patient has clinical features indicating Cushing syndrome but test results are normal, he or she should be referred to an endocrinologist. If a patient has ≥ 2 normal tests and probability of Cushing syndrome is unlikely, patients should be recommended for follow-up in 6 months to evaluate for any worsening of symptoms.¹⁸

Continue to: PHEOCHROMOCYTOMA

Pheochromocytoma is a condition in which there is secretion of excess catecholamines, epinephrine, norepinephrine, and dopamine due to a tumor of the adrenal medulla.²¹ This is a rare disease and accounts for only 0.2% to 0.6% of all causes of hypertension.²² Hypertension (persistent or paroxysmal) is the most common finding for patients with pheochromocy­toma, with 80% to 90% presenting with this finding.²³ It is important to note that approximately 10% of these patients will be normotensive. Three of the condition’s classic symptoms are headache, sweating, and palpitations.²⁴ Additional symptoms include anxiety, sense of impending doom, fever, nausea, or vomiting.²¹

If left untreated, there is risk for hypertensive retinopathy, nephropathy, myocardial infarction, stroke from cerebral infarction, intracranial hemorrhage, or embolism.²⁵ Due to the high rate of morbidity and mortality with untreated pheochromocytoma, laboratory testing should be initiated immediately upon suspicion of this diagnosis or if the patient has relevant family history.¹¹

Patients should be screened for pheochromocytoma if they have ≥ 1 of the following factors:

1. Resistant hypertension and hyperadrenergic symptoms (palpitations, perspiration, pallor, or headache)
2. Family history of pheochromocytoma
3. Any genetic syndrome with a known association to pheochromocytoma
4. An adrenal mass that is > 4 cm, is cystic, or has hemorrhagic changes.¹⁹

Pheochromocytoma is diagnosed by identifying high concentrations of plasma-free metanephrines or 24-hour fractionated metanephrines and catecholamines. Some medications can interfere with the accuracy of lab results and therefore may need to be temporarily stopped; it is important to check the specific lab guidelines and review the patient’s medication lists before tests are ordered and conducted.²⁵

ALWAYS SCREEN THE PATIENT

Although the causes of endocrine-related hypertension are very rare, screening for endocrine hypertension in patients who present with signs and symptoms of these conditions can greatly improve their lives. The endocrine disorders discussed in this article can be treated or controlled with appropriate diagnosis and treatment. In addition, resolving uncontrolled hypertension by addressing endocrine disorders can reduce the risk for long-term sequelae. It is important for clinicians to consider referral to an endocrine specialist if a patient has endocrine-related hypertension. In particular, patients with pheochromocytoma require quick referral due to a risk for high morbidity and mortality if left untreated.¹¹

Hypertension is one of the most common reasons for patient visits.¹ According to the US Preventive Services Task Force, more than 70 million individuals older than 20 have hypertension, which is defined as a blood pressure (BP) of ≥ 130/85 mm Hg.² Essential hypertension is the most common form of this condition; most affected patients will show improvement with evidence-based pharmacologic treatment, lifestyle modifications, and risk factor reductions.

For patients with refractory hypertension, however, identifying what steps to take in screening and diagnosis can be daunting for clinicians. It is important to identify cases of secondary hypertension, because if it is left undiagnosed and untreated, serious complications—such as cardiovascular and renal disease—are likely to occur.^3,4

Secondary hypertension can be caused by myriad disease states and disorders, including endocrine ­disorders, renal disease, neurologic disorders, acute stress, and drug-induced hypertension.⁵ Endocrine hypertension is most commonly caused by adrenal gland disorders, including primary aldosteronism, Cushing syndrome, and pheochromocytoma. (Of note, Cushing syndrome is caused by glucocorticoid-secreting adrenal tumors, while Cushing disease is a condition in which there is glucocorticoid excess caused by oversecretion of pituitary adrenocorticotropic hormone.⁶ Cushing disease is more common than Cushing syndrome, which is rare.⁷) While nonadrenal endocrine disorders are not as common, they pose significant health issues, including growth hormone excess or deficiency, thyroid disorders, testosterone deficiency, obesity, insulin resistance, and metabolic syndrome.⁸

Understanding the endocrine causes of hypertension is a valuable resource for clinicians to have in their toolbox. Although the negative consequences of endocrine disorders are significant, these conditions are often recognizable, and pharmacologic treatment and/or surgical interventions can potentially resolve or improve hypertension and reduce risk for other comorbidities. This article summarizes screening and diagnosis guidelines for several possible causes of endocrine hypertension: primary aldosteronism, Cushing syndrome, and pheochromocytoma.

PRIMARY ALDOSTERONISM

Primary aldosteronism occurs in 5% to 10% of all hypertensive patients and is a common cause of secondary and endocrine hypertension (although in younger—particularly female—patients, it most commonly causes renal artery stenosis).^9,10 Historically, primary aldosteronism was considered rare and not generally included in a differential diagnosis for patients presenting with resistant hypertension. However, clinical investigations have indicated that primary aldosteronism is more prevalent than previously thought.¹¹

Patients develop this condition when there is increased aldosterone production independent of the renin-angiotensin system. The resulting sodium retention can lead to hypertension, hypokalemia, and high plasma aldosterone/renin ratio (ARR).¹² Clinical findings and symptoms can be vague, increasing the difficulty in identifying primary aldosteronism as the diagnosis. Patients may be asymptomatic, with the only abnormal lab finding being hypokalemia (an infrequent finding, affecting < 25% of patients).¹³ If hypokalemia is present, symptoms can include nocturia, polyuria, muscle weakness, cramps, paresthesias, and palpitations.¹¹

The Endocrine Society has identified 8 characteristics that increase the likelihood of primary aldosteronism. Patients require further screening if they

1. Have a sustained elevated BP (≥ 150 mm Hg [systolic] and/or 100 mm Hg [diastolic])
2. Have hypertension (BP > 140/90 mm Hg) that is resistant to 3 conventional antihypertensive drugs, including a diuretic
3. Have controlled BP (BP < 140/90 mm Hg) with ≥ 4 antihypertensive drugs
4. Have hypertension and spontaneous or diuretic-induced hypokalemia
5. Have hypertension and adrenal incidentaloma
6. Have hypertension and obstructive sleep apnea
7. Have hypertension and a family history of early-onset hypertension or a cerebrovascular accident at a young age (< 40 years)
8. Are hypertensive and a first-degree relative of a patient with primary aldosteronism.¹⁴

Continue to: The most reliable screening test...

The most reliable screening test for primary aldosterone is the ARR, although false-negative and false-positive results are possible.¹¹ False-negative results can be caused by dietary salt restriction, hypokalemia, and use of medications including diuretics, calcium channel blockers, ACE inhibitors, and angiotensin receptor antagonists. Use of ß-adrenergic blockers, α-methyldopa, or NSAIDs can cause false-positive results.¹⁵ Patients should be encouraged to follow a liberal sodium diet before ARR testing, and efforts to correct hypokalemia should be implemented. Before ARR is measured, diuretics (specifically spironolactone) should be stopped for at least 4 weeks; other possible interfering medications should be stopped for at least 2 weeks.¹⁶

The ARR should be obtained multiple times to confirm elevated readings.¹⁶ Reference ranges vary, but generally plasma aldosterone concentrations > 20 ng/dL and plasma renin activity < 1 ng/mL/h indicate whether confirmatory testing should be completed.¹⁴ Further confirmatory testing can be achieved with efforts to suppress plasma aldosterone to < 10 ng/dL after an IV infusion of 2 L isotonic saline over 4 hours.¹² Oral sodium load is used as well and usually before IV infusion.

CUSHING SYNDROME

Cushing syndrome is caused by excess circulating levels of glucocorticoids and affects < 0.1% of the world population.¹⁷ Signs and symptoms include centripetal obesity, moon facies, facial plethora, easy bruising, buffalo hump (or posterior cervical fat pad), hirsutism, and wide-purple striae.¹⁸ Up to 80% of these patients also have hypertension.¹⁹ If these patients have chronic exposure to high levels of glucocorticoid (the most common source being therapeutic administration of exogenous glucocorticoids), multiple complications can occur.^6,20

The Endocrine Society Clinical Practice Guideline recommends the following patient groups be tested for Cushing syndrome:

1. Young patients with unusual medical conditions, such as osteoporosis and resistant hypertension
2. Patients with classic signs and symptoms, such as easy bruising, weight gain, facial plethora, and purple striae
3. Children with decreasing height percentile and increasing weight
4. Patients with adrenal incidentaloma compatible with adenoma.¹⁸

If Cushing syndrome is suspected, 1 of the following 3 initial tests can be completed: 24-hour, urine-free cortisol and creatinine; late-night salivary cortisol; or 1-mg overnight dexamethasone suppression test. Two of these tests must have abnormal results for confirmation before appropriate pituitary or adrenal imaging. If a patient has clinical features indicating Cushing syndrome but test results are normal, he or she should be referred to an endocrinologist. If a patient has ≥ 2 normal tests and probability of Cushing syndrome is unlikely, patients should be recommended for follow-up in 6 months to evaluate for any worsening of symptoms.¹⁸

Continue to: PHEOCHROMOCYTOMA

Pheochromocytoma is a condition in which there is secretion of excess catecholamines, epinephrine, norepinephrine, and dopamine due to a tumor of the adrenal medulla.²¹ This is a rare disease and accounts for only 0.2% to 0.6% of all causes of hypertension.²² Hypertension (persistent or paroxysmal) is the most common finding for patients with pheochromocy­toma, with 80% to 90% presenting with this finding.²³ It is important to note that approximately 10% of these patients will be normotensive. Three of the condition’s classic symptoms are headache, sweating, and palpitations.²⁴ Additional symptoms include anxiety, sense of impending doom, fever, nausea, or vomiting.²¹

If left untreated, there is risk for hypertensive retinopathy, nephropathy, myocardial infarction, stroke from cerebral infarction, intracranial hemorrhage, or embolism.²⁵ Due to the high rate of morbidity and mortality with untreated pheochromocytoma, laboratory testing should be initiated immediately upon suspicion of this diagnosis or if the patient has relevant family history.¹¹

Patients should be screened for pheochromocytoma if they have ≥ 1 of the following factors:

1. Resistant hypertension and hyperadrenergic symptoms (palpitations, perspiration, pallor, or headache)
2. Family history of pheochromocytoma
3. Any genetic syndrome with a known association to pheochromocytoma
4. An adrenal mass that is > 4 cm, is cystic, or has hemorrhagic changes.¹⁹

Pheochromocytoma is diagnosed by identifying high concentrations of plasma-free metanephrines or 24-hour fractionated metanephrines and catecholamines. Some medications can interfere with the accuracy of lab results and therefore may need to be temporarily stopped; it is important to check the specific lab guidelines and review the patient’s medication lists before tests are ordered and conducted.²⁵

ALWAYS SCREEN THE PATIENT

Although the causes of endocrine-related hypertension are very rare, screening for endocrine hypertension in patients who present with signs and symptoms of these conditions can greatly improve their lives. The endocrine disorders discussed in this article can be treated or controlled with appropriate diagnosis and treatment. In addition, resolving uncontrolled hypertension by addressing endocrine disorders can reduce the risk for long-term sequelae. It is important for clinicians to consider referral to an endocrine specialist if a patient has endocrine-related hypertension. In particular, patients with pheochromocytoma require quick referral due to a risk for high morbidity and mortality if left untreated.¹¹

Hypertension is one of the most common reasons for patient visits.¹ According to the US Preventive Services Task Force, more than 70 million individuals older than 20 have hypertension, which is defined as a blood pressure (BP) of ≥ 130/85 mm Hg.² Essential hypertension is the most common form of this condition; most affected patients will show improvement with evidence-based pharmacologic treatment, lifestyle modifications, and risk factor reductions.

For patients with refractory hypertension, however, identifying what steps to take in screening and diagnosis can be daunting for clinicians. It is important to identify cases of secondary hypertension, because if it is left undiagnosed and untreated, serious complications—such as cardiovascular and renal disease—are likely to occur.^3,4

Secondary hypertension can be caused by myriad disease states and disorders, including endocrine ­disorders, renal disease, neurologic disorders, acute stress, and drug-induced hypertension.⁵ Endocrine hypertension is most commonly caused by adrenal gland disorders, including primary aldosteronism, Cushing syndrome, and pheochromocytoma. (Of note, Cushing syndrome is caused by glucocorticoid-secreting adrenal tumors, while Cushing disease is a condition in which there is glucocorticoid excess caused by oversecretion of pituitary adrenocorticotropic hormone.⁶ Cushing disease is more common than Cushing syndrome, which is rare.⁷) While nonadrenal endocrine disorders are not as common, they pose significant health issues, including growth hormone excess or deficiency, thyroid disorders, testosterone deficiency, obesity, insulin resistance, and metabolic syndrome.⁸

Understanding the endocrine causes of hypertension is a valuable resource for clinicians to have in their toolbox. Although the negative consequences of endocrine disorders are significant, these conditions are often recognizable, and pharmacologic treatment and/or surgical interventions can potentially resolve or improve hypertension and reduce risk for other comorbidities. This article summarizes screening and diagnosis guidelines for several possible causes of endocrine hypertension: primary aldosteronism, Cushing syndrome, and pheochromocytoma.

PRIMARY ALDOSTERONISM

Primary aldosteronism occurs in 5% to 10% of all hypertensive patients and is a common cause of secondary and endocrine hypertension (although in younger—particularly female—patients, it most commonly causes renal artery stenosis).^9,10 Historically, primary aldosteronism was considered rare and not generally included in a differential diagnosis for patients presenting with resistant hypertension. However, clinical investigations have indicated that primary aldosteronism is more prevalent than previously thought.¹¹

Patients develop this condition when there is increased aldosterone production independent of the renin-angiotensin system. The resulting sodium retention can lead to hypertension, hypokalemia, and high plasma aldosterone/renin ratio (ARR).¹² Clinical findings and symptoms can be vague, increasing the difficulty in identifying primary aldosteronism as the diagnosis. Patients may be asymptomatic, with the only abnormal lab finding being hypokalemia (an infrequent finding, affecting < 25% of patients).¹³ If hypokalemia is present, symptoms can include nocturia, polyuria, muscle weakness, cramps, paresthesias, and palpitations.¹¹

The Endocrine Society has identified 8 characteristics that increase the likelihood of primary aldosteronism. Patients require further screening if they

1. Have a sustained elevated BP (≥ 150 mm Hg [systolic] and/or 100 mm Hg [diastolic])
2. Have hypertension (BP > 140/90 mm Hg) that is resistant to 3 conventional antihypertensive drugs, including a diuretic
3. Have controlled BP (BP < 140/90 mm Hg) with ≥ 4 antihypertensive drugs
4. Have hypertension and spontaneous or diuretic-induced hypokalemia
5. Have hypertension and adrenal incidentaloma
6. Have hypertension and obstructive sleep apnea
7. Have hypertension and a family history of early-onset hypertension or a cerebrovascular accident at a young age (< 40 years)
8. Are hypertensive and a first-degree relative of a patient with primary aldosteronism.¹⁴

Continue to: The most reliable screening test...

The most reliable screening test for primary aldosterone is the ARR, although false-negative and false-positive results are possible.¹¹ False-negative results can be caused by dietary salt restriction, hypokalemia, and use of medications including diuretics, calcium channel blockers, ACE inhibitors, and angiotensin receptor antagonists. Use of ß-adrenergic blockers, α-methyldopa, or NSAIDs can cause false-positive results.¹⁵ Patients should be encouraged to follow a liberal sodium diet before ARR testing, and efforts to correct hypokalemia should be implemented. Before ARR is measured, diuretics (specifically spironolactone) should be stopped for at least 4 weeks; other possible interfering medications should be stopped for at least 2 weeks.¹⁶

The ARR should be obtained multiple times to confirm elevated readings.¹⁶ Reference ranges vary, but generally plasma aldosterone concentrations > 20 ng/dL and plasma renin activity < 1 ng/mL/h indicate whether confirmatory testing should be completed.¹⁴ Further confirmatory testing can be achieved with efforts to suppress plasma aldosterone to < 10 ng/dL after an IV infusion of 2 L isotonic saline over 4 hours.¹² Oral sodium load is used as well and usually before IV infusion.

CUSHING SYNDROME

Cushing syndrome is caused by excess circulating levels of glucocorticoids and affects < 0.1% of the world population.¹⁷ Signs and symptoms include centripetal obesity, moon facies, facial plethora, easy bruising, buffalo hump (or posterior cervical fat pad), hirsutism, and wide-purple striae.¹⁸ Up to 80% of these patients also have hypertension.¹⁹ If these patients have chronic exposure to high levels of glucocorticoid (the most common source being therapeutic administration of exogenous glucocorticoids), multiple complications can occur.^6,20

The Endocrine Society Clinical Practice Guideline recommends the following patient groups be tested for Cushing syndrome:

1. Young patients with unusual medical conditions, such as osteoporosis and resistant hypertension
2. Patients with classic signs and symptoms, such as easy bruising, weight gain, facial plethora, and purple striae
3. Children with decreasing height percentile and increasing weight
4. Patients with adrenal incidentaloma compatible with adenoma.¹⁸

If Cushing syndrome is suspected, 1 of the following 3 initial tests can be completed: 24-hour, urine-free cortisol and creatinine; late-night salivary cortisol; or 1-mg overnight dexamethasone suppression test. Two of these tests must have abnormal results for confirmation before appropriate pituitary or adrenal imaging. If a patient has clinical features indicating Cushing syndrome but test results are normal, he or she should be referred to an endocrinologist. If a patient has ≥ 2 normal tests and probability of Cushing syndrome is unlikely, patients should be recommended for follow-up in 6 months to evaluate for any worsening of symptoms.¹⁸

Continue to: PHEOCHROMOCYTOMA

Pheochromocytoma is a condition in which there is secretion of excess catecholamines, epinephrine, norepinephrine, and dopamine due to a tumor of the adrenal medulla.²¹ This is a rare disease and accounts for only 0.2% to 0.6% of all causes of hypertension.²² Hypertension (persistent or paroxysmal) is the most common finding for patients with pheochromocy­toma, with 80% to 90% presenting with this finding.²³ It is important to note that approximately 10% of these patients will be normotensive. Three of the condition’s classic symptoms are headache, sweating, and palpitations.²⁴ Additional symptoms include anxiety, sense of impending doom, fever, nausea, or vomiting.²¹

If left untreated, there is risk for hypertensive retinopathy, nephropathy, myocardial infarction, stroke from cerebral infarction, intracranial hemorrhage, or embolism.²⁵ Due to the high rate of morbidity and mortality with untreated pheochromocytoma, laboratory testing should be initiated immediately upon suspicion of this diagnosis or if the patient has relevant family history.¹¹

Patients should be screened for pheochromocytoma if they have ≥ 1 of the following factors:

1. Resistant hypertension and hyperadrenergic symptoms (palpitations, perspiration, pallor, or headache)
2. Family history of pheochromocytoma
3. Any genetic syndrome with a known association to pheochromocytoma
4. An adrenal mass that is > 4 cm, is cystic, or has hemorrhagic changes.¹⁹

Pheochromocytoma is diagnosed by identifying high concentrations of plasma-free metanephrines or 24-hour fractionated metanephrines and catecholamines. Some medications can interfere with the accuracy of lab results and therefore may need to be temporarily stopped; it is important to check the specific lab guidelines and review the patient’s medication lists before tests are ordered and conducted.²⁵

ALWAYS SCREEN THE PATIENT

Although the causes of endocrine-related hypertension are very rare, screening for endocrine hypertension in patients who present with signs and symptoms of these conditions can greatly improve their lives. The endocrine disorders discussed in this article can be treated or controlled with appropriate diagnosis and treatment. In addition, resolving uncontrolled hypertension by addressing endocrine disorders can reduce the risk for long-term sequelae. It is important for clinicians to consider referral to an endocrine specialist if a patient has endocrine-related hypertension. In particular, patients with pheochromocytoma require quick referral due to a risk for high morbidity and mortality if left untreated.¹¹

PHILADELPHIA – Mutant huntingtin and neurofilament light are valid potential biomarkers in Huntington’s disease and could be used in future clinical trials, according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.

Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.

To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.

The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.

Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.

When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.

Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.

All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.

In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).

Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”

The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.

This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
 

This article was updated 6/18/19.

[email protected]

SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.

PHILADELPHIA – Mutant huntingtin and neurofilament light are valid potential biomarkers in Huntington’s disease and could be used in future clinical trials, according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.

Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.

To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.

The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.

Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.

When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.

Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.

All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.

In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).

Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”

The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.

This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
 

This article was updated 6/18/19.

[email protected]

SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.

PHILADELPHIA – Mutant huntingtin and neurofilament light are valid potential biomarkers in Huntington’s disease and could be used in future clinical trials, according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.

Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.

To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.

The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.

Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.

When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.

Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.

All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.

In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).

Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”

The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.

This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
 

This article was updated 6/18/19.

[email protected]

SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.

CHICAGO – Nearly two-thirds of more than 400 U.S.-based physician members of the Society of Gynecologic Oncology who participated in a recent survey reported experiencing sexual harassment in training or practice.

Notably, of the 255 women and 147 men who responded, 71% and 51%, respectively, reported such sexual harassment – and only 15% overall reported it to officials, Marina Stasenko, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The survey also addressed gender-based discrimination and disparities, including respondents’ views on pay disparities. In this video interview, Dr. Stasenko, a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, discusses the findings, their implications and context in this age of #MeToo and #TimesUp, and potential approaches to addressing the ongoing problem and the concerns victims have about reporting harassment.

“We need to start by setting an example, saying these things are not tolerated [and] put that into policy – really show folks how it can be reported and what is being done once that report is filed,” she said.

Dr. Stasenko reported having no disclosures.

[email protected]

SOURCE: Stasenko M et al. ASCO 2019, Abstract LBA10502.

CHICAGO – Nearly two-thirds of more than 400 U.S.-based physician members of the Society of Gynecologic Oncology who participated in a recent survey reported experiencing sexual harassment in training or practice.

Notably, of the 255 women and 147 men who responded, 71% and 51%, respectively, reported such sexual harassment – and only 15% overall reported it to officials, Marina Stasenko, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The survey also addressed gender-based discrimination and disparities, including respondents’ views on pay disparities. In this video interview, Dr. Stasenko, a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, discusses the findings, their implications and context in this age of #MeToo and #TimesUp, and potential approaches to addressing the ongoing problem and the concerns victims have about reporting harassment.

“We need to start by setting an example, saying these things are not tolerated [and] put that into policy – really show folks how it can be reported and what is being done once that report is filed,” she said.

Dr. Stasenko reported having no disclosures.

[email protected]

SOURCE: Stasenko M et al. ASCO 2019, Abstract LBA10502.

CHICAGO – Nearly two-thirds of more than 400 U.S.-based physician members of the Society of Gynecologic Oncology who participated in a recent survey reported experiencing sexual harassment in training or practice.

Notably, of the 255 women and 147 men who responded, 71% and 51%, respectively, reported such sexual harassment – and only 15% overall reported it to officials, Marina Stasenko, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The survey also addressed gender-based discrimination and disparities, including respondents’ views on pay disparities. In this video interview, Dr. Stasenko, a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, discusses the findings, their implications and context in this age of #MeToo and #TimesUp, and potential approaches to addressing the ongoing problem and the concerns victims have about reporting harassment.

“We need to start by setting an example, saying these things are not tolerated [and] put that into policy – really show folks how it can be reported and what is being done once that report is filed,” she said.

Dr. Stasenko reported having no disclosures.

[email protected]

SOURCE: Stasenko M et al. ASCO 2019, Abstract LBA10502.

SAN FRANCISCO – Baroreflex activation therapy met all four of its primary endpoints in its U.S. pivotal trial of 264 patients with advanced heart failure with reduced ejection fraction who were ineligible for cardiac resynchronization therapy.

Mitchel L. Zoler/MDedge News

The results showed that ongoing baroreflex activation therapy (BAT) via a single, stimulating electrode surgically placed on a patient’s carotid artery led to statistically significant and clinically meaningful improvements in quality of life and functional capacity while also reducing the level of a biomarker of heart failure severity in patients already on guideline-directed medical therapy, Michael R. Zile, MD, said at the annual scientific sessions of the Heart Rhythm Society. He estimated that the device is appropriate for perhaps a third or more of patients with heart failure with reduced ejection fraction (HFrEF), specifically patients with New York Heart Association functional class III disease who are not candidates for treatment with cardiac resynchronization therapy (CRT) and with a blood level of N-terminal pro–brain natriuretic peptide (NT-proBNP) of less than 1,600 pg/mL, a cutoff that excludes patients with very severe class III HFrEF and focuses on those who benefited in the study.

“To our knowledge, this is the first successful pivotal trial of device-based neuromodulation therapy in HFrEF patients,” said Dr. Zile, professor of medicine at the Medical University of South Carolina in Charleston. “We think that BAT fills an unmet need” in a large number of HFrEF patients. He stressed that the placement of the single, 2-mm, unilateral electrode on the baroreceptor-containing carotid sinus is an “extremely safe and simple” surgery. The electrode attaches to a small, subcutaneously placed generator.

Dr. Zile attributed the treatment’s success, in contrast to a prior, failed attempt to treat HFrEF by vagus nerve stimulation (J Am Coll Cardiol. 2016 Jul 12;68[2]:147-56) to BAT’s action via the patient’s brain, which processes the afferent signal it receives from stimulation to in turn inhibit sympathetic activation and upregulate parasympathetic innervation, with both actions benefiting HFrEF patients. “The integrated autonomic balance is the real difference with this device,” he said. Other helpful effects from BAT are reduced heart rate, reduced cardiac remodeling, increased vasodilation, a decrease in elevated blood pressure, increased diuresis, and a drop in renin secretion. The pivotal trial built on findings from a phase 2 study (JACC Heart Fail. 2015 Jun;3[6]:487-96).

Mitchel L. Zoler/MDedge News

These results “reconfirm the safety of BAT,” but are limited by a relatively short follow-up of 6 months, no data on survival benefit, and by not having echocardiographic data on possible cardiac remodeling, commented Sanjeev Saksena, MD, medical director of the Electrophysiology Research Foundation in Warren, N.J.

BeAT-HF was sponsored by CVRx, the company developing the baroreflex activation device. Dr. Zile has been a consultant to CVRx and to Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, and Novartis. Dr. Saksena had no disclosures.

[email protected]

SOURCE: Zile MR. Heart Rhythm 2019, Abstract, S-LBCT01-04.

SAN FRANCISCO – Baroreflex activation therapy met all four of its primary endpoints in its U.S. pivotal trial of 264 patients with advanced heart failure with reduced ejection fraction who were ineligible for cardiac resynchronization therapy.

Mitchel L. Zoler/MDedge News

The results showed that ongoing baroreflex activation therapy (BAT) via a single, stimulating electrode surgically placed on a patient’s carotid artery led to statistically significant and clinically meaningful improvements in quality of life and functional capacity while also reducing the level of a biomarker of heart failure severity in patients already on guideline-directed medical therapy, Michael R. Zile, MD, said at the annual scientific sessions of the Heart Rhythm Society. He estimated that the device is appropriate for perhaps a third or more of patients with heart failure with reduced ejection fraction (HFrEF), specifically patients with New York Heart Association functional class III disease who are not candidates for treatment with cardiac resynchronization therapy (CRT) and with a blood level of N-terminal pro–brain natriuretic peptide (NT-proBNP) of less than 1,600 pg/mL, a cutoff that excludes patients with very severe class III HFrEF and focuses on those who benefited in the study.

“To our knowledge, this is the first successful pivotal trial of device-based neuromodulation therapy in HFrEF patients,” said Dr. Zile, professor of medicine at the Medical University of South Carolina in Charleston. “We think that BAT fills an unmet need” in a large number of HFrEF patients. He stressed that the placement of the single, 2-mm, unilateral electrode on the baroreceptor-containing carotid sinus is an “extremely safe and simple” surgery. The electrode attaches to a small, subcutaneously placed generator.

Dr. Zile attributed the treatment’s success, in contrast to a prior, failed attempt to treat HFrEF by vagus nerve stimulation (J Am Coll Cardiol. 2016 Jul 12;68[2]:147-56) to BAT’s action via the patient’s brain, which processes the afferent signal it receives from stimulation to in turn inhibit sympathetic activation and upregulate parasympathetic innervation, with both actions benefiting HFrEF patients. “The integrated autonomic balance is the real difference with this device,” he said. Other helpful effects from BAT are reduced heart rate, reduced cardiac remodeling, increased vasodilation, a decrease in elevated blood pressure, increased diuresis, and a drop in renin secretion. The pivotal trial built on findings from a phase 2 study (JACC Heart Fail. 2015 Jun;3[6]:487-96).

Mitchel L. Zoler/MDedge News

These results “reconfirm the safety of BAT,” but are limited by a relatively short follow-up of 6 months, no data on survival benefit, and by not having echocardiographic data on possible cardiac remodeling, commented Sanjeev Saksena, MD, medical director of the Electrophysiology Research Foundation in Warren, N.J.

BeAT-HF was sponsored by CVRx, the company developing the baroreflex activation device. Dr. Zile has been a consultant to CVRx and to Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, and Novartis. Dr. Saksena had no disclosures.

[email protected]

SOURCE: Zile MR. Heart Rhythm 2019, Abstract, S-LBCT01-04.

SAN FRANCISCO – Baroreflex activation therapy met all four of its primary endpoints in its U.S. pivotal trial of 264 patients with advanced heart failure with reduced ejection fraction who were ineligible for cardiac resynchronization therapy.

Mitchel L. Zoler/MDedge News

The results showed that ongoing baroreflex activation therapy (BAT) via a single, stimulating electrode surgically placed on a patient’s carotid artery led to statistically significant and clinically meaningful improvements in quality of life and functional capacity while also reducing the level of a biomarker of heart failure severity in patients already on guideline-directed medical therapy, Michael R. Zile, MD, said at the annual scientific sessions of the Heart Rhythm Society. He estimated that the device is appropriate for perhaps a third or more of patients with heart failure with reduced ejection fraction (HFrEF), specifically patients with New York Heart Association functional class III disease who are not candidates for treatment with cardiac resynchronization therapy (CRT) and with a blood level of N-terminal pro–brain natriuretic peptide (NT-proBNP) of less than 1,600 pg/mL, a cutoff that excludes patients with very severe class III HFrEF and focuses on those who benefited in the study.

“To our knowledge, this is the first successful pivotal trial of device-based neuromodulation therapy in HFrEF patients,” said Dr. Zile, professor of medicine at the Medical University of South Carolina in Charleston. “We think that BAT fills an unmet need” in a large number of HFrEF patients. He stressed that the placement of the single, 2-mm, unilateral electrode on the baroreceptor-containing carotid sinus is an “extremely safe and simple” surgery. The electrode attaches to a small, subcutaneously placed generator.

Dr. Zile attributed the treatment’s success, in contrast to a prior, failed attempt to treat HFrEF by vagus nerve stimulation (J Am Coll Cardiol. 2016 Jul 12;68[2]:147-56) to BAT’s action via the patient’s brain, which processes the afferent signal it receives from stimulation to in turn inhibit sympathetic activation and upregulate parasympathetic innervation, with both actions benefiting HFrEF patients. “The integrated autonomic balance is the real difference with this device,” he said. Other helpful effects from BAT are reduced heart rate, reduced cardiac remodeling, increased vasodilation, a decrease in elevated blood pressure, increased diuresis, and a drop in renin secretion. The pivotal trial built on findings from a phase 2 study (JACC Heart Fail. 2015 Jun;3[6]:487-96).

Mitchel L. Zoler/MDedge News

These results “reconfirm the safety of BAT,” but are limited by a relatively short follow-up of 6 months, no data on survival benefit, and by not having echocardiographic data on possible cardiac remodeling, commented Sanjeev Saksena, MD, medical director of the Electrophysiology Research Foundation in Warren, N.J.

BeAT-HF was sponsored by CVRx, the company developing the baroreflex activation device. Dr. Zile has been a consultant to CVRx and to Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, Merck, and Novartis. Dr. Saksena had no disclosures.

[email protected]

SOURCE: Zile MR. Heart Rhythm 2019, Abstract, S-LBCT01-04.

SAN FRANCISCO – The more extensive a lupus patient’s smoking history, the greater the risk of chronic cutaneous manifestations of systemic lupus erythematosus (SLE) and irreversible skin damage, Nnenna Ezeh reported at an international congress on systemic lupus erythematosus.

Bruce Jancin/MDedge News

“We saw in our study a suggestion of a dose-response relationship. If we tell patients, ‘The more you smoke, the more likely you are to have chronic skin disease or skin damage that’s permanent,’ it could be a way to trigger more smoking cessation strategies in their mind,” said Ms. Ezeh, of the University of Wisconsin, Madison. “We know that skin manifestations of lupus have a major negative impact on a patient’s quality of life, so this could be a way to decrease smoking by saying, ‘Not only does smoking impact your heart and put you at risk for cardiovascular disease, it also affects your skin.’ It’s a way to bridge the priorities that physicians have with the priorities that patients have.”

She presented a retrospective study of the medical records of 632 consecutive SLE patients seen at the university medical center’s ambulatory rheumatology clinic. Slightly more than 60% of them were never smokers; 8.7% had a history of low smoking exposure, defined as less than 5 pack-years; 5.8% had a medium-smoking history of 5-10 pack-years; 15% had a high-smoking history, with more than 10 pack-years; and the smoking history of 10% of the patients was unrecorded.

In a multivariate analysis adjusted for age, sex, and race, the low-smoking group was ninefold more likely than never smokers to develop any mucocutaneous manifestations of SLE, including a malar or discoid rash, mucosal ulcers, photosensitivity, alopecia, or scarring. They were also 3.7 times more likely to meet any Systemic Lupus International Collaborating Clinics (SLICC) cutaneous criteria and twofold more likely than never smokers to meet any of the American College of Rheumatology cutaneous criteria. Patients with an intermediate smoking exposure history of 5-10 pack-years were 2.3-fold more likely to meet any SLICC cutaneous criteria.


The risks of meeting SLICC chronic cutaneous criteria and SLICC Damage Index skin damage criteria rose in a linear fashion with the number of pack-years of smoking. Those SLE patients with more than a 10 pack-year smoking history were 4.2-fold more likely than never smokers to fulfill any SLICC Damage Index skin damage criteria, which consist of scarring alopecia, extensive scarring, or skin ulcers. The heaviest smokers were also at 2.1-fold increased risk of discoid lupus and 2.2-fold more likely to meet SLICC chronic cutaneous criteria, according to Ms. Ezeh.

Patients of color, who comprised 18% of the study population, were significantly more likely to smoke than white patients. Independent of their smoking history, however, they had significantly increased risks of chronic cutaneous manifestations of lupus and of irreversible skin damage.

Ms. Ezeh reported having no financial conflicts regarding her study, supported by a grant from the Rheumatology Research Foundation.

[email protected]

SAN FRANCISCO – The more extensive a lupus patient’s smoking history, the greater the risk of chronic cutaneous manifestations of systemic lupus erythematosus (SLE) and irreversible skin damage, Nnenna Ezeh reported at an international congress on systemic lupus erythematosus.

Bruce Jancin/MDedge News

“We saw in our study a suggestion of a dose-response relationship. If we tell patients, ‘The more you smoke, the more likely you are to have chronic skin disease or skin damage that’s permanent,’ it could be a way to trigger more smoking cessation strategies in their mind,” said Ms. Ezeh, of the University of Wisconsin, Madison. “We know that skin manifestations of lupus have a major negative impact on a patient’s quality of life, so this could be a way to decrease smoking by saying, ‘Not only does smoking impact your heart and put you at risk for cardiovascular disease, it also affects your skin.’ It’s a way to bridge the priorities that physicians have with the priorities that patients have.”

She presented a retrospective study of the medical records of 632 consecutive SLE patients seen at the university medical center’s ambulatory rheumatology clinic. Slightly more than 60% of them were never smokers; 8.7% had a history of low smoking exposure, defined as less than 5 pack-years; 5.8% had a medium-smoking history of 5-10 pack-years; 15% had a high-smoking history, with more than 10 pack-years; and the smoking history of 10% of the patients was unrecorded.

In a multivariate analysis adjusted for age, sex, and race, the low-smoking group was ninefold more likely than never smokers to develop any mucocutaneous manifestations of SLE, including a malar or discoid rash, mucosal ulcers, photosensitivity, alopecia, or scarring. They were also 3.7 times more likely to meet any Systemic Lupus International Collaborating Clinics (SLICC) cutaneous criteria and twofold more likely than never smokers to meet any of the American College of Rheumatology cutaneous criteria. Patients with an intermediate smoking exposure history of 5-10 pack-years were 2.3-fold more likely to meet any SLICC cutaneous criteria.


The risks of meeting SLICC chronic cutaneous criteria and SLICC Damage Index skin damage criteria rose in a linear fashion with the number of pack-years of smoking. Those SLE patients with more than a 10 pack-year smoking history were 4.2-fold more likely than never smokers to fulfill any SLICC Damage Index skin damage criteria, which consist of scarring alopecia, extensive scarring, or skin ulcers. The heaviest smokers were also at 2.1-fold increased risk of discoid lupus and 2.2-fold more likely to meet SLICC chronic cutaneous criteria, according to Ms. Ezeh.

Patients of color, who comprised 18% of the study population, were significantly more likely to smoke than white patients. Independent of their smoking history, however, they had significantly increased risks of chronic cutaneous manifestations of lupus and of irreversible skin damage.

Ms. Ezeh reported having no financial conflicts regarding her study, supported by a grant from the Rheumatology Research Foundation.

[email protected]

SAN FRANCISCO – The more extensive a lupus patient’s smoking history, the greater the risk of chronic cutaneous manifestations of systemic lupus erythematosus (SLE) and irreversible skin damage, Nnenna Ezeh reported at an international congress on systemic lupus erythematosus.

Bruce Jancin/MDedge News

“We saw in our study a suggestion of a dose-response relationship. If we tell patients, ‘The more you smoke, the more likely you are to have chronic skin disease or skin damage that’s permanent,’ it could be a way to trigger more smoking cessation strategies in their mind,” said Ms. Ezeh, of the University of Wisconsin, Madison. “We know that skin manifestations of lupus have a major negative impact on a patient’s quality of life, so this could be a way to decrease smoking by saying, ‘Not only does smoking impact your heart and put you at risk for cardiovascular disease, it also affects your skin.’ It’s a way to bridge the priorities that physicians have with the priorities that patients have.”

She presented a retrospective study of the medical records of 632 consecutive SLE patients seen at the university medical center’s ambulatory rheumatology clinic. Slightly more than 60% of them were never smokers; 8.7% had a history of low smoking exposure, defined as less than 5 pack-years; 5.8% had a medium-smoking history of 5-10 pack-years; 15% had a high-smoking history, with more than 10 pack-years; and the smoking history of 10% of the patients was unrecorded.

In a multivariate analysis adjusted for age, sex, and race, the low-smoking group was ninefold more likely than never smokers to develop any mucocutaneous manifestations of SLE, including a malar or discoid rash, mucosal ulcers, photosensitivity, alopecia, or scarring. They were also 3.7 times more likely to meet any Systemic Lupus International Collaborating Clinics (SLICC) cutaneous criteria and twofold more likely than never smokers to meet any of the American College of Rheumatology cutaneous criteria. Patients with an intermediate smoking exposure history of 5-10 pack-years were 2.3-fold more likely to meet any SLICC cutaneous criteria.


The risks of meeting SLICC chronic cutaneous criteria and SLICC Damage Index skin damage criteria rose in a linear fashion with the number of pack-years of smoking. Those SLE patients with more than a 10 pack-year smoking history were 4.2-fold more likely than never smokers to fulfill any SLICC Damage Index skin damage criteria, which consist of scarring alopecia, extensive scarring, or skin ulcers. The heaviest smokers were also at 2.1-fold increased risk of discoid lupus and 2.2-fold more likely to meet SLICC chronic cutaneous criteria, according to Ms. Ezeh.

Patients of color, who comprised 18% of the study population, were significantly more likely to smoke than white patients. Independent of their smoking history, however, they had significantly increased risks of chronic cutaneous manifestations of lupus and of irreversible skin damage.

Ms. Ezeh reported having no financial conflicts regarding her study, supported by a grant from the Rheumatology Research Foundation.

[email protected]

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).

FDA approval was based on results of the randomized, multicenter, three-arm, open‑label, active‑controlled KEYNOTE-048 trial. The 882 patients in the trial had metastatic HNSCC, and they received either single-agent pembrolizumab; pembrolizumab, carboplatin or cisplatin, and platinum and fluorouracil; or cetuximab, carboplatin or cisplatin, and platinum and fluorouracil.

Patients who received pembrolizumab plus chemotherapy had a mean overall survival of 13.0 months, compared with 10.7 months in the cetuximab plus chemotherapy group (hazard ratio, 0.77; 95% CI, 0.63-0.93; P = .0067).

In the patient subgroups that received single-agent pembrolizumab, overall survival was 12.3 months in patients with a Combined Positive Score of at least 1, compared with 10.3 months for the cetuximab plus chemotherapy group (HR, 0.78; 95% CI, 0.64-0.96; P = .0171). In patients with a Combined Positive Score of at least 20, overall survival was 14.9 months in the pembrolizumab-only group and 10.7 months in the cetuximab plus chemotherapy group (HR, 0.61; 95% CI, 0.45-0.83; P = .0015).

The most common adverse events in patients who received single-agent pembrolizumab were fatigue, constipation, and rash. In patients who received pembrolizumab plus chemotherapy, the most common adverse events were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.

Pembrolizumab is approved for use in combination with platinum and fluorouracil for all patients and as a single agent for patients whose tumors express programmed death–ligand 1, the FDA said.

The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with HNSCC for treatment with pembrolizumab as a single agent.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).

FDA approval was based on results of the randomized, multicenter, three-arm, open‑label, active‑controlled KEYNOTE-048 trial. The 882 patients in the trial had metastatic HNSCC, and they received either single-agent pembrolizumab; pembrolizumab, carboplatin or cisplatin, and platinum and fluorouracil; or cetuximab, carboplatin or cisplatin, and platinum and fluorouracil.

Patients who received pembrolizumab plus chemotherapy had a mean overall survival of 13.0 months, compared with 10.7 months in the cetuximab plus chemotherapy group (hazard ratio, 0.77; 95% CI, 0.63-0.93; P = .0067).

In the patient subgroups that received single-agent pembrolizumab, overall survival was 12.3 months in patients with a Combined Positive Score of at least 1, compared with 10.3 months for the cetuximab plus chemotherapy group (HR, 0.78; 95% CI, 0.64-0.96; P = .0171). In patients with a Combined Positive Score of at least 20, overall survival was 14.9 months in the pembrolizumab-only group and 10.7 months in the cetuximab plus chemotherapy group (HR, 0.61; 95% CI, 0.45-0.83; P = .0015).

The most common adverse events in patients who received single-agent pembrolizumab were fatigue, constipation, and rash. In patients who received pembrolizumab plus chemotherapy, the most common adverse events were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.

Pembrolizumab is approved for use in combination with platinum and fluorouracil for all patients and as a single agent for patients whose tumors express programmed death–ligand 1, the FDA said.

The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with HNSCC for treatment with pembrolizumab as a single agent.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).

FDA approval was based on results of the randomized, multicenter, three-arm, open‑label, active‑controlled KEYNOTE-048 trial. The 882 patients in the trial had metastatic HNSCC, and they received either single-agent pembrolizumab; pembrolizumab, carboplatin or cisplatin, and platinum and fluorouracil; or cetuximab, carboplatin or cisplatin, and platinum and fluorouracil.

Patients who received pembrolizumab plus chemotherapy had a mean overall survival of 13.0 months, compared with 10.7 months in the cetuximab plus chemotherapy group (hazard ratio, 0.77; 95% CI, 0.63-0.93; P = .0067).

In the patient subgroups that received single-agent pembrolizumab, overall survival was 12.3 months in patients with a Combined Positive Score of at least 1, compared with 10.3 months for the cetuximab plus chemotherapy group (HR, 0.78; 95% CI, 0.64-0.96; P = .0171). In patients with a Combined Positive Score of at least 20, overall survival was 14.9 months in the pembrolizumab-only group and 10.7 months in the cetuximab plus chemotherapy group (HR, 0.61; 95% CI, 0.45-0.83; P = .0015).

The most common adverse events in patients who received single-agent pembrolizumab were fatigue, constipation, and rash. In patients who received pembrolizumab plus chemotherapy, the most common adverse events were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.

Pembrolizumab is approved for use in combination with platinum and fluorouracil for all patients and as a single agent for patients whose tumors express programmed death–ligand 1, the FDA said.

The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with HNSCC for treatment with pembrolizumab as a single agent.

Find the full press release on the FDA website.

[email protected]

CHICAGO – The phosphoinositide 3-kinase–delta inhibitor ME-401, given with or without rituximab, produced an overall response rate of 80% in a phase 1b trial of patients with relapsed or refractory follicular lymphoma.

Jennifer Smith/ MDedge News

Response rates were similar between patients who received ME-401 alone and those who received it in combination with rituximab.

Response rates were also similar between patients on an intermittent dosing schedule and those on a continuous dosing schedule. However, intermittent dosing decreased the rate of delayed grade 3 adverse events (AEs).

“The idea that continuous inhibition of target is absolutely essential for activity of this class of drugs has not been proven,” said Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

“The promising results of this somewhat novel intermittent schedule that we used with ME-401 suggests to me that we can maintain efficacy and reduce toxicity.”

Dr. Zelenetz and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

Patients and dosing

Data were presented for 54 patients with relapsed/refractory follicular lymphoma enrolled on this study. The patients had a median age of 63.5 years, and 80% were male. They had received a median of 2 prior therapies (range, 1-10).

Initially, patients received ME-401 at 60 mg, 120 mg, or 180 mg once daily continuously on a 28-day cycle. However, the dose-escalation portion of the study was closed because response rates were comparable among the three doses, the safety profile was similar, and there were no dose-limiting toxicities.

Two additional groups of patients received ME-401 at 60 mg daily for two cycles, followed by an intermittent schedule (IS) of 60 mg on days 1-7, repeated every 28 days.

The researchers had observed delayed grade 3 AEs on the continuous schedule (CS), and they hypothesized that the IS might prevent these events. Patients could revert to the CS if they had stable disease or progressed on the IS.

“One of the advantages of this particular agent is the very long half-life,” Dr. Zelenetz said. “So, essentially, we have 2 weeks on drug and 2 weeks off [with the IS]. It takes about a week to clear the drug because it has about a 30-hour half-life.”

In all, 40 patients received ME-401 monotherapy, and 14 received ME-401 plus rituximab at 375 mg/m² weekly for 4 weeks and then on day 1 of cycles 3-6. There were 31 patients who received ME-401 on the CS and 23 who received ME-401 on the IS.

Results

A total of 50 patients were evaluable for efficacy. The overall response rate in these patients was 80% (40/50), and 20% (10/50) achieved a complete response.

The overall response rate was 79% (30/38) in patients who received ME-401 alone, 83% (10/12) in those who received ME-401 plus rituximab, 83% (25/30) in patients on the CS, and 75% (15/20) in those on the IS.

The median duration of response and median progression-free survival have not been reached. The median follow-up for response duration is 8.8 months in the IS group and 8.3 months in the CS group. The median follow-up for progression-free survival is 5.5 months and 6.5 months, respectively.

A total of 18 patients on the IS (78%) were still on therapy at the data cutoff, as were 14 patients (45%) on the CS.

Seven patients (23%) on the CS and two patients (9%) on the IS discontinued treatment due to progression. Four patients in the IS group and two in the CS group who were switched to IS dosing reverted to CS dosing after experiencing progression.

Four CS patients (13%) discontinued treatment because of AEs, but none of the IS patients did.

AEs occurring in at least 15% of patients were diarrhea/colitis (40.7%), fatigue (35.2%), cough (33.3%), rash (24.1%), ALT increase (24.1%), nausea (24.1%), AST increase (22.2%), and decreased appetite (16.7%).

There were no grade 4-5 AEs. Grade 3 drug-related AEs of special interest (in the CS and IS groups, respectively) were diarrhea/colitis (16.1% and 8.7%), rash (12.9% and 0%), ALT increase (6.5% and 4.3%), AST increase (6.5% and 0%), pneumonia (6.5% and 0%), and mucositis (1.9% and 0%).

“[W]hile the grade 3 immune-related events seem to be very consistent in terms of class effects, they did seem to improve with transition to intermittent schedule,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.

“And I think that this novel design helps to create an opportunity to limit treatment and mitigate toxicity without necessarily compromising efficacy.”

The phase 1b trial is sponsored by MEI Pharma. Dr. Zelenetz reported relationships with MEI Pharma and several other companies. Dr. Casulo reported relationships with Gilead Sciences, Celgene, and Roche.

[email protected]

SOURCE: Zelenetz A et al. ASCO 2019, Abstract 7512.

CHICAGO – The phosphoinositide 3-kinase–delta inhibitor ME-401, given with or without rituximab, produced an overall response rate of 80% in a phase 1b trial of patients with relapsed or refractory follicular lymphoma.

Jennifer Smith/ MDedge News

Response rates were similar between patients who received ME-401 alone and those who received it in combination with rituximab.

Response rates were also similar between patients on an intermittent dosing schedule and those on a continuous dosing schedule. However, intermittent dosing decreased the rate of delayed grade 3 adverse events (AEs).

“The idea that continuous inhibition of target is absolutely essential for activity of this class of drugs has not been proven,” said Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

“The promising results of this somewhat novel intermittent schedule that we used with ME-401 suggests to me that we can maintain efficacy and reduce toxicity.”

Dr. Zelenetz and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

Patients and dosing

Data were presented for 54 patients with relapsed/refractory follicular lymphoma enrolled on this study. The patients had a median age of 63.5 years, and 80% were male. They had received a median of 2 prior therapies (range, 1-10).

Initially, patients received ME-401 at 60 mg, 120 mg, or 180 mg once daily continuously on a 28-day cycle. However, the dose-escalation portion of the study was closed because response rates were comparable among the three doses, the safety profile was similar, and there were no dose-limiting toxicities.

Two additional groups of patients received ME-401 at 60 mg daily for two cycles, followed by an intermittent schedule (IS) of 60 mg on days 1-7, repeated every 28 days.

The researchers had observed delayed grade 3 AEs on the continuous schedule (CS), and they hypothesized that the IS might prevent these events. Patients could revert to the CS if they had stable disease or progressed on the IS.

“One of the advantages of this particular agent is the very long half-life,” Dr. Zelenetz said. “So, essentially, we have 2 weeks on drug and 2 weeks off [with the IS]. It takes about a week to clear the drug because it has about a 30-hour half-life.”

In all, 40 patients received ME-401 monotherapy, and 14 received ME-401 plus rituximab at 375 mg/m² weekly for 4 weeks and then on day 1 of cycles 3-6. There were 31 patients who received ME-401 on the CS and 23 who received ME-401 on the IS.

Results

A total of 50 patients were evaluable for efficacy. The overall response rate in these patients was 80% (40/50), and 20% (10/50) achieved a complete response.

The overall response rate was 79% (30/38) in patients who received ME-401 alone, 83% (10/12) in those who received ME-401 plus rituximab, 83% (25/30) in patients on the CS, and 75% (15/20) in those on the IS.

The median duration of response and median progression-free survival have not been reached. The median follow-up for response duration is 8.8 months in the IS group and 8.3 months in the CS group. The median follow-up for progression-free survival is 5.5 months and 6.5 months, respectively.

A total of 18 patients on the IS (78%) were still on therapy at the data cutoff, as were 14 patients (45%) on the CS.

Seven patients (23%) on the CS and two patients (9%) on the IS discontinued treatment due to progression. Four patients in the IS group and two in the CS group who were switched to IS dosing reverted to CS dosing after experiencing progression.

Four CS patients (13%) discontinued treatment because of AEs, but none of the IS patients did.

AEs occurring in at least 15% of patients were diarrhea/colitis (40.7%), fatigue (35.2%), cough (33.3%), rash (24.1%), ALT increase (24.1%), nausea (24.1%), AST increase (22.2%), and decreased appetite (16.7%).

There were no grade 4-5 AEs. Grade 3 drug-related AEs of special interest (in the CS and IS groups, respectively) were diarrhea/colitis (16.1% and 8.7%), rash (12.9% and 0%), ALT increase (6.5% and 4.3%), AST increase (6.5% and 0%), pneumonia (6.5% and 0%), and mucositis (1.9% and 0%).

“[W]hile the grade 3 immune-related events seem to be very consistent in terms of class effects, they did seem to improve with transition to intermittent schedule,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.

“And I think that this novel design helps to create an opportunity to limit treatment and mitigate toxicity without necessarily compromising efficacy.”

The phase 1b trial is sponsored by MEI Pharma. Dr. Zelenetz reported relationships with MEI Pharma and several other companies. Dr. Casulo reported relationships with Gilead Sciences, Celgene, and Roche.

[email protected]

SOURCE: Zelenetz A et al. ASCO 2019, Abstract 7512.

CHICAGO – The phosphoinositide 3-kinase–delta inhibitor ME-401, given with or without rituximab, produced an overall response rate of 80% in a phase 1b trial of patients with relapsed or refractory follicular lymphoma.

Jennifer Smith/ MDedge News

Response rates were similar between patients who received ME-401 alone and those who received it in combination with rituximab.

Response rates were also similar between patients on an intermittent dosing schedule and those on a continuous dosing schedule. However, intermittent dosing decreased the rate of delayed grade 3 adverse events (AEs).

“The idea that continuous inhibition of target is absolutely essential for activity of this class of drugs has not been proven,” said Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

“The promising results of this somewhat novel intermittent schedule that we used with ME-401 suggests to me that we can maintain efficacy and reduce toxicity.”

Dr. Zelenetz and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

Patients and dosing

Data were presented for 54 patients with relapsed/refractory follicular lymphoma enrolled on this study. The patients had a median age of 63.5 years, and 80% were male. They had received a median of 2 prior therapies (range, 1-10).

Initially, patients received ME-401 at 60 mg, 120 mg, or 180 mg once daily continuously on a 28-day cycle. However, the dose-escalation portion of the study was closed because response rates were comparable among the three doses, the safety profile was similar, and there were no dose-limiting toxicities.

Two additional groups of patients received ME-401 at 60 mg daily for two cycles, followed by an intermittent schedule (IS) of 60 mg on days 1-7, repeated every 28 days.

The researchers had observed delayed grade 3 AEs on the continuous schedule (CS), and they hypothesized that the IS might prevent these events. Patients could revert to the CS if they had stable disease or progressed on the IS.

“One of the advantages of this particular agent is the very long half-life,” Dr. Zelenetz said. “So, essentially, we have 2 weeks on drug and 2 weeks off [with the IS]. It takes about a week to clear the drug because it has about a 30-hour half-life.”

In all, 40 patients received ME-401 monotherapy, and 14 received ME-401 plus rituximab at 375 mg/m² weekly for 4 weeks and then on day 1 of cycles 3-6. There were 31 patients who received ME-401 on the CS and 23 who received ME-401 on the IS.

Results

A total of 50 patients were evaluable for efficacy. The overall response rate in these patients was 80% (40/50), and 20% (10/50) achieved a complete response.

The overall response rate was 79% (30/38) in patients who received ME-401 alone, 83% (10/12) in those who received ME-401 plus rituximab, 83% (25/30) in patients on the CS, and 75% (15/20) in those on the IS.

The median duration of response and median progression-free survival have not been reached. The median follow-up for response duration is 8.8 months in the IS group and 8.3 months in the CS group. The median follow-up for progression-free survival is 5.5 months and 6.5 months, respectively.

A total of 18 patients on the IS (78%) were still on therapy at the data cutoff, as were 14 patients (45%) on the CS.

Seven patients (23%) on the CS and two patients (9%) on the IS discontinued treatment due to progression. Four patients in the IS group and two in the CS group who were switched to IS dosing reverted to CS dosing after experiencing progression.

Four CS patients (13%) discontinued treatment because of AEs, but none of the IS patients did.

AEs occurring in at least 15% of patients were diarrhea/colitis (40.7%), fatigue (35.2%), cough (33.3%), rash (24.1%), ALT increase (24.1%), nausea (24.1%), AST increase (22.2%), and decreased appetite (16.7%).

There were no grade 4-5 AEs. Grade 3 drug-related AEs of special interest (in the CS and IS groups, respectively) were diarrhea/colitis (16.1% and 8.7%), rash (12.9% and 0%), ALT increase (6.5% and 4.3%), AST increase (6.5% and 0%), pneumonia (6.5% and 0%), and mucositis (1.9% and 0%).

“[W]hile the grade 3 immune-related events seem to be very consistent in terms of class effects, they did seem to improve with transition to intermittent schedule,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.

“And I think that this novel design helps to create an opportunity to limit treatment and mitigate toxicity without necessarily compromising efficacy.”

The phase 1b trial is sponsored by MEI Pharma. Dr. Zelenetz reported relationships with MEI Pharma and several other companies. Dr. Casulo reported relationships with Gilead Sciences, Celgene, and Roche.

[email protected]

SOURCE: Zelenetz A et al. ASCO 2019, Abstract 7512.

SAN ANTONIO – Compared with their cisgender counterparts, transgender college students are nearly three times more likely to be diagnosed with and treated for insomnia symptoms, results from a large national population-based survey showed.

Doug Brunk/MDedge News

“That was a stronger association than we expected,” one of the study’s researchers, Lisa B. Matlen, MD, said during an interview at the annual meeting of the Associated Professional Sleep Societies.

According to Dr. Matlen, a fellow in the division of sleep medicine at the University of Michigan, Ann Arbor, the transgender population is “extremely understudied” when it comes to research on sleep disturbances. In an effort to examine the prevalence of sleep disturbances and the association between transgender identity and sleep disturbances among transgender college students in the United States, she and her colleagues drew from the 2016 and 2017 American College Health Association National College Health Assessment II, a confidential, voluntary, electronically administered survey of college and university students. In all, 224,233 students were polled, and the researchers analyzed their responses to questions about gender identity, sleep symptoms, and diagnoses.

The mean age of the respondents was 23 years, and most (82%) were undergraduate students. Of the 224,233 students, 3,471 (1.6%) self-identified as transgender. More than half of the transgender population (61.9%) was white, 10.6% were Hispanic/Latino, 10.5% were Asian or Pacific Islander, 6.3% were biracial or multiracial, 4.6% were black, and the rest were from other ethnicities. Compared with cisgender students, transgender students had increased odds of sleep disturbances (odds ratio, 1.6), not feeling well rested on 4 or more days per week (OR, 1.8), going to bed early on 3 or more days per week due to sleepiness (OR, 1.3), and having insomnia 3 or more days per week (OR, 1.7). In addition, transgender students were nearly three times more likely to have an insomnia diagnosis and treatment, compared with their cisgender counterparts (OR, 2.9).

Dr. Matlen acknowledged certain limitations of the study, including the fact that it drew from a population-based sample and that the survey was based on self-reported information. The study’s first author was Ronald R. Gavidia Romero, MD. The researchers reported having no financial disclosures.

[email protected]

SAN ANTONIO – Compared with their cisgender counterparts, transgender college students are nearly three times more likely to be diagnosed with and treated for insomnia symptoms, results from a large national population-based survey showed.

Doug Brunk/MDedge News

“That was a stronger association than we expected,” one of the study’s researchers, Lisa B. Matlen, MD, said during an interview at the annual meeting of the Associated Professional Sleep Societies.

According to Dr. Matlen, a fellow in the division of sleep medicine at the University of Michigan, Ann Arbor, the transgender population is “extremely understudied” when it comes to research on sleep disturbances. In an effort to examine the prevalence of sleep disturbances and the association between transgender identity and sleep disturbances among transgender college students in the United States, she and her colleagues drew from the 2016 and 2017 American College Health Association National College Health Assessment II, a confidential, voluntary, electronically administered survey of college and university students. In all, 224,233 students were polled, and the researchers analyzed their responses to questions about gender identity, sleep symptoms, and diagnoses.

The mean age of the respondents was 23 years, and most (82%) were undergraduate students. Of the 224,233 students, 3,471 (1.6%) self-identified as transgender. More than half of the transgender population (61.9%) was white, 10.6% were Hispanic/Latino, 10.5% were Asian or Pacific Islander, 6.3% were biracial or multiracial, 4.6% were black, and the rest were from other ethnicities. Compared with cisgender students, transgender students had increased odds of sleep disturbances (odds ratio, 1.6), not feeling well rested on 4 or more days per week (OR, 1.8), going to bed early on 3 or more days per week due to sleepiness (OR, 1.3), and having insomnia 3 or more days per week (OR, 1.7). In addition, transgender students were nearly three times more likely to have an insomnia diagnosis and treatment, compared with their cisgender counterparts (OR, 2.9).

Dr. Matlen acknowledged certain limitations of the study, including the fact that it drew from a population-based sample and that the survey was based on self-reported information. The study’s first author was Ronald R. Gavidia Romero, MD. The researchers reported having no financial disclosures.

[email protected]

SAN ANTONIO – Compared with their cisgender counterparts, transgender college students are nearly three times more likely to be diagnosed with and treated for insomnia symptoms, results from a large national population-based survey showed.

Doug Brunk/MDedge News

“That was a stronger association than we expected,” one of the study’s researchers, Lisa B. Matlen, MD, said during an interview at the annual meeting of the Associated Professional Sleep Societies.

According to Dr. Matlen, a fellow in the division of sleep medicine at the University of Michigan, Ann Arbor, the transgender population is “extremely understudied” when it comes to research on sleep disturbances. In an effort to examine the prevalence of sleep disturbances and the association between transgender identity and sleep disturbances among transgender college students in the United States, she and her colleagues drew from the 2016 and 2017 American College Health Association National College Health Assessment II, a confidential, voluntary, electronically administered survey of college and university students. In all, 224,233 students were polled, and the researchers analyzed their responses to questions about gender identity, sleep symptoms, and diagnoses.

The mean age of the respondents was 23 years, and most (82%) were undergraduate students. Of the 224,233 students, 3,471 (1.6%) self-identified as transgender. More than half of the transgender population (61.9%) was white, 10.6% were Hispanic/Latino, 10.5% were Asian or Pacific Islander, 6.3% were biracial or multiracial, 4.6% were black, and the rest were from other ethnicities. Compared with cisgender students, transgender students had increased odds of sleep disturbances (odds ratio, 1.6), not feeling well rested on 4 or more days per week (OR, 1.8), going to bed early on 3 or more days per week due to sleepiness (OR, 1.3), and having insomnia 3 or more days per week (OR, 1.7). In addition, transgender students were nearly three times more likely to have an insomnia diagnosis and treatment, compared with their cisgender counterparts (OR, 2.9).

Dr. Matlen acknowledged certain limitations of the study, including the fact that it drew from a population-based sample and that the survey was based on self-reported information. The study’s first author was Ronald R. Gavidia Romero, MD. The researchers reported having no financial disclosures.

[email protected]

A large Kaiser Permanente study paints a nuanced picture of the acellular pertussis vaccine, with more cases occurring in fully vaccinated children, but the highest risk of disease occurring among the under- and unvaccinated.

Sean Locke/iStockphoto

Among nearly half a million children, the unvaccinated were 13 times more likely to develop pertussis than fully vaccinated children, Ousseny Zerbo, PhD, of Kaiser Permanente Northern California in Oakland and colleagues wrote in Pediatrics. But 82% of cases occurred in fully vaccinated children and just 5% in undervaccinated children – and rates increased in both groups the farther they were in time from the last vaccination.

“Within our study population, greater than 80% of pertussis cases occurred among age-appropriately vaccinated children,” the team wrote. “Children who were further away from their last DTaP dose were at increased risk of pertussis, even after controlling for undervaccination. Our results suggest that, in this population, possibly in conjunction with other factors not addressed in this study, suboptimal vaccine efficacy and waning [immunity] played a major role in recent pertussis epidemics.”

The results are consistent with several prior studies, including one finding that the odds of the disease increased by 33% for every additional year after the third or fifth DTaP dose (Pediatrics. 2015;135[2]:331-43).

The current study comprised 469,982 children aged between 3 months and 11 years, who were followed for a mean of 4.6 years. Over the entire study period, there were 738 lab-confirmed pertussis cases. Most of these (515; 70%) occurred in fully vaccinated children. Another 99 (13%) occurred in unvaccinated children, 36 (5%) in undervaccinated children, and 88 (12%) in fully vaccinated plus one dose.

In a multivariate analysis, the risk of pertussis was 13 times higher among the unvaccinated (adjusted hazard ratio, 13) and almost 2 times higher among the undervaccinated (aHR, 1.9), compared with fully vaccinated children. Those who had been fully vaccinated and received a booster had the lowest risk, about half that of fully vaccinated children (aHR, 0.48).

Risk varied according to age, but also was significantly higher among unvaccinated children at each time point. Risk ranged from 4 times higher among those aged 3-5 months to 23 times higher among those aged 19-84 months. Undervaccinated children aged 5-7 months and 19-84 months also were at significantly increased risk for pertussis, compared with fully vaccinated children. Children who were fully vaccinated plus one dose had a significantly reduced risk at 7-19 months and at 19-84 months, compared with the fully vaccinated reference group.

“Across all follow-up and all age groups, VE [vaccine effectiveness] was 86% ... for undervaccinated children, compared with unvaccinated children,” Dr. Zerbo and associates wrote. “VE was even higher for fully vaccinated children [93%] and for those who were fully vaccinated plus one dose [96%].”

But VE waned as time progressed farther from the last DTaP dose. The multivariate model found more than a 100% increased risk for those whose last DTaP was at least 3 years past, compared with less than 1 year past (aHR, 2.58).

The model also found time-bound risk increases among fully vaccinated children, with a more than 300% increased risk among those at least 6 years out from the last DTaP dose, compared with 3 years out (aHR, 4.66).

The results indicate that other factors besides adherence to the recommended vaccine schedule may be at work in recent pertussis outbreaks.

“Although waning immunity is clearly an important factor driving pertussis epidemics in recent years, other factors that we did not evaluate in this study might also contribute to pertussis epidemics individually or in synergy,” Dr. Zerbo and associates wrote. “Results from studies in baboons suggest that the acellular pertussis vaccines are unable to prevent colonization, carriage, and transmission. If this is also true for humans, this could contribute to pertussis epidemics. The causes of recent pertussis epidemics are complex, and we were only able to address some aspects in our study.”

The study was funded by Kaiser Permanente Northern California, the National Institutes of Health, and in part by a National Institute of Allergy and Infectious Diseases grant. One coauthor reported receiving research grant support from Sanofi Pasteur, Novartis, GlaxoSmithKline, Merck, MedImmune, Pfizer, and Dynavax for unrelated studies; the other authors reported no relevant financial disclosures.

[email protected]

SOURCE: Zerbo O et al. Pediatrics. 2019 Jun 10. doi: 10.1542/peds.2018-3466.

A large Kaiser Permanente study paints a nuanced picture of the acellular pertussis vaccine, with more cases occurring in fully vaccinated children, but the highest risk of disease occurring among the under- and unvaccinated.

Sean Locke/iStockphoto

Among nearly half a million children, the unvaccinated were 13 times more likely to develop pertussis than fully vaccinated children, Ousseny Zerbo, PhD, of Kaiser Permanente Northern California in Oakland and colleagues wrote in Pediatrics. But 82% of cases occurred in fully vaccinated children and just 5% in undervaccinated children – and rates increased in both groups the farther they were in time from the last vaccination.

“Within our study population, greater than 80% of pertussis cases occurred among age-appropriately vaccinated children,” the team wrote. “Children who were further away from their last DTaP dose were at increased risk of pertussis, even after controlling for undervaccination. Our results suggest that, in this population, possibly in conjunction with other factors not addressed in this study, suboptimal vaccine efficacy and waning [immunity] played a major role in recent pertussis epidemics.”

The results are consistent with several prior studies, including one finding that the odds of the disease increased by 33% for every additional year after the third or fifth DTaP dose (Pediatrics. 2015;135[2]:331-43).

The current study comprised 469,982 children aged between 3 months and 11 years, who were followed for a mean of 4.6 years. Over the entire study period, there were 738 lab-confirmed pertussis cases. Most of these (515; 70%) occurred in fully vaccinated children. Another 99 (13%) occurred in unvaccinated children, 36 (5%) in undervaccinated children, and 88 (12%) in fully vaccinated plus one dose.

In a multivariate analysis, the risk of pertussis was 13 times higher among the unvaccinated (adjusted hazard ratio, 13) and almost 2 times higher among the undervaccinated (aHR, 1.9), compared with fully vaccinated children. Those who had been fully vaccinated and received a booster had the lowest risk, about half that of fully vaccinated children (aHR, 0.48).

Risk varied according to age, but also was significantly higher among unvaccinated children at each time point. Risk ranged from 4 times higher among those aged 3-5 months to 23 times higher among those aged 19-84 months. Undervaccinated children aged 5-7 months and 19-84 months also were at significantly increased risk for pertussis, compared with fully vaccinated children. Children who were fully vaccinated plus one dose had a significantly reduced risk at 7-19 months and at 19-84 months, compared with the fully vaccinated reference group.

“Across all follow-up and all age groups, VE [vaccine effectiveness] was 86% ... for undervaccinated children, compared with unvaccinated children,” Dr. Zerbo and associates wrote. “VE was even higher for fully vaccinated children [93%] and for those who were fully vaccinated plus one dose [96%].”

But VE waned as time progressed farther from the last DTaP dose. The multivariate model found more than a 100% increased risk for those whose last DTaP was at least 3 years past, compared with less than 1 year past (aHR, 2.58).

The model also found time-bound risk increases among fully vaccinated children, with a more than 300% increased risk among those at least 6 years out from the last DTaP dose, compared with 3 years out (aHR, 4.66).

The results indicate that other factors besides adherence to the recommended vaccine schedule may be at work in recent pertussis outbreaks.

“Although waning immunity is clearly an important factor driving pertussis epidemics in recent years, other factors that we did not evaluate in this study might also contribute to pertussis epidemics individually or in synergy,” Dr. Zerbo and associates wrote. “Results from studies in baboons suggest that the acellular pertussis vaccines are unable to prevent colonization, carriage, and transmission. If this is also true for humans, this could contribute to pertussis epidemics. The causes of recent pertussis epidemics are complex, and we were only able to address some aspects in our study.”

The study was funded by Kaiser Permanente Northern California, the National Institutes of Health, and in part by a National Institute of Allergy and Infectious Diseases grant. One coauthor reported receiving research grant support from Sanofi Pasteur, Novartis, GlaxoSmithKline, Merck, MedImmune, Pfizer, and Dynavax for unrelated studies; the other authors reported no relevant financial disclosures.

[email protected]

SOURCE: Zerbo O et al. Pediatrics. 2019 Jun 10. doi: 10.1542/peds.2018-3466.

A large Kaiser Permanente study paints a nuanced picture of the acellular pertussis vaccine, with more cases occurring in fully vaccinated children, but the highest risk of disease occurring among the under- and unvaccinated.

Sean Locke/iStockphoto

Among nearly half a million children, the unvaccinated were 13 times more likely to develop pertussis than fully vaccinated children, Ousseny Zerbo, PhD, of Kaiser Permanente Northern California in Oakland and colleagues wrote in Pediatrics. But 82% of cases occurred in fully vaccinated children and just 5% in undervaccinated children – and rates increased in both groups the farther they were in time from the last vaccination.

“Within our study population, greater than 80% of pertussis cases occurred among age-appropriately vaccinated children,” the team wrote. “Children who were further away from their last DTaP dose were at increased risk of pertussis, even after controlling for undervaccination. Our results suggest that, in this population, possibly in conjunction with other factors not addressed in this study, suboptimal vaccine efficacy and waning [immunity] played a major role in recent pertussis epidemics.”

The results are consistent with several prior studies, including one finding that the odds of the disease increased by 33% for every additional year after the third or fifth DTaP dose (Pediatrics. 2015;135[2]:331-43).

The current study comprised 469,982 children aged between 3 months and 11 years, who were followed for a mean of 4.6 years. Over the entire study period, there were 738 lab-confirmed pertussis cases. Most of these (515; 70%) occurred in fully vaccinated children. Another 99 (13%) occurred in unvaccinated children, 36 (5%) in undervaccinated children, and 88 (12%) in fully vaccinated plus one dose.

In a multivariate analysis, the risk of pertussis was 13 times higher among the unvaccinated (adjusted hazard ratio, 13) and almost 2 times higher among the undervaccinated (aHR, 1.9), compared with fully vaccinated children. Those who had been fully vaccinated and received a booster had the lowest risk, about half that of fully vaccinated children (aHR, 0.48).

Risk varied according to age, but also was significantly higher among unvaccinated children at each time point. Risk ranged from 4 times higher among those aged 3-5 months to 23 times higher among those aged 19-84 months. Undervaccinated children aged 5-7 months and 19-84 months also were at significantly increased risk for pertussis, compared with fully vaccinated children. Children who were fully vaccinated plus one dose had a significantly reduced risk at 7-19 months and at 19-84 months, compared with the fully vaccinated reference group.

“Across all follow-up and all age groups, VE [vaccine effectiveness] was 86% ... for undervaccinated children, compared with unvaccinated children,” Dr. Zerbo and associates wrote. “VE was even higher for fully vaccinated children [93%] and for those who were fully vaccinated plus one dose [96%].”

But VE waned as time progressed farther from the last DTaP dose. The multivariate model found more than a 100% increased risk for those whose last DTaP was at least 3 years past, compared with less than 1 year past (aHR, 2.58).

The model also found time-bound risk increases among fully vaccinated children, with a more than 300% increased risk among those at least 6 years out from the last DTaP dose, compared with 3 years out (aHR, 4.66).

The results indicate that other factors besides adherence to the recommended vaccine schedule may be at work in recent pertussis outbreaks.

“Although waning immunity is clearly an important factor driving pertussis epidemics in recent years, other factors that we did not evaluate in this study might also contribute to pertussis epidemics individually or in synergy,” Dr. Zerbo and associates wrote. “Results from studies in baboons suggest that the acellular pertussis vaccines are unable to prevent colonization, carriage, and transmission. If this is also true for humans, this could contribute to pertussis epidemics. The causes of recent pertussis epidemics are complex, and we were only able to address some aspects in our study.”

The study was funded by Kaiser Permanente Northern California, the National Institutes of Health, and in part by a National Institute of Allergy and Infectious Diseases grant. One coauthor reported receiving research grant support from Sanofi Pasteur, Novartis, GlaxoSmithKline, Merck, MedImmune, Pfizer, and Dynavax for unrelated studies; the other authors reported no relevant financial disclosures.

[email protected]

SOURCE: Zerbo O et al. Pediatrics. 2019 Jun 10. doi: 10.1542/peds.2018-3466.